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DRUG:

S63845

i
Other names: S63845, NSC-798846, NSC798846, S-63845, NSC 798846, S 63845
Company:
HitGen, Novartis, Servier
Drug class:
MCL1 inhibitor
17d
Osteosarcoma cells depend on MCL-1 for survival, and osteosarcoma metastases respond to MCL-1 antagonism plus regorafenib in vivo. (PubMed, BMC Cancer)
Chemotherapy, consisting of doxorubicin, cisplatin and methotrexate (MAP) increased the 5-year osteosarcoma survival rate from 20% to approximately 60% by the 1980s...Patients whose disease fails to respond to MAP receive second-line treatments such as etoposide and, in more recent years, the kinase inhibitor regorafenib...Importantly, we found that inhibition of MCL-1 with the BH3-mimetic S63845 combined with regorafenib significantly prolonged the survival of mice bearing pulmonary osteosarcoma metastases. Together, our results highlight the importance of MCL-1 in osteosarcoma cell survival and present a potential therapeutic avenue that may improve metastatic osteosarcoma patient outcomes.
Preclinical • Journal
|
BCL2 (B-cell CLL/lymphoma 2) • MCL1 (Myeloid cell leukemia 1) • BCL2L1 (BCL2-like 1)
|
cisplatin • doxorubicin hydrochloride • Stivarga (regorafenib) • etoposide IV • methotrexate • S63845
23d
Characterizing and Targeting of BCL-2 Family Members in Nasopharyngeal Carcinoma. (PubMed, Head Neck)
Our study demonstrates the therapeutic potential of combining cisplatin and S63845, which warrants further investigation.
Journal • IO biomarker
|
BCL2 (B-cell CLL/lymphoma 2) • MCL1 (Myeloid cell leukemia 1) • BCL2L1 (BCL2-like 1)
|
BCL2 expression • MCL1 expression
|
Venclexta (venetoclax) • cisplatin • S63845 • ABT-737
1m
Comprehensive functional evaluation of head and neck squamous cell carcinoma with BH3-profiling demonstrates apoptotic competency and therapeutic efficacy of BH3-mimetics. (PubMed, Oral Oncol)
We assessed response to BH3 mimetics including ABT-263 (navitoclax), an inhibitor of Bcl-2/Bcl-xL/Bcl-w, and S63845, an inhibitor of Mcl-1, both as single agents and in combination. We found the combination to be highly synergistic in 2D culture and in 3D organoid models of HHNSCC. Given our findings that co-dependency on Bcl-xL and Mcl-1 is common, and co-inhibition of these molecules is synergistic for growth suppression in HNSCC cells, these results elucidate the therapeutic potential of BCL-xL and MCL-1 inhibition in HNSCC.
Journal
|
BCL2 (B-cell CLL/lymphoma 2) • BCL2L1 (BCL2-like 1) • BCL2L2 (BCL2 Like 2)
|
MCL1 expression
|
navitoclax (ABT 263) • S63845
6ms
Metformin as an Enhancer for the Treatment of Chemoresistant CD34+ Acute Myeloid Leukemia Cells. (PubMed, Genes (Basel))
Treatment with cytarabine, idarubicin, venetoclax, metformin, and S63845 upregulated some cell surface markers like HLA-DR expression, and metformin upregulated CD9, CD31, and CD105 cell surface marker expression. In conclusion, we believe that metformin has the potential to be used as an adjuvant in the treatment of resistant-to-first-line-chemotherapy AML cells. Also, we believe that the results of our study will stimulate further research and the potential use of changes in the expression of cell surface markers in the development of new therapeutic strategies.
Journal • IO biomarker
|
CD38 (CD38 Molecule) • CD34 (CD34 molecule) • CD14 (CD14 Molecule) • CD9 (CD9 Molecule) • ITGAM (Integrin, alpha M) • CD31 (Platelet and endothelial cell adhesion molecule 1) • ENG (Endoglin) • PECAM1 (Platelet And Endothelial Cell Adhesion Molecule 1)
|
Venclexta (venetoclax) • cytarabine • S63845 • idarubicin hydrochloride • metformin
7ms
FLT3 and IRAK4 Inhibitor Emavusertib in Combination with BH3-Mimetics in the Treatment of Acute Myeloid Leukemia. (PubMed, Curr Issues Mol Biol)
The FLT3 and IRAK4 inhibitor emavusertib (CA4948), the MCL1 inhibitor S63845, the BCL2 inhibitor venetoclax, and the HSP90 inhibitor PU-H71 were assessed as single agents and in combination for their ability to induce apoptosis and cell death in leukemic cells in vitro. The combination of CA4948 and BH3-mimetics may be effective in the treatment in FLT3-mutated AML with differential target specificity for MCL1 and BCL2 inhibitors. Moreover, the combination of CA4948 and PU-H71 may be a candidate combination treatment in FLT3-mutated AML.
Journal • Combination therapy • IO biomarker
|
FLT3 (Fms-related tyrosine kinase 3) • KIT (KIT proto-oncogene, receptor tyrosine kinase) • NPM1 (Nucleophosmin 1) • CD34 (CD34 molecule) • ITGAM (Integrin, alpha M) • IRAK4 (Interleukin 1 Receptor Associated Kinase 4)
|
FLT3-ITD mutation • FLT3 mutation • NPM1 mutation
|
Venclexta (venetoclax) • S63845 • emavusertib (CA-4948) • zelavespib intravenous (PU-H71 IV)
7ms
Co-operation of MCL-1 and BCL-XL anti-apoptotic proteins in stromal protection of MM cells from carfilzomib mediated cytotoxicity. (PubMed, Front Oncol)
Pro-survival proteins: MCL-1, BCL-2 and BCL-XL were inhibited using S63845, ABT-199 and A-1331852 respectively. Furthermore, MCL-1 inhibition led to enhanced binding between BCL-XL and BIM, while blocking BCL-XL increased MCL-1/BIM complex formation, indicating the cooperative role of these proteins. Stromal interactions alter the dependence on BCL-2 family members, providing a rationale for dual inhibition to abrogate the protective effect of stroma and restore sensitivity to CFZ.
Journal • IO biomarker • Stroma
|
BCL2 (B-cell CLL/lymphoma 2) • MCL1 (Myeloid cell leukemia 1) • BCL2L1 (BCL2-like 1)
|
BCL2 expression • MCL1 expression
|
Venclexta (venetoclax) • carfilzomib • S63845 • A-1331852
8ms
Effective Targeting of Melanoma Cells by Combination of Mcl-1 and Bcl-2/Bcl-xL/Bcl-w Inhibitors. (PubMed, Int J Mol Sci)
Thus, we investigated the effects of ABT-737 and ABT-263, which target Bcl-2, Bcl-xL and Bcl-w as well as the Bcl-2-selective ABT-199 and the Mcl-1-selective S63845, in a panel of four BRAF-mutated and BRAF-WT melanoma cell lines. These findings demonstrate that melanoma cells can be efficiently targeted by BH3 mimetics, but the right combinations have to be selected. The observed pronounced activation of apoptosis pathways demonstrates the decisive role of apoptosis in the loss of cell viability by BH3 mimetics.
Journal • IO biomarker
|
BRAF (B-raf proto-oncogene) • BCL2 (B-cell CLL/lymphoma 2) • MCL1 (Myeloid cell leukemia 1) • BCL2L1 (BCL2-like 1) • BCL2L2 (BCL2 Like 2) • XIAP (X-Linked Inhibitor Of Apoptosis)
|
BRAF mutation • BRAF wild-type
|
Venclexta (venetoclax) • navitoclax (ABT 263) • S63845 • ABT-737
8ms
AMPK inhibition sensitizes acute leukemia cells to BH3 mimetic-induced cell death. (PubMed, Cell Death Differ)
BH3 mimetics, including the BCL2/BCLXL/BCLw inhibitor navitoclax and MCL1 inhibitors S64315 and tapotoclax, have undergone clinical testing for a variety of neoplasms...Building on the observation that BH3 mimetic monotherapy induces AMP kinase (AMPK) activation in multiple acute leukemia cell lines, we report that the AMPK inhibitors (AMPKis) dorsomorphin and BAY-3827 sensitize these cells to navitoclax or MCL1 inhibitors...Conversely, dorsomorphin synergizes with navitoclax or the MCL1 inhibitor S63845 to induce cell death in primary acute leukemia samples ex vivo and increases the antitumor effects of navitoclax or S63845 in several xenograft models in vivo with little or no increase in toxicity in normal tissues. These results suggest that AMPK inhibition can sensitize acute leukemia to multiple BH3 mimetics, potentially allowing administration of lower doses while inducing similar antineoplastic effects.
Journal • IO biomarker
|
BCL2 (B-cell CLL/lymphoma 2) • BCL2L1 (BCL2-like 1) • BCL2L2 (BCL2 Like 2) • AMPK (Protein Kinase AMP-Activated Catalytic Subunit Alpha 1)
|
navitoclax (ABT 263) • S63845 • tapotoclax (AMG 176) • dorsomorphin (Compound C) • BAY-3827 • MIK665
11ms
A p53 score derived from TP53 CRISPR/Cas9 HMCLs predicts survival and reveals major role of BAX in BH3 mimetics response. (PubMed, Blood)
At the functional level, we showed that among the 13 genes, p53-regulated BAX expression correlated to, and directly impacted, the MCL1 BH3 mimetic S63845 sensitivity of myeloma cells by decreasing MCL1-BAX complexes...Nevertheless, scRNAseq analysis showed that myeloma cells surviving to the combination had lower p53 score, showing that myeloma cells with higher p53 score were more sensitive to BH3 mimetics. Taken together, we established a functional p53 score that identifies myeloma cells with biallelic TP53 invalidation, demonstrated that p53-regulated BAX is critical for optimal cell response to BH3 mimetics, and showed that MCL1 and BCL2 BH3 mimetics combination may be of interest for patients with biallelic TP53 invalidation, for whom there is still an unmet medical need.
Journal • IO biomarker
|
TP53 (Tumor protein P53) • BCL2 (B-cell CLL/lymphoma 2) • MCL1 (Myeloid cell leukemia 1) • BAX (BCL2-associated X protein)
|
Chr t(4;14) • MCL1 expression • TP53 expression • BAX expression
|
S63845
12ms
Drug Resistance Can be Overcome in Multiple Myeloma and Acute Myeloid Leukemia By Targeting Mcl-1 with the Small Chemical KS18 (ASH 2023)
5µM, KS18 demonstrated efficacy against bortezomib-resistant MM cells, outperforming other Mcl-1 inhibitors in clinical trials such as S63845, VU661013, and AZD5991. According to these results, KS18 may be able to overcome resistance by concentrating on Mcl-1. These encouraging findings have prompted the development of many models of drug-resistant MM and AML for in vivo evaluation of this potential chemical.
IO biomarker
|
BCL2 (B-cell CLL/lymphoma 2)
|
MCL1 overexpression
|
bortezomib • S63845 • AZD5991
12ms
Long-Acting E. coli-Derived Asparaginase Potentiates the Anti-Leukemic Effect of BCL2 Inhibition, but Not MCL1 Inhibition, in Preclinical Models of Acute Myeloid Leukemia (ASH 2023)
Our previous studies have shown that pegcrisantaspase (PegC), a long-acting pegylated crisantaspase, synergizes with the BCL2 inhibitor, Venetoclax (Ven), to kill several AML cell lines and patient-derived primary AML cells with complex karyotype in vitro and in vivo in a xenograft mouse model... Using a panel of 4 human AML cell lines (MOLM14, MV411, MonoMac6, HL60) as well as primary AML patient samples, weestablished the anti-leukemic activity of the BCL2 inhibitor S55746 and the MCL1 inhibitor S63845 alone and in combination with the long-acting E. coli asparaginase, calaspargase pegol-mknl (CalPegA)... We report that the E. coli asparaginase, CalPegA, enhances the anti-leukemic effect of the BCL2 inhibitor, S55746, but does not impact the activity of the MCL1 inhibitor, S63845, in AML cell lines, patient derived primary AML samples, and in an AML xenograft mouse model. Ongoing studies are further investigating the anti-leukemic mechanism of S55476/S63845 + CalPegA and examining the efficacy and pharmacodynamic/pharmacokinetic effects of these agents in a patient derived xenograft model of AML.
Preclinical
|
EIF4EBP1 (Eukaryotic translation initiation factor 4E binding protein 1)
|
Venclexta (venetoclax) • S63845 • Asparlas (calaspargase pegol-mknl) • S55746 • Asparec (PEGylated recombinant Erwinia chrysantemi-derived L-asparaginase)
12ms
Combining BCL-XL Inhibition with Brentuximab Vedotin to Overcome Chemoresistance in EBV-Related T/NK Lymphoma (ASH 2023)
MethodsA diverse panel of EBV+ T/NK lymphoma cell lines including SNK1, MECO4, SNK6, SNT8, SNK10, SNT15 and SNT16 were evaluated for sensitivity to MMAE alone and with specific BH3 family inhibitors including A1331852, inhibiting BCL-XL, venetoclax inhibiting and BCL-2 and the MCL-1 inhibitor S63845 (Generon). These data show the potential of BV with BCL-XL inhibition to be an effective and tolerable treatment for ENKTL. We are now planning a detailed preclinical study to better understand the efficacy and safety of this combination in vivo and progress towards a future clinical trial.
IO biomarker
|
BCL2 (B-cell CLL/lymphoma 2) • TNFRSF8 (TNF Receptor Superfamily Member 8) • BCL2L1 (BCL2-like 1)
|
TNFRSF8 positive • TNFRSF8 expression
|
Venclexta (venetoclax) • Adcetris (brentuximab vedotin) • S63845 • A-1331852
1year
Increased MCL1 dependency leads to new applications of BH3-mimetics in drug-resistant neuroblastoma. (PubMed, Br J Cancer)
These data highlight that the application of BH3-mimetics may differ between first line treatment and relapsed disease. Combination of NK cell-based immunotherapy with BH3-mimetics may further increase killing of chemoresistant neuroblastoma, outlining a new treatment strategy for relapsed neuroblastoma.
Journal • IO biomarker
|
BCL2 (B-cell CLL/lymphoma 2) • MCL1 (Myeloid cell leukemia 1) • BCL2L1 (BCL2-like 1)
|
MCL1 expression
|
cisplatin • navitoclax (ABT 263) • S63845
1year
Statin-induced mitochondrial priming sensitizes multiple myeloma cells to BCL2 and MCL1 inhibitors. (PubMed, Cancer Res Commun)
Additionally, statins sensitize to apoptosis induced by MCL1 inhibitor, S63845. Statins sensitize MM cells to venetoclax by upregulating two pro-apoptotic proteins: PUMA via a p53-independent mechanism, and NOXA via the integrated stress response. These findings provide rationale for prospective testing of statins with venetoclax regimens in MM.
Journal
|
BCL2 (B-cell CLL/lymphoma 2)
|
Venclexta (venetoclax) • S63845
1year
Targeting BCL-XL with a Novel VHL-Based BCL-XL Degrader DT-2216 in Pre-Clinical JAK2-Mutant AML Post-MPN Models (ASH 2023)
However, the clinical utility of navitoclax, a BCL-xL and BCL-2 dual inhibitor, as demonstrated in combination with JAK2 inhibitor ruxolitinib in patients with myelofibrosis (Harrison et al...In this study, we evaluated the pre-clinical efficacy of DT2216 in combination with ruxolitinib, 5-azacytidine (AZA), or MCL-1 inhibitor S63845 in JAK2-mut AML models...CONCLUSIONS These findings highlight the promising efficacy of DT2216 in JAK2-mut AML, as evidenced by reduced cell viability, on-target degradation of BCL-xL, and synergistic anti-leukemia effects when combined with AZA, ruxolitinib or MCL-1 inhibitor. These results provide valuable insights into future therapeutic strategies for the treatment of JAK2-mut AML, particularly in the context of post-MPN AML.
Preclinical • IO biomarker
|
JAK2 (Janus kinase 2) • BCL2L1 (BCL2-like 1)
|
BCL2 expression • MCL1 expression • JAK2 mutation
|
azacitidine • Jakafi (ruxolitinib) • navitoclax (ABT 263) • S63845 • DT2216
1year
Pre-Clinical Activity of Navitoclax in TCR-Driven and Non-ALCL Mature T-Cell Lymphomas (ASH 2023)
In an effort to further confirm these results, and examine the extent to which peptide-based BH3 profiling predicts sensitivity to selective BH3 mimetics in MTCL, cell lines were treated with venetoclax, A1155463 (a BCL-xL selective antagonist), navitoclax (a BCL-2/BCL-xL antagonist), or S63845 (MCL-1 antagonist), and cell viability determined. These findings suggest that BCL-xL is a therapeutic vulnerability for MTCL subsets, particularly non-ALCL subtypes that are TCR dependent, and provide a robust pre-clinical rationale for future studies investigating navitoclax in these lymphomas.
Preclinical • IO biomarker
|
BCL2 (B-cell CLL/lymphoma 2) • MCL1 (Myeloid cell leukemia 1) • BCL2L1 (BCL2-like 1) • CD28 (CD28 Molecule) • BCL2L2 (BCL2 Like 2)
|
BCL2 overexpression • BCL2 expression • BCL2 positive • MCL1 expression
|
Venclexta (venetoclax) • navitoclax (ABT 263) • S63845
1year
Venetoclax Resistance Results in Broad Resistance to Majority of Anti-MM Agents Due to the Suppression of Apoptosis but Can be Overcome By BCMA-Targeted Immunotherapy (ASH 2023)
We observed that venetoclax-resistant clones were resistant to most standard-of-care anti-MM agents including alkylating agents (Melphalan, cyclophosphamide, bendamustine), proteasome inhibitors (bortezomib and carfilzomib) or immunomodulatory drugs (lenalidomide and pomalidomide) than parental cells, suggesting a broad resistance to anti-cancer agents possibly due to reduced apoptotic signaling...Simultaneous inhibition of MCL1 (via S63845) or BCL-XL (via A155463) and BCL2 (via venetoclax) increased BIM release and enhanced cell death in the resistant clones compared to single agents, with combination index (CI) values < 0.3 in all doses tested...We observed that both antibody-dependent cellular cytotoxicity (ADCC) induced by Daratumumab and BCMA targeting CAR-T cells induced comparable cell death in venetoclax-resistant clones and parental cells. Moreover, myeloma cells from a patient with t(11; 14) MM progressing on venetoclax, showed significant cytotoxicity to anti-BCMA CAR T cells in vitro and achieved a deep response subsequently when treated with Cilta-cel. In conclusion, we report that resistance to venetoclax confers broad resistance to standard-of-care myeloma drugs and that immunotherapies, especially CAR-T cells and CD38 monoclonal antibody, may remain effective, thus conferring potential benefits in managing acquired resistance to venetoclax.
IO biomarker
|
BCL2 (B-cell CLL/lymphoma 2) • BCL2L1 (BCL2-like 1) • BCL2L2 (BCL2 Like 2)
|
BCL2 expression • MCL1 expression
|
Venclexta (venetoclax) • lenalidomide • bortezomib • cyclophosphamide • Darzalex (daratumumab) • carfilzomib • S63845 • pomalidomide • bendamustine • melphalan • Carvykti (ciltacabtagene autoleucel)
1year
Targeting ADSS2 Enhances BH3 Mimetics Treatment Induced Mitochondrial Apoptosis in AML Cells (ASH 2023)
Recently, the BH3 mimetic-Bcl2 inhibitor venetoclax (VEN), has been approved by FDA in 2018 for the treatment of patients with AML in combination with a hypomethylating agent (HMA) such as azacytidine (AZA)...ADSS2 KO also led to a noteworthy reduction in the IC50 values of both VEN and the Mcl1 inhibitor S63845 in these cell lines...Collectively, our observation revealed that targeting ADSS2 is critical for sensitizing AML cells to BH3 mimetics. We are now conducting preclinical assessments of ADSS2 inhibitors.
IO biomarker
|
PRKAA2 (Protein Kinase AMP-Activated Catalytic Subunit Alpha 2)
|
Venclexta (venetoclax) • azacitidine • S63845
1year
Acquired Venetoclax Resistance in an In Vivo Model of B-Cell Precursor Acute Lymphoblastic Leukemia Is Characterized By Altered Functions of Apoptosis Regulators (ASH 2023)
This shift was also reflected in an ex vivo drug treatment assay showing decreased sensitivity to the MCL-1 inhibitor S63845 and the BCL-XL inhibitor A-1331852 in ALL cells from VEN- treated mice compared to control- treated mice (S63845 EC50 1.5 vs. 2.2 µM, A-1331852 EC50 9.3 vs. 15.3 µM). Taken together, acquired VEN-resistance was recapitulated in a co-clinical trial model of BCP-ALL with repeated in vivo treatment cycles showing lower drug sensitivities along with increasingly reduced in vivo anti-ALL activity of VEN. Characterization of acquired VEN-resistance revealed decreased functional dependency on anti-apoptotic proteins and downregulation of pro-apoptotic BIM and BAX, thus pointing to an imbalance of pro- and anti-apoptotic molecules, which can be potentially targeted by directed compounds bypassing resistance to specific BCL-2 inhibition.
Preclinical • IO biomarker
|
KMT2A (Lysine Methyltransferase 2A) • BCL2L1 (BCL2-like 1)
|
BAX expression • MLL fusion
|
Venclexta (venetoclax) • S63845 • A-1331852
1year
Pro-Apoptotic Activity of MCL-1 Inhibitor in Trametinib-Resistant Melanoma Cells Depends on Their Phenotypes and Is Modulated by Reversible Alterations Induced by Trametinib Withdrawal. (PubMed, Cancers (Basel))
Our study supports the notion that the efficiency of an agent designed to target a single protein can largely depend on the phenotype of cancer cells. Thus, it is important to define appropriate phenotype determinants to stratify the patients for the novel therapy.
Journal
|
CASP3 (Caspase 3) • PMAIP1 (Phorbol-12-Myristate-13-Acetate-Induced Protein 1) • CASP7 (Caspase 7) • ANXA5 (Annexin A5)
|
Mekinist (trametinib) • S63845
1year
Myeloid Cell Leukemia 1 Small Molecule Inhibitor S63845 Synergizes with Cisplatin in Triple-Negative Breast Cancer. (PubMed, Cancers (Basel))
The use of combined MCL1 inhibitors with cisplatin in TNBC effectively initiates TAp73 anti-tumor effects on cell cycle arrest and apoptosis. This observation provides a molecular profile that can be exploited to identify sensitive TNBCs.
Journal
|
MCL1 (Myeloid cell leukemia 1) • TP73 (Tumor Protein P73)
|
MCL1 expression
|
cisplatin • S63845
1year
HSP90 Inhibitor PU-H71 in Combination with BH3-Mimetics in the Treatment of Acute Myeloid Leukemia. (PubMed, Curr Issues Mol Biol)
Elevated susceptibility to PU-H71 and venetoclax was associated with primary AML with CD117 > 80% and CD11b < 45%. The combination of HSP90 inhibitor PU-H71 and MCL1 inhibitor S63845 may be a candidate treatment for FLT3-mutated AML with moderate CD34 positivity while the combination of HSP90 inhibitor PU-H71 and BCL2 inhibitor venetoclax may be more effective in the treatment of primitive AML with high CD117 and low CD11b positivity.
Journal • Combination therapy • IO biomarker
|
TP53 (Tumor protein P53) • FLT3 (Fms-related tyrosine kinase 3) • KIT (KIT proto-oncogene, receptor tyrosine kinase) • CD34 (CD34 molecule) • ITGAM (Integrin, alpha M)
|
TP53 mutation • FLT3-ITD mutation • FLT3 mutation • CD34 positive
|
Venclexta (venetoclax) • S63845 • zelavespib intravenous (PU-H71 IV)
1year
Intracellular BAPTA directly inhibits PFKFB3, thereby impeding mTORC1-driven Mcl-1 translation and killing MCL-1-addicted cancer cells. (PubMed, Cell Death Dis)
Previously, we demonstrated that BAPTA enhanced apoptosis induced by venetoclax, a BCL-2 antagonist, in diffuse large B-cell lymphoma (DLBCL)...In this study, we discovered that BAPTA alone induced apoptosis in hematological cancer cell lines that were highly sensitive to S63845, an MCL-1 antagonist...Secondly, cellular effects caused by BAPTA are not necessarily related to Ca signaling. Our data support the need for a reassessment of the role of Ca in cellular processes when findings were based on the use of BAPTA.
Journal
|
BCL2 (B-cell CLL/lymphoma 2) • MCL1 (Myeloid cell leukemia 1) • PFKFB3 (6-Phosphofructo-2-Kinase/Fructose-2,6-Biphosphatase 3)
|
Venclexta (venetoclax) • S63845
1year
Acquisition of venetoclax resistance is characterized by higher expression of anti-apoptotic regulators, less mitochondrial priming, and broader resistance to anti-MM agents. (IMW 2023)
The Bellini study demonstrated that combination therapy of BH3-mimetic venetoclax with velcade improves progression-free survival (PFS) and response rates in this subgroup of MM patients...Simultaneous inhibition of MCL1 (via S63845) or BCL-XL (via A155463) and BCL2 (via venetoclax) increased BIM release and enhanced cell death in the resistant clones compared to single agents, with combination index (CI) values < 0.3 in all doses tested. In conclusion, we report that resistance to Venetoclax in in vitro models of MM evolves from the outgrowth of persister clones with a shift in mitochondrial dependency that confers broad resistance to all anti-tumor agents, including standard-of-care myeloma drugs.
IO biomarker
|
BCL2 (B-cell CLL/lymphoma 2) • BCL2L1 (BCL2-like 1) • BCL2L2 (BCL2 Like 2)
|
BCL2 expression • BCL2 mutation • MCL1 expression
|
Venclexta (venetoclax) • bortezomib • S63845
1year
FUS-ERG induces late-onset azacitidine resistance in acute myeloid leukaemia cells. (PubMed, Sci Rep)
We tested the efficacy of BH3 mimetics, including venetoclax and S63845, in primary Aza-resistant AML cells treated with FUS-ERG. The disturbance of chromatin organisation might induce this by co-repressors, including BCOR, NCOR2, and RCOR1. MCL1 inhibition could partially overcome Aza resistance in FUS-ERG-harbouring AML cells.
Journal • IO biomarker
|
BCL2 (B-cell CLL/lymphoma 2) • BCOR (BCL6 Corepressor) • NCOR2 (Nuclear Receptor Corepressor 2) • FUS (FUS RNA Binding Protein) • TRA (T Cell Receptor Alpha Locus)
|
Venclexta (venetoclax) • azacitidine • S63845
over1year
Characterizing Specificities of Chronic Lymphoid Leukemia Harboring a BCL2 Rearrangement, an update from the FILO group (IWCLL 2023)
Ex vivo drug treatments included: BCL2i (inhibitor): venetoclax; MCL-1i: AZD5991, S63845 and BCLXLi: A133. The genomic landscape of BCL2-R CLL is characterized by a high frequency of trisomy 12, subclonal NOTCH and RAS pathway mutations, as well as BCL2 and MLL2 mutations. Protein expression, BH3 profiling and viability assays data are consistent with nearly exclusive dependence on Bcl-2.
IO biomarker
|
KRAS (KRAS proto-oncogene GTPase) • BRAF (B-raf proto-oncogene) • TP53 (Tumor protein P53) • NRAS (Neuroblastoma RAS viral oncogene homolog) • BCL2 (B-cell CLL/lymphoma 2) • NOTCH1 (Notch 1) • MYD88 (MYD88 Innate Immune Signal Transduction Adaptor) • EZH2 (Enhancer of zeste 2 polycomb repressive complex 2 subunit) • SF3B1 (Splicing Factor 3b Subunit 1) • KMT2D (Lysine Methyltransferase 2D) • BCL2L1 (BCL2-like 1) • FBXW7 (F-Box And WD Repeat Domain Containing 7) • CREBBP (CREB binding protein) • BIRC3 (Baculoviral IAP repeat containing 3) • BCL2L11 (BCL2 Like 11) • EP300 (E1A binding protein p300) • MLL2 (Myeloid/lymphoid or mixed-lineage leukemia 2) • ANXA5 (Annexin A5)
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TP53 mutation • BRAF mutation • NOTCH1 mutation • RAS mutation • KMT2D mutation • EZH2 mutation • MYD88 L265P • BCL2 expression • BCL2 mutation • MCL1 expression • BCL2 G101V • MLL2 mutation • BCL2 rearrangement • TS 12
|
Venclexta (venetoclax) • S63845 • AZD5991
over1year
AKT inhibition sensitizes acute leukemia cells to S63845-induced apoptosis. (PubMed, Hematology)
Here we describe that the AKT inhibitors MK-2206 and Gsk690693 sensitize multiple leukemia cells to the MCL1 inhibitor S63845. Knockdown of BAD significantly inhibits MK-2206-induced sensitization to S63845. Thus, our results suggest that MK-2206 sensitizes multiple leukemia cells to S63845-induced apoptosis, with the mechanisms involving BAD dephosphorylation and BCLX downregulation.
Journal
|
BCL2L1 (BCL2-like 1)
|
MK-2206 • S63845 • GSK690693
over1year
CLL Targets Beyond BTKi and Bcl2i (ICLLM 2023)
1, 2 Treatment of CLL cells with entospletinib, but not other BCR-signaling inhibitors, led to a disruption of BAFF-BCR cross-talk and downmodulation of MCL1 mRNA and protein, thus implicating SYK in transduction of multiple pro-survival signals emanating from the tumor microenvironment.1 Entospletinib has shown promising clinical activity in CLL, alone or in combination with obinutuzumab, including in patients with high-risk disease such as TP53 aberrant.3, 4 The drug is very well tolerated, however its development in CLL has been halted. Meanwhile, we have shown that luxeptinib, a dual SYK/BTK kinase inhibitor, has activity in BTK inhibitor-resistant lymphoid models in vitro.5 Luxeptinib is now being investigated in lcinical trials in hematologic malignancies...The early results of MS-553, a selective PKC-β inhibitor, indicates that this agent is tolerable and effective both as single agent and in combination with venetoclax.8 Proteolysis-targeting chimeras (PROTACs) are a new class of small molecules with two covalently-linked ligands recruiting target protein and E3 ubiquitin ligase together to trigger and enable proteasomal degradation of the target protein.9 “BTK degraders”, such as NRX- 2127 (Nurix Therapeutics) and BGB-16673 (Beigene), have entered clinical trials in patients with lymphoid malignancies...Additionally, NX-2127 has shown preclinical activity similar to immunomodulatory drugs (IMiDs) by catalyzing the ubiquitination of Ikaros (IKZF1) and Aiolos (IKZF3), resulting in increased T-cell activation.10 Early results of an ongoing clinical trial of NX-2127 demonstrate an ORR of 33% in heavily pre-treated patients with CLL, and overall good tolerability 11...The preclinical activity of AZD5991 has shown that selective targeting of MCL1 induced metabolic dysfunction and abrogated survival of diffuse large B cell lymphoma and ibrutinib-resistant mantle cell lymphoma cell lines in vivo and in vitro.13 Other BH3-mimetics targeting MCL1 include AMG176 and S63845.14-16 In an experimental design testing the effects of AMG-176 on CLL and normal hematopoietic cell death it was demonstrated that AMG-176 is an active agent in inducing CLL cell death while sparing normal blood cells...Anti-CD20 monoclonal antibodies – rituximab, obinutuzumab and ofatumumab – have significantly improved the survival outcomes. The B cell activating factor receptor (BAFF-R) is one of the main pro-survival receptors in B cells.18 In a preclinical study, ianalumab (VAY-736), a humanized defucosylated engineered antibody directed against BAFF-R, antagonized pro-survival effects of BAFF in CLL cells and showed promising activity both as a single agent and in combination with ibrutinib.19 A phase 1 study of dose escalation and dose expansion investigated the combination of ianalumab with ibrutinib in 32 patients with CLL with median one prior line of therapy (range, 0-4)...This study showed promising results not expected with ibrutinib alone.20 Tafasitamab – a Fc-enhanced, humanized, monoclonal antibody to CD19 – in combination with idelalisib or venetoclax in 24 patients has been associated with an ORR of 77% and 91%, respectively...In a phase 1 study involving 26 patients with R/R CLL, cirmtuzumab administered at four biweekly infusions was shown to have a long plasma half-life and did not have dose-limiting toxicity, potentially providing another treatment opportunity for patients with CLL.22 Immune Cell Enabling Therapies...A recent report of a phase 1/2 study of lisocabtagene maraleucel, an autologous CD19-directed CAR T-cell therapy (TRANSCEND CLL 004), confirmed efficacy in patients with R/R CLL.23 In this study, 23 patients with median 4 prior lines of therapy (range 2-11) were enrolled, 10 of whom were considered double exposed/refractory...In total, 65% of patients required administration of tocilizumab and/or corticosteroids.23 In addition to the ongoing phase 2 portion of this study, efforts now focus on innovative CAR T-cell designs as well as combination strategies...A phase 1b/2 ongoing trial is currently examining the safety and tolerability of the product in patients with R/R CLL. The early results suggest that epcoritamab administered subcutaneously is well tolerated in a heavily pretreated patient population with multiple high-risk features and shows clinical activity.25 Furthermore, an ongoing study is demonstrating preliminary efficacy of epcoritamab in patients with Richters transformation, a notoriously difficult-to-treat complication of CLL.26
IO biomarker
|
TP53 (Tumor protein P53) • CD19 (CD19 Molecule) • CD8 (cluster of differentiation 8) • IGH (Immunoglobulin Heavy Locus) • IKZF1 (IKAROS Family Zinc Finger 1) • ROR1 (Receptor Tyrosine Kinase Like Orphan Receptor 1) • CD4 (CD4 Molecule) • IKZF3 (IKAROS Family Zinc Finger 3) • SYK (Spleen tyrosine kinase) • PRKCB (Protein Kinase C Beta)
|
TP53 mutation • ROR1 expression • CD20 expression • CD19 expression • BTK C481 • BTK overexpression
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Venclexta (venetoclax) • Imbruvica (ibrutinib) • Rituxan (rituximab) • Gazyva (obinutuzumab) • Zydelig (idelalisib) • Breyanzi (lisocabtagene maraleucel) • entospletinib (GS-9973) • S63845 • Epkinly (epcoritamab-bysp) • luxeptinib (CG-806) • zilovertamab (UC-961) • AZD5991 • Actemra IV (tocilizumab) • Monjuvi (tafasitamab-cxix) • tapotoclax (AMG 176) • NX-2127 • BGB-16673 • MS-553 • ianalumab (VAY736)
over1year
MCL-1 INHIBITION AFFECTS LIPIDOME WHICH MAY BE LINKED TO TUMOR IMMUNITY AND CANCER-RELATED INFLAMMATION IN ACUTE MYELOID LEUKEMIA (EHA 2023)
The findings of this study suggest that S63845 may reduce cell proliferation by modulating the lipid compositions, especially, by increasing ceramide levels in AML cell lines. Additionally, the study highlights that S63845 has a distinct impact on the lipid profiles of different AML cell lines, indicating the potential of using lipidomic profiles asmarkers. Importantly, our study proposes that the increases in Cer levels in response to S63845 treatment may occur due to SM hydrolysis and may be linked to the anti-inflammatory effects of S63845 in AML cell lines, which deserve further investigation to fully understand the specific mechanisms.
IO biomarker
|
IL10 (Interleukin 10) • LAMP3 (Lysosomal Associated Membrane Protein 3) • CD53 (CD53 Molecule) • SPHK1 (Sphingosine Kinase 1)
|
MCL1 expression
|
S63845
over1year
DELE1 LOSS AND DYSFUNCTIONAL INTEGRATED STRESS SIGNALING IN TP53 MUTATED AML IS A NOVEL PATHWAY FOR VENETOCLAX RESISTANCE (EHA 2023)
Background: Venetoclax (ven) in combination with hypomethylating agents or low dose cytarabine leads to rapid and durable remission in patients (pts) with acute myeloid leukemia (AML) unfit for intensive chemotherapy (IC), however, pts with TP53 mutations ( TP53 mut ) exhibit adverse prognosis...Deletion of DELE1 or OMA1 in AML cell lines blocked eIF2α activation and induction of the transcription factor ATF4, a critical ISR effector, in response to the mitochondrial stressor FCCP, ven, and azacitidine, and resulted in ven resistance similar to that of TP53 deficient cells...Further screening of these cell lines for ven sensitizing activity revealed the BH3 mimetic S63845, which targets MCL1, as the top hit, suggesting that combined BH3 mimetics may overcome ven resistance during ISR pathway defects... These data suggest that defective ISR signaling may be a factor in TP53 mut AML treatment outcome and point to DELE1 dysregulation as a driver of ISR inactivation in pts with TP53 mut AML. The ISR induces the expression of NOXA, which displaces MCL1 from BIM and lowers the apoptotic threshold. Our data identify p53, DELE1, and OMA1 as regulators of NOXA expression post ven treatment and indicate that co-targeting MCL1 in pts with TP53 mut AML may be beneficial to overcome ven resistance.
IO biomarker
|
TP53 (Tumor protein P53) • BCL2 (B-cell CLL/lymphoma 2) • PMAIP1 (Phorbol-12-Myristate-13-Acetate-Induced Protein 1) • ATF4 (Activating Transcription Factor 4)
|
TP53 mutation • TP53 wild-type • MCL1 expression • TP53 expression
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Venclexta (venetoclax) • cytarabine • azacitidine • S63845
over1year
AN ORAL COMBINATION THERAPY OF OR-2100 AND VENETOCLAX IN ACUTE MYELOID LEUKEMIA (EHA 2023)
Although oral AZA, CC486, and Oral DAC, ASTX727, are currently available in some countries, OR21 has the advantage that it is a single compound and less myelosuppressive...We found that MCL-1 expression correlates inversely with sensitivity to OR21 plus Ven, but not to OR21 plus S63845, a selective MCL-1 inhibitor... Ven increased ROS with reduction of AMPK and suppression of autophagy. OR21 enhanced ROS accumulation with attenuated mitophagy response, leading to increased anti-leukemia effects. OR21 plus Ven is a promising oral combination therapy for AML.
Combination therapy • IO biomarker
|
BCL2 (B-cell CLL/lymphoma 2) • GLI2 (GLI Family Zinc Finger 2) • AMPK (Protein Kinase AMP-Activated Catalytic Subunit Alpha 1)
|
MCL1 expression
|
Venclexta (venetoclax) • S63845 • Inqovi (decitabine/cedazuridine) • Onureg (azacitidine oral)
over1year
BCL-2/BCL-XL INHIBITION INDUCES APOPTOSIS AND CIRCUMVENTS VENETOCLAX RESISTANCE IN TP53-MUTATED ACUTE MYELOID LEUKEMIA (EHA 2023)
109 AML samples' blast-specific ex vivo responses to venetoclax (BCL-2 inhibitor), navitoclax (BCL-2/BCL-XL inhibitor), A-1331852 (BCL-XL inhibitor) and S-63845 (MCL-1 inhibitor) were profiled by flow cytometry... In the computational comparison analysis of VenEx trial participants' genetic aberrations and BH3 mimetic ex vivo responses, TP53 mutation (p=0.005) and complex karyotype (p=0.003) were the strongest predictors of venetoclax resistance, while IDH2 (p=0.006) and SRSF2 (p=0.007) mutations predicted favorable responses (Figure A)... This study showed that AML patients harboring TP53 mutations have reduced ex vivo sensitivity to venetoclax, which might be associated with decreased BCL-2 protein expression. In contrast, our BH3 mimetic drug screening results demonstrated that the dual inhibition of BCL-2 and BCL-XL by navitoclax is capable of inducing apoptosis in myeloid blast cells regardless of TP53 mutation status. However, larger patient cohorts and more extensive functional analysis of the anti/pro-apoptotic dependencies in this patient group is warranted.
IO biomarker
|
TP53 (Tumor protein P53) • BCL2 (B-cell CLL/lymphoma 2) • IDH2 (Isocitrate Dehydrogenase (NADP(+)) 2) • BCL2L1 (BCL2-like 1) • SRSF2 (Serine and arginine rich splicing factor 2) • CD34 (CD34 molecule)
|
TP53 mutation • TP53 wild-type • BCL2 expression • SRSF2 mutation • TP53 expression
|
Venclexta (venetoclax) • navitoclax (ABT 263) • S63845 • A-1331852
over1year
Synergistic Action of MCL-1 Inhibitor with BCL-2/BCL-XL or MAPK Pathway Inhibitors Enhances Acute Myeloid Leukemia Cell Apoptosis and Differentiation. (PubMed, Int J Mol Sci)
Combined treatment with S63845 and ABT-737 or MAPK pathway inhibitor enhanced apoptosis but also induced differentiation of tested cells, as well as altering the expression of the MCL-1 protein. Taken together, our data provide the rationale for further studies regarding the use of MCL-1 inhibitor in combination with other pro-survival protein inhibitors.
Journal • IO biomarker
|
BCL2 (B-cell CLL/lymphoma 2) • BCL2L1 (BCL2-like 1)
|
MCL1 expression
|
S63845 • ABT-737
over1year
Dual targeting of BCL-2 and MCL-1 in the presence of BAX breaks venetoclax resistance in human small cell lung cancer. (PubMed, Br J Cancer)
The current study reveals the subtype specificity of BCL-2 expression and sheds light on the mechanism of venetoclax resistance in SCLC. Additionally, we provide preclinical evidence that combined BCL-2 and MCL-1 targeting is an effective approach to overcome venetoclax resistance in high BCL-2-expressing SCLCs with intact BAX.
Journal • IO biomarker
|
BCL2 (B-cell CLL/lymphoma 2) • BAX (BCL2-associated X protein) • POU2F3 (POU Class 2 Homeobox 3) • ASCL1 (Achaete-Scute Family BHLH Transcription Factor 1)
|
MCL1 overexpression • BCL2 expression • MCL1 expression • BAX expression • BAX overexpression
|
Venclexta (venetoclax) • S63845
over1year
MCL-1 Inhibitor S63845 Distinctively Affects Intramedullary and Extramedullary Hematopoiesis. (PubMed, Pharmaceutics)
The maturation of the erythroid lineage in the intramedullary and extramedullary segments was blocked to varying degrees, and both the intramedullary and extramedullary lymphoid lineages were inhibited. This study provides a complete description of the effects of MCL-1 inhibitor on the intramedullary and extramedullary hematopoietic lineages, which is important for the selection of combinations of antitumor drugs and the prevention of adverse hematopoiesis-related effects.
Journal
|
BCL2 (B-cell CLL/lymphoma 2)
|
S63845
over1year
The roles of protocadherin-7 in colorectal cancer cells on cell proliferation and its chemoresistance. (PubMed, Front Pharmacol)
Our data indicated that PCDH7 mediated the resistance of CRC cells to ABT-263 (a small-molecule Bcl-2 inhibitor that induces apoptosis) by inhibiting cell apoptosis, which was supported by the downregulation of caspase-3, caspase-9, and PARP cleavage. Taken together, although PCDH7 inhibited the migration and invasion of CRC cells, it could facilitate the development of drug resistance in colorectal cancer cells by positively modulating Mcl-1 expression. The application of the Mcl-1 inhibitor S63845 could be a potential strategy for CRC chemotherapy, especially in CRC with high levels of PCDH7.
Journal • PARP Biomarker • IO biomarker
|
KRAS (KRAS proto-oncogene GTPase) • BRAF (B-raf proto-oncogene) • NRAS (Neuroblastoma RAS viral oncogene homolog) • MYC (V-myc avian myelocytomatosis viral oncogene homolog) • CTNNB1 (Catenin (cadherin-associated protein), beta 1) • CASP3 (Caspase 3) • CASP9 (Caspase 9) • CDH23 (Cadherin Related 23) • PCDH7 (Protocadherin 7)
|
KRAS mutation • BRAF mutation • NRAS mutation • MYC expression • MCL1 expression
|
navitoclax (ABT 263) • S63845
over1year
The mtDNA-STING pathway plays an important role in both navitoclax- and S63845-induced autophagy and enhances cell death. (PubMed, Cell Biol Toxicol)
BH3 mimetics such as ABT-737 not only induce cell death, but also activate autophagy. Furthermore, STING KO diminishes navitoclax- or S63845-induced apoptosis, suggesting that STING activation enhances rather than inhibits apoptosis. Thus, our findings provide new insights into the regulations of navitoclax- or S63845-induced autophagy and cell death.
Journal
|
BCL2 (B-cell CLL/lymphoma 2) • BCL2L1 (BCL2-like 1) • STING (stimulator of interferon response cGAMP interactor 1) • BCL2L2 (BCL2 Like 2) • BECN1 (Beclin 1)
|
navitoclax (ABT 263) • S63845 • ABT-737
over1year
Synergistic combination therapy delivered via layer-by-layer nanoparticles induces solid tumor regression of ovarian cancer. (PubMed, Bioeng Transl Med)
Co-inhibition of BCL2 and BCL-XL (ABT-263) with inhibition of MCL1 (S63845) induces potent synergistic cytotoxicity in multiple HGSOC models. Thus, these results support the exploration of LbL NPs as a strategy to deliver potent drug combinations to recurrent HGSOC. While these findings are described for co-encapsulation of a BCL2/XL and a MCL1 inhibitor, the modular nature of LbL assembly provides flexibility in the range of therapies that can be incorporated, making LbL NPs an adaptable vehicle for delivery of additional combinations of pathway inhibitors and other oncology drugs.
Journal • Combination therapy
|
BCL2 (B-cell CLL/lymphoma 2) • BCL2L1 (BCL2-like 1)
|
BCL2 expression • MCL1 expression
|
navitoclax (ABT 263) • S63845
over1year
Enhanced Apoptosis and Loss of Cell Viability in Melanoma Cells by Combined Inhibition of ERK and Mcl-1 Is Related to Loss of Mitochondrial Membrane Potential, Caspase Activation and Upregulation of Proapoptotic Bcl-2 Proteins. (PubMed, Int J Mol Sci)
However, in combination with the Mcl-1 inhibitor S63845, the effects of vemurafenib were strongly enhanced in BRAF-mutated cell lines, and the effects of SCH772984 were enhanced in both BRAF-mutated and BRAF-WT cells. The combination finally resulted in downregulation of antiapoptotic Bcl-2 and enhanced expression of the proapoptotic Noxa. In conclusion, combined inhibition of ERK and Mcl-1 revealed an impressive efficacy both in BRAF-mutated and WT melanoma cells, and may thus represent a new strategy for overcoming drug resistance.
Journal • PARP Biomarker • IO biomarker
|
BCL2 (B-cell CLL/lymphoma 2)
|
BRAF mutation • BRAF wild-type
|
Zelboraf (vemurafenib) • S63845 • SCH772984
over1year
The Role of BCL-2 and PD-1/PD-L1 Pathway in Pathogenesis of Myelodysplastic Syndromes. (PubMed, Int J Mol Sci)
The challenge is the observed resistance to venetoclax, for which the MCL-1 protein may be largely responsible. Molecules with the potential to break the associated resistance include S63845, S64315, chidamide and arsenic trioxide (ATO)...Knockdown of the PD-L1 gene in preclinical studies was associated with increased levels of BCL-2 and MCL-1 in lymphocytes T, which could increase their survival and promote tumor apoptosis. A trial (NCT03969446) is currently underway to combine inhibitors from both groups.
Review • Journal
|
BCL2 (B-cell CLL/lymphoma 2) • MCL1 (Myeloid cell leukemia 1)
|
Venclexta (venetoclax) • Epidaza (chidamide) • S63845 • arsenic trioxide • MIK665