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DRUG:

A-1331852

i
Other names: A-1331852, A1331852
Company:
AbbVie
Drug class:
Bcl-xL inhibitor
6ms
Evaluation of BH3 mimetics as a combination therapy with irradiation in head and neck squamous cell carcinoma. (PubMed, Biomed Pharmacother)
Our findings encourage the further preclinical investigation of BH3 mimetics, particularly A-1331852, as a single agent or combined with irradiation as a treatment for HNSCC.
Journal • Combination therapy
|
BCL2 (B-cell CLL/lymphoma 2)
|
navitoclax (ABT 263) • A-1331852
6ms
Profiling of BCLxL Protein Complexes in Non-Small Cell Lung Cancer Cells via Multiplexed Single-Molecule Pull-Down and Co-Immunoprecipitation. (PubMed, Anal Chem)
Notably, the NSCLC cell line EBC-1 exhibited high BCLxL-BAX and BCLxL-BAK levels, which closely paralleled a strong response to the BCLxL inhibitor A-1331852. This streamlined method offers the potential for quantitative biomarkers derived from protein complex profiling, paving the way for their application in protein complex-targeted therapies.
Journal
|
BCL2L1 (BCL2-like 1)
|
A-1331852
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
10ms
Combination drug screen identifies synergistic drug interaction of BCL-XL and class I histone deacetylase inhibitors in MYC-amplified medulloblastoma cells. (PubMed, J Neurooncol)
Our study identifies the combination of class I HDACi and BCL-XL inhibitors as a potential new approach for the treatment of MYC-amplified MB cells. Graphical abstract created with BioRender.com, illustrating the workflow and summarizing main results.
Journal • Epigenetic controller
|
MYC (V-myc avian myelocytomatosis viral oncogene homolog) • BCL2L1 (BCL2-like 1) • CASP3 (Caspase 3)
|
navitoclax (ABT 263) • Jingzhuda (entinostat) • A-1331852
10ms
Bcl-xL targeting eliminates ageing tumor-promoting neutrophils and inhibits lung tumor growth. (PubMed, EMBO Mol Med)
Targeting Bcl-xL activity with a specific BH3 mimetic, A-1331852, blocked the induced neutrophil survival without impacting their normal lifespan...Finally, our human tumor data indicate the same role for Bcl-xL on pro-tumoral neutrophil survival. These results altogether provide preclinical evidence for safe neutrophil targeting based on their aberrant intra-tumor longevity.
Journal
|
BCL2L1 (BCL2-like 1) • CSF2 (Colony stimulating factor 2)
|
A-1331852
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
The drug efficacy testing in 3D cultures platform identifies effective drugs for ovarian cancer patients. (PubMed, NPJ Precis Oncol)
Notably, carboplatin and A-1331852 (Bcl-xL inhibitor) showed an additive effect in four of eight OC samples tested, while afatinib and A-1331852 led to synergy in five of seven OC models. In conclusion, our 3D DET3Ct platform can rapidly define potential, clinically relevant data on efficacy of existing drugs in OC for precision medicine purposes, as well as provide insights on emerging drugs and drug combinations that warrant testing in clinical trials.
Journal
|
BCL2L1 (BCL2-like 1)
|
Gilotrif (afatinib) • carboplatin • A-1331852
1year
BCL-Xl Represents a Novel Therapeutic Target in Type 2 Mutant Calr-Driven Myeloproliferative Neoplasms (ASH 2023)
In cells treated with JAK inhibitor ruxolitinib, we found that while BCL-xL expression levels decreased nearly 90% in ruxolitinib treated CALRdel52 cells, this decrease was much more modest in CALRins5 cells, suggesting JAK/STAT activation is only partially responsible for BCL-xL up-regulation in CALRins5 MPN cells. We observed that CALRins5 cells displayed decreased viability in response to A-1331852 alone and in combination treatments, suggesting an increased sensitivity to BCL-xL inhibition. In conclusion, we demonstrate that CALRins5-driven MPN cells display an enhanced sensitivity to BCL-xL inhibition, which may represent an effective therapeutic approach for CALRins5+ MPN patients.
IO biomarker
|
BCL2 (B-cell CLL/lymphoma 2) • BCL2L1 (BCL2-like 1) • CALR (Calreticulin) • ATF6 (Activating Transcription Factor 6) • HSP90AA1 (Heat Shock Protein 90 Alpha Family Class A Member 1Heat Shock Protein 90 Alpha Family Class A Member 1)
|
CALR mutation
|
Jakafi (ruxolitinib) • A-1331852
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
Identification of vulnerabilities for targeting BCL-2 family members in T-Cell Acute Lymphoblastic Leukemia (ASH 2023)
Venetoclax is a selective BCL-2 inhibitor and is successfully used in CLL and AML, but heterogeneous sensitivity to venetoclax has been described in ALL and inhibitors of other BCL-2 family members including BCL-XL-selective A-1331852 and MCL-1 selective AZD5991 have been developed. Moreover, a dual inhibitor of the anti-apoptotic BCL-2 family members BCL-2 and BCL-XL (AZD4320) with its dendrimer conjugate (AZD0466) has recently shown anti-tumor activity in hematologic cancer models with manageable toxicity...Taken together, we found vulnerabilities of T-ALL to BCL-2 family inhibition, particularly to dual BCL-2/BCL-XL inhibition by AZD4320, and we demonstrated on-target activities. Using BH3-profiling, we identified BAD-priming as a marker of response for AZD4320 and MCL-1 dependence as a resistance mechanism that can be targeted by combination treatment, suggesting further clinical evaluation.
IO biomarker
|
BCL2 (B-cell CLL/lymphoma 2) • BCL2L1 (BCL2-like 1)
|
Venclexta (venetoclax) • A-1331852 • AZD5991 • AZD0466 • AZD4320
1year
BCL2L1 inhibitor A-1331852 inhibits MCL1 transcription and triggers apoptosis in acute myeloid leukemia cells. (PubMed, Biochem Pharmacol)
Furthermore, A-1331852 acted synergistically with the BCL2 inhibitor ABT-199 to induce U937 and ABT-199-resistant U937 cell death by inhibiting MCL1 expression. A similar phenomenon caused A-1331852-induced MCL1 downregulation and cytotoxicity in AML HL-60 cells. Collectively, our data suggest that A-1331852 shows an off-target effect of inhibiting MCL1 transcription, ultimately leading to U937 and HL-60 cell death.
Journal • IO biomarker
|
BCL2L1 (BCL2-like 1) • PPP2CA (Protein Phosphatase 2 Catalytic Subunit Alpha 2)
|
MCL1 expression
|
Venclexta (venetoclax) • A-1331852
over1year
Transcriptome sequencing and single-cell sequencing analysis identify GARS1 as a potential prognostic and immunotherapeutic biomarker for multiple cancers, including bladder cancer. (PubMed, Front Immunol)
Notably, Ifosfamide, auranofin, DMAPT, and A-1331852 emerged as potential therapeutic agents for GARS1-upregulated tumors. Our experimental findings strongly suggest that GARS1 promotes the proliferation and migration of bladder cancer cells. GARS1 holds promise as a potential prognostic marker and therapeutic target for pan-cancer immunotherapy, offering valuable insights for the development of more precise and personalized approaches to tumor treatment in the future.
Journal • PD(L)-1 Biomarker • IO biomarker
|
CD276 (CD276 Molecule)
|
ifosfamide • A-1331852
over1year
Anti-apoptotic protein BCL-XL as a therapeutic vulnerability in gastric cancer. (PubMed, Animal Model Exp Med)
We identified BCL-XL as a promising therapeutic target in a subset of GC cases with high levels of BCL-XL protein expression. Functionally, we demonstrated that both selective BCL-XL inhibitors and VHL-based PROTAC BCL-XL can potently kill GC cells that are reliant on BCL-XL for survival. However, we found that BCL2L1 copy number variations (CNVs) cannot reliably predict BCL-XL expression, but the BCL-XL protein level serves as a useful biomarker for predicting the sensitivity of GC cells to BCL-XL-targeting compounds. Taken together, our study pinpointed BCL-XL as potential druggable target for specific subsets of GC.
Journal • IO biomarker
|
BCL2L1 (BCL2-like 1)
|
BCL2 expression
|
navitoclax (ABT 263) • A-1331852 • DT2216
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
B-cell lymphoma extra-large (Bcl-xL) is a promising drug target in Merkel cell carcinoma. (PubMed, Br J Dermatol)
Bcl-xL, which is highly expressed in MCC, appears to be an attractive therapeutic target for the treatment of this tumor; especially since the effect of specific Bcl-xL inhibitors is synergistically enhanced by simultaneous PARP inhibition.
Journal • PARP Biomarker • IO biomarker
|
BCL2L1 (BCL2-like 1)
|
Lynparza (olaparib) • A-1331852
over1year
Targeting endogenous and therapy-induced dependence on BCL-XL in high grade serous ovarian carcinoma (AACR 2023)
We used well-established HGSOC cell lines and human primary tumors to measure sensitivity to inhibitors of pro-survival BCL-2 family proteins as single agents and in combination with the front-line ovarian cancer chemotherapy drugs carboplatin and paclitaxel. Based on BH3 profiling, flow cytometry-based cell death analysis and colony formation assays, we found that HGSOC cells are particularly sensitive to BCL-XL inhibitors including the first-generation BH3 mimetics ABT-263 and A1331852 as well as novel proteolysis-targeting chimeras (PROTACs) that degrade BCL-XL...We also detected BCL-XL dependence in ovarian cancer tumorigenesis models utilizing human fallopian tube secretory epithelial cells, the putative cell of origin for HGSOC. Overall, we find that BCL-XL inhibitors, especially PROTACs, can safely enhance the chemosensitivity of HGSOC cells in vitro and in vivo and may therefore prevent tumor recurrence in women diagnosed with this disease.
IO biomarker
|
BCL2 (B-cell CLL/lymphoma 2) • BCL2L1 (BCL2-like 1)
|
BCL2 expression • BAX expression
|
carboplatin • paclitaxel • navitoclax (ABT 263) • A-1331852
over1year
Lurbinectedin exhibits combinatorial activity with BCL2/BCL2L1 inhibitors in vitro and in vivo by modulation of MCL1 expression (AACR 2023)
In solid tumor lines other than SCLC, the combination of lurbinectedin with a specific BCL2L1 inhibitor (A-1331852) was also synergistic. Correspondingly in vivo, enhancement in the efficacy of lurbinectedin was observed in combination with venetoclax in SCLC models, while in solid tumor models other than SCLC the combination with a specific BCL2L1 inhibitor enhanced efficacy. Collectively, these data identify MCL1 as a specific lurbinectedin target and suggest that combinations that target other pro-survival proteins may represent a viable strategy to enhance the anti-tumor activity of lurbinectedin.
Preclinical • IO biomarker
|
BCL2 (B-cell CLL/lymphoma 2) • MCL1 (Myeloid cell leukemia 1) • BCL2L1 (BCL2-like 1)
|
BCL2 expression • MCL1 expression
|
Venclexta (venetoclax) • Zepzelca (lurbinectedin) • A-1331852
over1year
Combined treatment with the epigenetic drug CM272 and an anti-BCL-XL proapoptotic drug sensitizes solid tumors to immune checkpoint blockade (AACR 2023)
In vivo, the triple combination CM272, A1331852 (BCL-XL inhibitor) and an anti-PD-1 moAb significantly reduced tumor growth and increased overall survival in three subcutaneous lung cancer models (LLC, 393P, Lacun-3) in comparison to double treatments...The mechanisms underneath the antitumor responses include the modulation of the energy metabolism in tumor cells, leading to cell death boosted by an anti-BCL-XL pro-apoptotic drug, along with fostering the immune system to generate an efficient anti-tumor response assisted by ICB. This study reveals the potential of epigenetic therapeutics to treat and cure patients with solid tumors.
Checkpoint inhibition • PD(L)-1 Biomarker • IO biomarker • Checkpoint block
|
BCL2 (B-cell CLL/lymphoma 2) • CD8 (cluster of differentiation 8) • BCL2L1 (BCL2-like 1) • IFIH1 (Interferon Induced With Helicase C Domain 1)
|
A-1331852
almost2years
Bcl-xL prevents the arginine starvation induced by PEGylated arginine deiminase (ADI-PEG20) from inducing apoptosis (ESMO-TAT 2023)
Methods Cell lines were treated with ADI-PEG20 and A-1331852 (Bcl-xL inhibitor) and monitored for cell death using the Incucyte. Bcl-xL inhibition synergies with ADI-PEG20 to induce apoptosis. This study provides the preclinical rationale for combining ADI-PEG20 with next generation Bcl-xL inhibitors such as the Bcl-xL PROTAC in a phase I clinical trial.
PARP Biomarker • IO biomarker
|
BCL2 (B-cell CLL/lymphoma 2) • BCL2L1 (BCL2-like 1) • ASS1 (Argininosuccinate synthase 1) • CASP3 (Caspase 3)
|
BCL2 expression • MCL1 expression
|
A-1331852 • Hepacid (pegargiminase)
almost2years
Erythroid/megakaryocytic differentiation confers BCL-XL dependency and venetoclax resistance in acute myeloid leukemia. (PubMed, Blood)
High-throughput screening of > 500 compounds identified the BCL-XL-selective inhibitor A-1331852 and navitoclax as highly effective against erythroid/megakaryoblastic leukemia cell lines. Combining BCL-XL inhibitor with the JAK inhibitor ruxolitinib showed synergistic and durable responses in cell lines. Our results suggest targeting BCL-XL as a potential therapy option in erythroid/megakaryoblastic leukemias and highlight an AML subgroup with potentially reduced sensitivity to venetoclax-based treatments.
Journal • IO biomarker
|
MCL1 (Myeloid cell leukemia 1) • BCL2L1 (BCL2-like 1)
|
Venclexta (venetoclax) • Jakafi (ruxolitinib) • navitoclax (ABT 263) • A-1331852
almost2years
Bcl-xL inhibition radiosensitizes PIK3CA/PTEN wild-type triple negative breast cancers with low Mcl-1 expression. (PubMed, Cancer Res Commun)
We demonstrate that pan Bcl-2 family inhibition (ABT-263, rER: 1.52-1.56) or Bcl-xL specific inhibition (WEHI-539, A-1331852; rER: 1.31-2.00) radiosensitized wild-type PIK3CA/PTEN TNBC (MDA-MB-231, CAL-120) but failed to radiosensitize mutant PIK3CA/PTEN TNBC (rER: 0.90 - 1.07; MDA-MB-468, CAL-51, SUM-159). In vivo, ABT-263 or A-1331852 in combination with RT decreased tumor growth and increased tumor tripling time (p < 0.0001) in PIK3CA/PTEN wild-type TNBC cell line and patient-derived xenografts. Collectively, this study provides the preclinical rationale for early phase clinical trials testing the safety, tolerability, and efficacy of Bcl-xL inhibition and RT in women with wild-type PIK3CA/PTEN wild-type TNBC at high risk for recurrence.
Journal • PARP Biomarker • IO biomarker
|
PIK3CA (Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha) • PTEN (Phosphatase and tensin homolog) • BCL2 (B-cell CLL/lymphoma 2) • AKT1 (V-akt murine thymoma viral oncogene homolog 1) • MCL1 (Myeloid cell leukemia 1) • BCL2L1 (BCL2-like 1) • CASP3 (Caspase 3)
|
PIK3CA mutation • MCL1 overexpression • MCL1 expression • PIK3CA wild-type
|
navitoclax (ABT 263) • A-1331852 • acalisib (GS-9820)
almost2years
BH3 mimetics in combination with nilotinib or ponatinib represent a promising therapeutic strategy in blast phase chronic myeloid leukemia. (PubMed, Cell Death Discov)
Co-treatment of four BP-CML cell lines with the TKIs nilotinib or ponatinib and either BCL-2 (venetoclax), MCL-1 (S63845) or BCL-xL (A-1331852) inhibitors resulted in a synergistic reduction in cell viability and increase in phosphatidylserine (PS) presentation. Gene expression and protein level analysis suggests a protective upregulation of alternative BCL-2 prosurvival proteins in response to BH3 mimetic single-treatment in BP-CML. Our results suggest that BH3 mimetics represent an interesting avenue for further exploration in myeloid BP-CML, for which alternative treatment options are desperately sought.
Journal • Combination therapy • IO biomarker
|
BCL2 (B-cell CLL/lymphoma 2) • MCL1 (Myeloid cell leukemia 1) • BCL2L1 (BCL2-like 1) • CD34 (CD34 molecule)
|
Venclexta (venetoclax) • Iclusig (ponatinib) • Tasigna (nilotinib) • S63845 • A-1331852
2years
The Flavonoid Brusatol Induces Apoptosis in Aggressive Lymphoma Cells and Exhibits Synergistic Effect with Venetoclax (ASH 2022)
Despite the available chemoimmunotherapy R-CHOP, one third of DLBCL patients still have primary refractory disease or relapse, and the incidence of these lymphomas continuously increases...Furthermore, co-treatment of Brusatol with inhibitors of Bcl-2 (Venetoclax), Bcl-XL (A-1331852), Mcl-1 (S63845), BTK (Ibrutinib), PI3K (Idealisib), Myc (EN4, JQ1), respectively, was performed in the same four cell lines and Annexin V levels were measured after 24h...Additionally, the combination of Brusatol with Venetoclax results in enhanced induction of apoptosis. Thus, our study suggests that Brusatol, alone or in combination with Venetoclax, represents a very interesting agent for further development of novel anti-lymphoma therapies.
PARP Biomarker • IO biomarker
|
MYC (V-myc avian myelocytomatosis viral oncogene homolog) • BCL2L1 (BCL2-like 1) • CASP3 (Caspase 3) • ANXA5 (Annexin A5)
|
MYC expression
|
Venclexta (venetoclax) • Imbruvica (ibrutinib) • Rituxan (rituximab) • JQ-1 • S63845 • A-1331852
2years
Erythroid/Megakaryocytic Differentiation Confers BCL-XL Dependency and Venetoclax Resistance in Acute Myeloid Leukemia (ASH 2022)
The high-throughput screens identified BCL-XL-selective inhibitors including A-1331852 as highly effective against erythroid and megakaryoblastic leukemia cell lines in comparison with 15 cell lines representing other AML types (Figure B). Combining BCL-XL inhibition with the JAK inhibitor ruxolitinib, the BCL-2 inhibitor venetoclax, or the hypomethylating agent azacitidine showed potential for more durable responses both in a 3-day ex vivo assay as well as long-term treatments spanning over a month. Collectively, our results suggest targeting BCL-XL as a potential therapy option in erythroid and megakaryoblastic leukemias and highlight an AML subgroup with potentially reduced sensitivity to venetoclax-based treatments.
IO biomarker
|
MCL1 (Myeloid cell leukemia 1) • BCL2L1 (BCL2-like 1)
|
Venclexta (venetoclax) • azacitidine • Jakafi (ruxolitinib) • A-1331852
2years
Rationale for Combining the BCL2 Inhibitor Venetoclax with the PI3K Inhibitor Bimiralisib in the Treatment of IDH2- and FLT3-Mutated Acute Myeloid Leukemia. (PubMed, Int J Mol Sci)
In this study, the BCL-XL inhibitor A1331852, MCL1-inhibitor S63845, dual PI3K-mTOR inhibitor bimiralisib (PQR309), BMI-1 inhibitor unesbulin (PTC596), MEK-inhibitor trametinib (GSK1120212), and STAT3 inhibitor C-188-9 were assessed as single agents and in combination with venetoclax, for their ability to induce apoptosis and cell death in leukemic cells grown in the absence or presence of bone marrow stroma. For the venetoclax and bimiralisib combination treatment, responders were enriched for IDH2 and FLT3 mutations, whereas non-responders were associated with PTPN11 mutations. The combination of PI3K/mTOR dual pathway inhibition with bimiralisib and BCL2 inhibition with venetoclax has emerged as a candidate treatment in IDH2- and FLT3-mutated AML.
Journal • IO biomarker
|
FLT3 (Fms-related tyrosine kinase 3) • IDH2 (Isocitrate Dehydrogenase (NADP(+)) 2) • BCL2L1 (BCL2-like 1) • PTPN11 (Protein Tyrosine Phosphatase Non-Receptor Type 11)
|
FLT3 mutation • PTPN11 mutation
|
Venclexta (venetoclax) • Mekinist (trametinib) • S63845 • A-1331852 • unesbulin (BMIi-1) • TTI-101 oral • bimiralisib (PQR309)
over2years
Carfilzomib (CFZ) resistance is associated with significant deregulation of the BH3 family proteins in multiple myeloma (MM) (IMW 2022)
All 7 CFZ resistant MM cell lines developed cross resistances to the MCL-1 inhibitors S63845 and AZD-5991...Moreover, a slight increase in sensitivity to venetoclax or A1331852 was observed in resistant OPM-2 or NCI-H929 and U266 cells, respectively...Exposure to ixazomib (IXA) upregulated BCL-xL and BAK in CFZ resistant cell lines... Our data show significant deregulation of BH3 proteins in CFZ resistant cell lines highlighting the importance of the apoptosis signaling pathway in PI resistance. Consistent deregulation of BCL-xL and BAK throughout CFZ and IXA exposed CFZ resistant cell lines suggests that this might not be a CFZ specific effect. BH3 profiling indicates a change in dependency on anti-apoptotic BH3 proteins in CFZ resistant vs.
IO biomarker
|
ABCB1 (ATP Binding Cassette Subfamily B Member 1) • BCL2L1 (BCL2-like 1) • BCL2L2 (BCL2 Like 2) • ANXA5 (Annexin A5)
|
Venclexta (venetoclax) • Ninlaro (ixazomib) • carfilzomib • S63845 • A-1331852 • AZD5991
over2years
A Mesenchymal Tumor Cell State Confers Increased Dependency on the BCL-XL Anti-apoptotic Protein in Kidney Cancer. (PubMed, Clin Cancer Res)
Our studies uncovered an unexpected link between cell state and BCL-XL dependence in ccRCC. Therapeutic agents that specifically target BCL-XL are available. Our work justifies testing the utility of BCL-XL blockade to target, likely, a clinically aggressive subset of human kidney cancers.
Journal • IO biomarker
|
BCL2 (B-cell CLL/lymphoma 2) • BCL2L1 (BCL2-like 1)
|
A-1331852
over2years
CARFILZOMIB RESISTANCE IS ASSOCIATED WITH SIGNIFICANT DEREGULATION OF THE BH3 FAMILY PROTEINS (EHA 2022)
For instance, the sensitivity to the BCL-2 inhibitor venetoclax is increased in PI resistant AMO-1 cells and a deregulation of BH3 proteins Noxa and MCL1 was noted in MM cell lines exposed to bortezomib...Results Viability assays indicate that all 7 tested carfilzomib resistant MM cell lines developed a cross resistance to the MCL-1 inhibitors S63845 and AZD-5991. Decreased sensitivity to the BCL-2 inhibitor venetoclax as well as to the BCL-xL inhibitor A1331852 was observed in resistant KMS12PE cells...This is further emphasized by the coherent deregulation of BCL-xL and BAK throughout carfilzomib exposed carfilzomib resistant cell lines when compared to their sensitive cell line variants. Moreover, BH3 profiling indicates a change in dependency on anti-apoptotic BH3 protein in carfilzomib resistant vs. sensitive MM cell lines.
IO biomarker
|
ABCB1 (ATP Binding Cassette Subfamily B Member 1) • BCL2L1 (BCL2-like 1) • BCL2L2 (BCL2 Like 2)
|
Venclexta (venetoclax) • bortezomib • carfilzomib • S63845 • A-1331852 • AZD5991
over2years
PREDICTING THE RESPONSE OF DLBCL CELLS TO BH3-MIMETICS USING SYSTEMS BIOLOGY (EHA 2022)
Bcl-2 (ABT-199), Mcl-1 (S63845) and Bcl-x L (A1331852) inhibitors are simulated to predict cell viability and compared to experimental results. Using a combination of in silico and in vitro experiments, we show that a computational model can predict the sensitivity of a cell to targeted therapies. Future work will test the ability of the model to predict patient responses to targeted therapies in order to enable a personalised medicine approach.
IO biomarker
|
BCL2 (B-cell CLL/lymphoma 2) • MCL1 (Myeloid cell leukemia 1) • BCL2L1 (BCL2-like 1)
|
BCL2 overexpression • BCL2 expression
|
Venclexta (venetoclax) • S63845 • A-1331852
over2years
THE DUAL BCL-2 AND BCL-XL INHIBITOR AZD4320 SHOWS ON-TARGET ACTIVITY IN ALL AND ACTS SYNERGISTICALLY WITH MCL-1 INHIBITION (EHA 2022)
AZD4320 was developed as a dual inhibitor of BCL-2 and BCL-XL, and its dendrimer conjugate (AZD0466) was recently reported to demonstrate anti-tumor activity in hematological cancer models, while showing only a transient thrombocytopenia. Aims In this study, the anti-leukemia activities of the dual BCL-2 and BCL-XL inhibitor AZD4320 and of MCL-1-selective AZD5991 were evaluated and compared to the effects of other BH3-mimetics (BCL-2-selective venetoclax, BCL-XL-selective A-1331852 and MCL-1-selective S63845)...Importantly, the highest synergism was found at low concentrations of both inhibitors, suggesting efficacy at moderate concentrations, which could potentially be achieved in vivo . Conclusion In summary, our study demonstrates sensitivity, on-target activity and synergism of the dual BCL-2 and BCL-XL inhibitor AZD4320 with inhibition of MCL-1, thereby providing strong evidence for further clinical evaluation in ALL.
IO biomarker
|
BCL2 (B-cell CLL/lymphoma 2) • BCL2L1 (BCL2-like 1)
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Venclexta (venetoclax) • S63845 • A-1331852 • AZD5991 • AZD0466 • AZD4320
over2years
Synergistic activity of combined inhibition of anti-apoptotic molecules in B-cell precursor ALL. (PubMed, Leukemia)
Interestingly, some venetoclax-resistant leukemias were sensitive to the MCL-1-selective antagonist S63845 and/or BCL-XL-selective A-1331852 suggesting functional mutual substitution. The effect of combining BCL-2 and MCL-1 inhibition by venetoclax and S63845 was evaluated in vivo and strongly enhanced anti-leukemia activity was found in a pre-clinical patient-derived xenograft model. Our study offers in-depth molecular analysis of mutual substitution of BCL-2 family proteins in acute lymphoblastic leukemia and provides targets for combination treatment in vivo and in ongoing clinical studies.
Journal
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BCL2L1 (BCL2-like 1)
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Venclexta (venetoclax) • S63845 • A-1331852
over2years
BH3 mimetic drugs cooperate with Temozolomide, JQ1 and inducers of ferroptosis in killing glioblastoma multiforme cells. (PubMed, Cell Death Differ)
U251 and SNB-19 cells were more readily killed by a combination of BH3 mimetics targeting BCL-XL and MCL-1 as opposed to dual treatment with the BCL-2 inhibitor Venetoclax and a BCL-XL inhibitor...In an orthotopic mouse model of GBM, we demonstrate that the BCL-XL inhibitor A1331852 can penetrate the brain, with A1331852 detected in both tumour and healthy brain regions. We also investigated the impact of combining small molecule inducers of ferroptosis, erastin and RSL3, with BH3 mimetic drugs. We found that a BCL-XL or an MCL-1 inhibitor potently cooperates with inducers of ferroptosis in killing U251 cells. Overall, these findings demonstrate the potential of dual targeting of distinct PCD signalling pathways in GBM and may guide the utility of BCL-XL inhibitors and inducers of ferroptosis with standard of care treatment for improved therapies for GBM.
Journal • PARP Biomarker • IO biomarker
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BCL2L1 (BCL2-like 1) • CASP3 (Caspase 3)
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Venclexta (venetoclax) • temozolomide • JQ-1 • A-1331852 • erastin • RSL3
over2years
Selective BH3 mimetics synergize with BET inhibition to induce mitochondrial apoptosis in rhabdomyosarcoma cells. (PubMed, Neoplasia)
By selectively inhibiting BCL-2, BCL-x, or MCL-1 (i.e. ABT-199, A-1331852, S63845) they shift the balance of pro- and anti-apoptotic proteins in favor of apoptosis. Interestingly, NOXA played a different role in both treatments, as genetic silencing of NOXA significantly rescued from JQ1/A-1331852-mediated apoptosis but not from JQ1/S63845-mediated apoptosis. In summary, JQ1/A-1331852 and JQ1/S63845 co-treatment represent new promising therapeutic strategies to synergistically trigger mitochondrial apoptosis in RMS.
Journal • IO biomarker
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BCL2 (B-cell CLL/lymphoma 2) • MCL1 (Myeloid cell leukemia 1) • BCL2L1 (BCL2-like 1)
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BCL2 overexpression
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Venclexta (venetoclax) • JQ-1 • S63845 • A-1331852
over2years
The first-in-class ERK inhibitor ulixertinib (BVD-523) shows activity in MAPK-driven pediatric low-grade glioma models as single agent and in combination with MEK inhibitors or senolytics (AACR 2022)
Furthermore, ulixertinib treatment slowed tumor growth and significantly increased survival in NSG mice with orthotopic BT40 xenografts.Ulixertinib showed indications for anti-proliferative synergy in vitro, according to the Loewe and Bliss independence models, in combination with MEK inhibitors (trametinib, binimetinib) or senolytics (navitoclax, A1331852). Combinations with chemotherapy (carboplatin, vinblastine) were at most additive...The combination of ulixertinib with navitoclax was further investigated in the BT40 PDX mouse model, where tumor growth and survival were comparable to ulixertinib monotherapy.In conclusion, our data indicate a strong potential for ulixertinib as a clinically relevant therapeutic option for the treatment of pLGG to be further investigated in upcoming clinical trials. Potential synergism with MEK inhibitors and senolytics was noted and warrants further investigation.
Clinical • Combination therapy
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BRAF (B-raf proto-oncogene) • CDKN2A (Cyclin Dependent Kinase Inhibitor 2A) • CDKN2B (Cyclin Dependent Kinase Inhibitor 2B)
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BRAF V600E • BRAF V600 • CDKN2A deletion • CDKN2A mutation • BRAF fusion • CDKN2A mutation + BRAF V600E
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Mekinist (trametinib) • carboplatin • Mektovi (binimetinib) • navitoclax (ABT 263) • ulixertinib (BVD-523) • A-1331852 • vinblastine
over2years
Development of the drug efficacy testing in ex vivo 3D cultures (DETECT) platform and its application to functional precision medicine in ovarian cancer (AACR 2022)
Some of the most common responses were seen for the BCL-XL inhibitor A-1331852 (9/15 patients), Topotecan (7), Dactinomycin (7), Omipalisib (6) and Omacetaxine (6). Combination screening revealed that Carboplatin and A-1331852, a BCL-XL inhibitor, showed increased efficacy in 3 of the 5 tested patient samples. In conclusion, our 3D HT-drug testing assay DETECT with a combination screening capability could in the future be useful for guiding individualized treatment in a clinical setting as well as for identifying existing and emerging drugs and drug combinations for repurposing in OC.
Preclinical
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BCL2L1 (BCL2-like 1)
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carboplatin • omipalisib (GSK2126458) • topotecan • dactinomycin • A-1331852 • Synribo (omacetaxine mepesuccinate)
over2years
Pre-clinical investigations utilizing Bcl2 inhibitors in glioblastoma (AACR 2022)
IC50s were determined for afore mentioned cell lines using MTS assay for Temozolomide (TMZ, alkylating agent), Bcl-2 inhibitor ABT199, Bcl-xL inhibitor A1331852, Mcl-1 inhibitor AZD5991, and BTK inhibitor Ibrutinib. Our preclinical data suggests synergism of Bcl-2 protein inhibitors in GBM cells, both TMZ-naïve and TMZ-resistant. Our ongoing research is investigating the biological relevance of Bcl-2 in conjugation with other tumor suppressor proteins, in vitro and in vivo.
Preclinical • IO biomarker
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BCL2L1 (BCL2-like 1)
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BCL2 expression
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Venclexta (venetoclax) • Imbruvica (ibrutinib) • temozolomide • A-1331852 • AZD5991
over2years
Dual inhibition of anti-apoptotic proteins BCL-XL and MCL-1 enhances cytotoxicity of Nasopharyngeal carcinoma cells. (PubMed, Discov Oncol)
Co-inhibition of MCL-1 and BCL-2 with MCL-1 selective inhibitor S63845 and BCL-2 selective inhibitor ABT-199 inhibited NPC cell proliferation but the effect on cell viability was more profound with co-inhibition of MCL-1 and BCL-XL with S63845 and A-1331852, implying that MCL-1 and BCL-XL are crucial for NPC cell survival. Deletion of BFL-1 sensitized NPC cells to A-1331852 suggesting that BFL-1 may play a role in NPC cell survival. Taken together co-inhibition of BCL-XL and MCL-1/BFL-1 could be potential treatment strategies for NPC.
Journal • IO biomarker
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BCL2 (B-cell CLL/lymphoma 2) • MCL1 (Myeloid cell leukemia 1) • BCL2L1 (BCL2-like 1) • BCL2L2 (BCL2 Like 2)
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MCL1 expression
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Venclexta (venetoclax) • S63845 • A-1331852
almost3years
Targeting entry into mitochondria for increased anticancer efficacy of BCL-X-selective inhibitors in lung cancer. (PubMed, Pharmacol Res)
Our results indicated that NA-2a was selectively enriched in mitochondria transported by organic-anion-transporting polypeptide (OATP) transporters, which altered the permeability of the mitochondrial membrane, thereby promoting the entrance of A-1331852 to mitochondria and enhancing its disruption of the BIM-BCL-X complex, which finally led to the increased anticancer activity in vitro and in vivo. Collectively, our data provided overwhelming evidence that the combination of NA-2a and A-1331852 could be used as a promising synergistic therapeutic agent in NSCLC therapy.
Journal
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BCL2L1 (BCL2-like 1)
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A-1331852
almost3years
Pediatric multicellular tumor spheroid models illustrate a therapeutic potential by combining BH3 mimetics with Natural Killer (NK) cell-based immunotherapy. (PubMed, Cell Death Discov)
Treatment with either the Bcl-X inhibitor A1331852 or the Mcl-1 inhibitor S63845 increased the cytotoxicity of NK cells and reduced spheroid size, while the Bcl-2 inhibitor ABT-199 had no effect on NK cell-mediated killing. Taken together, this is the first study to describe the combination of BH3 mimetics targeting Bcl-X or Mcl-1 with NK cell-based immunotherapy, highlighting the potential of BH3 mimetics in immunotherapy.
Clinical • Journal
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BCL2L1 (BCL2-like 1)
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Venclexta (venetoclax) • S63845 • A-1331852