^
7ms
Mcl-1 mediates intrinsic resistance to RAF inhibitors in mutant BRAF papillary thyroid carcinoma. (PubMed, Cell Death Discov)
The development of mutant-selective BRAF inhibitors (BRAFi), like vemurafenib, has been efficacious in patients with metastatic melanoma, but the response rate is low for mutant BRAF PTC patients...We found that cells presenting with minority MOMP-like phenotypes are dependent on the apoptotic regulator, Mcl-1, as treatment with the Mcl-1 inhibitor, AZD5991, potently induced cell death in resistant cells. Furthermore, PI3K/AKT inhibitors sensitized resistant cells to BRAFi; an effect that was at least in part associated with reduced Mcl-1 levels. Together, these data implicate minority MOMP as a mechanism associated with intrinsic drug resistance and underscore the benefits of targeting Mcl-1 in mutant BRAF PTC.
Journal
|
BRAF (B-raf proto-oncogene) • MCL1 (Myeloid cell leukemia 1)
|
BRAF V600E • BRAF mutation • BRAF V600
|
Zelboraf (vemurafenib) • AZD5991
12ms
AZD4573 in Combination with CHOP Increases Combination Benefit in Preclinical Peripheral T-Cell Lymphomas Models (ASH 2023)
Current standard of care for pTCL revolves around the chemotherapy regimens CHOP/E and for CD30-postive pTCLs, brentuximab vedotin is approved...Using the MCL-1 inhibitor AZD5991, we have shown statistically significant benefit in survival when combined with CHOP in 2 MCL-1 dependent preclinical pTCL PDX models (Koch et al...These data suggested that treatment with AD4573 either as a monotherapy or in combination with CHOP, would be an effective therapeutic strategy in pTCL. AZD4573 monotherapy is currently being evaluated in a phase 2 study (NCT05140382) to assess the efficacy, safety, and PK in patients with relapsed/refractory pTCL.
Preclinical • Combination therapy • IO biomarker
|
MYC (V-myc avian myelocytomatosis viral oncogene homolog) • BCL2 (B-cell CLL/lymphoma 2) • TNFRSF8 (TNF Receptor Superfamily Member 8) • BCL2L1 (BCL2-like 1) • CASP3 (Caspase 3) • BCL2A1 (BCL2 Related Protein A1) • CASP7 (Caspase 7)
|
MYC overexpression • BCL2 expression • MCL1 expression
|
Adcetris (brentuximab vedotin) • AZD5991 • zemirciclib (AZD4573)
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
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
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)
|
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
Screening of predicted synergistic multi-target therapies in glioblastoma identifies new treatment strategies. (PubMed, Neurooncol Adv)
The highest synergies were observed in the drug combinations Lapatinib with Thapsigargin and Lapatinib with Obatoclax Mesylate, both targeting epidermal growth factor receptor and affecting the apoptosis pathway. To further elaborate on the apoptosis cascade, we investigated other, more clinically relevant, apoptosis inducers and observed a strong synergistic effect while combining Venetoclax (BCL targeting) and AZD5991 (MCL1 targeting). Overall, we have identified via a high-throughput drug screening several new treatment strategies for GBM. Moreover, an exceptionally strong synergistic interaction was discovered between kinase targeting and apoptosis induction which is suitable for further clinical evaluation as multi-targeted combination therapy.
Journal
|
EGFR (Epidermal growth factor receptor)
|
IDH wild-type
|
Venclexta (venetoclax) • lapatinib • AZD5991 • obatoclax (GX 15-070)
over1year
Journal
|
AZD5991 • tapotoclax (AMG 176)
over1year
Preclinical investigations of the efficacy of the glutaminase inhibitor CB-839 alone and in combinations in chronic lymphocytic leukemia. (PubMed, Front Oncol)
In the primary lymphocytes, no significant effects of CB-839 alone or in combination with venetoclax, ibrutinib, or AZD-5991 were observed. Our findings suggest that CB-839 has limited efficacy in CLL treatment and shows limited synergy in combination with widely used CLL drugs.
Preclinical • Journal
|
Venclexta (venetoclax) • Imbruvica (ibrutinib) • telaglenastat (CB-839) • AZD5991
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
|
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
Design of rigid protein-protein interaction inhibitors enables targeting of undruggable Mcl-1. (PubMed, Proc Natl Acad Sci U S A)
Despite being previously considered undruggable, seven small-molecule Mcl-1 inhibitors have recently entered clinical trials. Here, we report the crystal structure of the clinical-stage inhibitor AMG-176 bound to Mcl-1 and analyze its interaction along with clinical inhibitors AZD5991 and S64315...Nuclear Magnetic Resonance (NMR)-based free ligand conformer analysis demonstrates that such unprecedented induced fit is uniquely achieved by designing highly rigid inhibitors, preorganized in their bioactive conformation. By elucidating key chemistry design principles, this work provides a roadmap for targeting the largely untapped PPI class more successfully.
Journal
|
BCL2 (B-cell CLL/lymphoma 2)
|
AZD5991 • tapotoclax (AMG 176) • MIK665 • murizatoclax (AMG 397)
over1year
SAFETY, TOLERABILITY, PHARMACOKINETICS, AND PRELIMINARY ANTITUMOR ACTIVITY OF AZD5991 IN RELAPSED/ REFRACTORY HEMATOLOGIC MALIGNANCIES: A PHASE 1 FIRST-IN-HUMAN STUDY (EHA 2023)
Background: Myeloid cell leukemia 1 protein (MCL-1) plays an important role in tumor cell survival, progression, and resistance to therapies, including venetoclax. Systemic administration of the MCL-1 inhibitor AZD5991 is associated with high incidence of laboratory troponin elevation while producing a low overall response rate. This unfavorable risk/benefit ratio led to study closure.
Clinical • P1 data • PK/PD data
|
BCL2 (B-cell CLL/lymphoma 2)
|
Venclexta (venetoclax) • AZD5991
over1year
Large scale pan cancer drug combination screening to identify effective and actionable combinations and biomarker hypothesis (AACR 2023)
We selected 4 combinations based on clinical need and validated them further in vitro and in vivo (selumetinib plus venetoclax or AZD5991, AZD2811 plus venetoclax, and capivasertib plus AZD5991).To understand how molecular context affects drug response, we also used GDSC tools ANOVA to perform over 5.4 million statistical tests to identify statistically significant associations between drug response metrics and multi-omics features including mutations, CNAs, gene expression and methylation. This resulted in identification of 1,631 ‘emergent’ biomarkers.In summary, our screen and pipeline have been designed to optimize preclinical interpretation with a focus on actionability, particularly by our unique approach, and to provide a valuable resource for exploration by the wider research community. As a result of this screen, we identified and validated novel combination-tumor types in multiple cancer types.
IO biomarker • Pan tumor
|
KRAS (KRAS proto-oncogene GTPase) • BRAF (B-raf proto-oncogene) • TP53 (Tumor protein P53) • PIK3CA (Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha) • PTEN (Phosphatase and tensin homolog) • KMT2D (Lysine Methyltransferase 2D) • MLL2 (Myeloid/lymphoid or mixed-lineage leukemia 2) • AURKB (Aurora Kinase B)
|
Venclexta (venetoclax) • Koselugo (selumetinib) • Truqap (capivasertib) • AZD5991 • barasertib-HQPA (AZD2811)
over1year
Chimeric antigen receptor (CAR) T cells overexpressing Bcl-xL increase proliferation and antitumor activity alone and in combination with BH3 mimetics (AACR 2023)
Of the tested antiapoptotic proteins, Bcl-xL overexpressing CAR T cells proved superior, having higher proliferation and increased anti-tumor activity in combination with or without BH3 mimetics, providing a new strategy to optimize CAR T cell function for the treatment of leukemia and lymphoma.
Combination therapy • IO biomarker
|
BCL2L1 (BCL2-like 1)
|
BCL2L1 overexpression • BCL2 G101V
|
Venclexta (venetoclax) • navitoclax (ABT 263) • AZD5991
over1year
MAPK-driven MCL1 expression promotes osteosarcoma survival in the metastatic niche (AACR 2023)
To optimize dosing and determine tolerance in vivo, we treated metastasis-bearing mice with different doses of AZD5991 +/- cyclophosphamide. Our data suggest growth factors in the lung activate ERK in the early metastatic niche, and ERK-dependent MCL1 expression is required for survival of anchor cells. MCL1-targeting agents may have utility in disrupting colonization of the lungs.
Metastases
|
MCL1 (Myeloid cell leukemia 1)
|
MCL1 expression
|
cyclophosphamide • AZD5991
almost2years
Effects of immune inflammation in head and neck squamous cell carcinoma: Tumor microenvironment, drug resistance, and clinical outcomes. (PubMed, Front Genet)
We also screened for susceptibility between the high-risk and low-risk groups and showed that patients in the high-risk group were more sensitive to talazoparib-1259, camptothecin-1003, vincristine-1818, Azd5991-1720, Teniposide-1809, and Nutlin-3a (-) -1047.Finally, we examined the expression of OLR1, SCN1B, and PDE4B genes in HNSCC pathological tissues and validated that these genes could be used to predict the prognosis of HNSCC. It is a non-invasive genomic characterization prediction method that has shown satisfactory and effective performance in predicting patient survival outcomes and treatment response. More interdisciplinary areas combining medicine and electronics will be explored in the future.
Clinical data • Journal • PARP Biomarker
|
ROS1 (Proto-Oncogene Tyrosine-Protein Kinase ROS) • CXCL8 (Chemokine (C-X-C motif) ligand 8) • TNFRSF9 (TNF Receptor Superfamily Member 9) • IL1A (Interleukin 1, alpha) • OLR1 (Oxidized Low Density Lipoprotein Receptor 1) • ITGA5 (Integrin Subunit Alpha 5)
|
Talzenna (talazoparib) • vincristine • AZD5991 • Vumon (teniposide) • Nutlin-3
2years
Regulatory Role of Sphingosine-1-Phosphate and C16:0 Ceramide, in Immunogenic Cell Death of Colon Cancer Cells Induced by Bak/Bax-Activation. (PubMed, Cancers (Basel))
Herein, we demonstrate that ABT-263 and AZD-5991, inhibitors of Bcl-2/Bcl-X and Mcl-1, respectively, induce the production of ectoCRT, indicative of ICD. While ceramide, produced by the inhibition of SphK1 is required for production of the cell surface marker of ICD, ectoCRT. Thus, inhibition of SphK1 represents a means to enhance the therapeutic efficacy of ICD-inducing agents.
Journal • IO biomarker
|
BCL2 (B-cell CLL/lymphoma 2) • MCL1 (Myeloid cell leukemia 1) • BCL2L1 (BCL2-like 1) • CASP8 (Caspase 8) • CALR (Calreticulin)
|
navitoclax (ABT 263) • AZD5991
2years
Mechanisms of MCL-1 protein stability induced by MCL-1 antagonists in B-cell malignancies. (PubMed, Clin Cancer Res)
We conclude that MCL-1i blocked Mcl-1 ubiquitination via enhanced deubiquitination and dissociation of Mcl-1 from Noxa, Bak and Bax, and Mule de-stabilization. These are critical events associated with increased Mcl-1 protein stability with AMG-176 and AZD5991.
Journal
|
MCL1 (Myeloid cell leukemia 1) • USP9X (Ubiquitin Specific Peptidase 9 X-Linked)
|
AZD5991 • tapotoclax (AMG 176)
2years
Development of a Robust BH3 Profiling Toolkit for Precision Medicine in Hematologic Malignancies (ASH 2022)
Next, we treated them with BH3 mimetics (or vehicle): Venetoclax (VEN, Bcl2 inhibitor), Navitoclax (Bcl2 and Bcl-xl inhibitor), AZD-5991 (AZD, Mcl1 inhibitor), A-1155463 (Bcl-xl inhibitor) for 4h. We believe that our results show the robustness of the BH3 toolkit and its ability to detect potential new therapeutic strategies in HM cell lines and primary cells. Detailed results will be presented at the meeting, as well as data on primary lymphoma and myeloma cells.
IO biomarker
|
BCL2L1 (BCL2-like 1) • ANXA5 (Annexin A5)
|
Venclexta (venetoclax) • navitoclax (ABT 263) • AZD5991
2years
Effects of Glutaminase Inhibition on Venetoclax, Ibrutinib, and AZD-5991 Resistance in Chronic Lymphocytic Leukemia Cell Lines (ASH 2022)
Combinations of CB-839 with other agents targeting multiple mechanisms have the potential to overcome metabolic adaptation. Our findings suggest that CB-839 has limited efficacy in overcoming ibrutinib CLL resistance. However, the synergism with apoptosis inducers such as venetoclax and AZD-5991 require further investigations.
Preclinical
|
ANXA5 (Annexin A5)
|
Venclexta (venetoclax) • Imbruvica (ibrutinib) • telaglenastat (CB-839) • AZD5991
2years
Retreatment with Polatuzumab Vedotin in Combination with Rituximab Increases Antitumor Activity Against Polatuzumab Vedotin-Resistant DLBCL Cells (ASH 2022)
Polatuzumab vedotin (Pola) is a monoclonal antibody against B-cell antigen CD79b conjugated to monomethyl auristatin E (MMAE), and is approved in combination with bendamustine and rituximab (Rit) in relapsed/refractory diffuse large B-cell lymphoma (r/r DLBCL) in various countries. Moreover, in the POLARIX study, Pola-R-CHP (cyclophosphamide, doxorubicin, and prednisone) achieved a significantly improved progression-free survival compared to R-CHOP (CHP plus vincristine) in previously untreated DLBCL...Interestingly, treatment with 1 μg/mL of Pola for 7 days further increased the IC50 value (16.8-fold) and the expression of MDR1 (3.6-fold)in SU-DHL-4-Pola-R cells.MDR1 inhibitor verapamil increased sensitivity to Pola, indicating that overexpression of MDR1 is one of the mechanisms of resistance to Pola in these cells...Mcl-1 inhibitor AZD5991 significantly increased CDC sensitivity, suggesting that Pola-mediated downregulation of Mcl-1 could upregulate the sensitivity to CDC in these cells...Combination treatment of Pola with Rit enhanced antitumor activity in STR-428-Pola-R xenografted mice. These results indicate that retreatment with Pola in combination with Rit could be a therapeutic option in patients with Pola-resistant tumors.
Combination therapy
|
ABCB1 (ATP Binding Cassette Subfamily B Member 1) • CD79B (CD79b Molecule) • BCL2L11 (BCL2 Like 11)
|
ABCB1 overexpression • MCL1 expression
|
Rituxan (rituximab) • doxorubicin hydrochloride • cyclophosphamide • vincristine • prednisone • bendamustine • AZD5991 • Polivy (polatuzumab vedotin-piiq)
2years
Combined Inhibition of MCL1 By AZD5991 and BCL2/Bclxl By AZD4320 As Promising Strategies to Overcome Acute Leukemia Tumor Burden and Niche Chemoresistance (ASH 2022)
To investigate the in vitro, ex vivo and in vivo effects of AZD5991 (AstraZeneca), a novel MCL1 inhibitor compound, alone or in combination with AZD4320 (BCL-2/BCL-XL inhibitor compound), venetoclax, cytarabine and doxorubicin. MCL1 overexpression in mononuclear cells from patients with acute leukemia and that present or not resistance to venetoclax treatment, is associated with poor prognosis and relapse disease. Our results demonstrated that co-targeting MCL-1, BCL-2 and BCL-xL, through the AZD5991 and AZD4320 compounds in the treatment of acute leukemias, may enhance therapeutic specificity, overcome chemoresistance and contribute with the cure of these aggressive malignant disorders.
IO biomarker
|
BCL2 (B-cell CLL/lymphoma 2) • BCL2L1 (BCL2-like 1) • CD34 (CD34 molecule) • ANXA5 (Annexin A5)
|
MCL1 overexpression
|
Venclexta (venetoclax) • cytarabine • doxorubicin hydrochloride • AZD5991 • AZD4320
2years
Pharmacological Profiling of Cells from Patients with Chronic Lymphocytic Leukemia (CLL) Treated with Pirtobrutinib (ASH 2022)
We incubated peripheral blood mononuclear cells for three days with cBTKi – ibrutinib; glutathione inhibitor (also known as mtTP53 modulator) - APR-246; Bcl-2 antagonist - venetoclax; and Mcl-1 antagonist - AZD5991; as single agent and in double or triple combinations and apoptosis was assessed by flow cytometry. Patients were re-sensitized to ibrutinib after loss of C481S clone. Genomic and genetic profile along with pharmacological landscape provide precision medicine for these heavily pretreated patients whose disease is resistant to BTK inhibitors.
Clinical • IO biomarker
|
BCL2 (B-cell CLL/lymphoma 2) • NOTCH1 (Notch 1) • MCL1 (Myeloid cell leukemia 1) • PLCG2 (Phospholipase C Gamma 2)
|
TP53 mutation • ATM mutation • NOTCH1 mutation • BTK C481S • BTK C481 • TS 12
|
Venclexta (venetoclax) • Imbruvica (ibrutinib) • eprenetapopt (APR-246) • Jaypirca (pirtobrutinib) • AZD5991
2years
Combinatorial Effects of BH3 Mimetics and CAR T Cells Targeting T-Cell Lymphomas (ASH 2022)
First, we did not observe a reduction in CAR-37 T cell viability when cultured in vitro in the presence of TCL target cells and either venetoclax 0.5μM, navitoclax 0.5μM, or AZD5991 0.1μM for 48 hours. These results could be used to nominate and/or deprioritize future combination strategies both for TCL and for other patients being treated with effector T cells for a range of hematologic malignancies. AZD5991 was kindly provided by AstraZeneca.
CAR T-Cell Therapy • PD(L)-1 Biomarker • IO biomarker
|
BCL2 (B-cell CLL/lymphoma 2) • PD-1 (Programmed cell death 1) • IFNG (Interferon, gamma) • LAG3 (Lymphocyte Activating 3) • BCL2L1 (BCL2-like 1) • HAVCR2 (Hepatitis A Virus Cellular Receptor 2) • CSF2 (Colony stimulating factor 2)
|
LAG3 expression • IFNG expression
|
Venclexta (venetoclax) • navitoclax (ABT 263) • AZD5991 • CAR-37 T Cells
2years
c-Myc plays a critical role in the antileukemic activity of the Mcl-1-selective inhibitor AZD5991 in acute myeloid leukemia. (PubMed, Apoptosis)
The combination also showed promising and synergistic antileukemic activity in vitro against AML cell lines with acquired resistance to the main chemotherapeutic drug AraC and primary AML cells derived from a patient at relapse post chemotherapy. The oncoprotein c-Myc represents a potential biomarker of AZD5991 sensitivity and inhibition of c-Myc synergistically enhances the antileukemic activity of AZD5991 against AML.
Journal
|
MYC (V-myc avian myelocytomatosis viral oncogene homolog) • MCL1 (Myeloid cell leukemia 1)
|
MYC overexpression • MCL1 overexpression • MYC expression • MYC negative
|
AZD5991
2years
Novel Agents in Chronic Lymphocytic Leukemia (CLL) (SOHO 2022)
The subsequent key areas hold promise: Alternative Inhibitors of BTK Here, non-covalent BTK inhibitors, such as pirtobrutinib (LOXO- 305) and nemtabrutinib (ARQ-531), have shown effi cacy in CLL resistant to covalent BTK inhibitors...AZD5991 is a highly selective BH3-mimetic that demonstrates high potency in MCL1-dependent cell lines.9 Our group has shown that selective targeting Mcl-1 induced metabolic dysfunction and abrogated survival of lymphoid cells in vitro and in vivo.10 Other BH3- mimetics targeting Mcl-1 include AMG-176 and S63845.11,12 However, Mcl-1 targeting agents may be associated with toxicities, including against the hematopoietic stem and progenitor cells, potentially leading to cytopenias in the clinic.13 The therapeutic window for these agents needs to be defi ned. BH3-mimetics which target Bcl-xL, such as navitoclax, are not being developed in CLL due to concerns of thrombocytopenia.14 However, AZD4320, an alternative Bcl-2/xL inhibitor, is being studied in lymphoid malignancies as an intravenous formulation, with hope to mitigate its effect on platelets.15 Therapeutic Antibodies Targeting surface receptors and inducing both direct and immunemediated apoptosis has been a success story in CLL with use of anti-CD20 agents...Lanalumab (VAY-736), a humanized defucosylated engineered antibody directed against BAFF-R, antagonized pro-survival effects of BAFF in CLL cells.16 In a phase 1 study in combination with ibrutinib in 32 patients with CLL, CR was achieved in 38% of patients, and 42% demonstrated undetectable minimal residual disease (uMRD) in the blood/bone marrow, a promising result not expected with ibrutinib alone.17 Alternative targets for therapeutic antibodies include ROR1 (cirmtuzumab) and CD19 (tafasitamab)...A recent report of a phase 1/2 study of lisocabtagene maraleucel, an autologous CD19-directed CAR T-cell therapy (TRANSCEND CLL 004), confi rmed effi cacy in patients with relapsed/refractory CLL.18 In this study, patients had a median of 4 prior therapies, including ibrutinib and venetoclax...In a Phase 1/2 trial, HLA-mismatched CD19-targeting CAR NK cells induced CRs in patients with CLL after a single infusion and without CRS or neurotoxicity attributable to the cellular product.19 Finally, bi-specifi c antibodies have demonstrated impressive effi cacy in non-Hodgkin lymphoma and are also an off-the-shelf product which boasts high tolerability. Development of bi-specifi c antibodies in CLL is still in early stages, however epcoritamab (a subcutaneously administered CD3xCD20 Duobody) demonstrated responses in an ongoing Phase 1 study.20 In sum, targeted therapy replaced chemo-immunotherapy in treatment of CLL, and emerging small molecule and cell therapy approaches auger an expansion of the therapeutic armamentarium for CLL in the next decade.
IO biomarker
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TP53 (Tumor protein P53) • CD19 (CD19 Molecule) • BCL2L1 (BCL2-like 1) • ROR1 (Receptor Tyrosine Kinase Like Orphan Receptor 1)
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CD19 expression
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Venclexta (venetoclax) • Imbruvica (ibrutinib) • Breyanzi (lisocabtagene maraleucel) • navitoclax (ABT 263) • S63845 • Jaypirca (pirtobrutinib) • Epkinly (epcoritamab-bysp) • zilovertamab (UC-961) • AZD5991 • Monjuvi (tafasitamab-cxix) • tapotoclax (AMG 176) • AZD4320 • ianalumab (VAY736) • nemtabrutinib (MK-1026)
2years
Inhibition of Mcl-1 Synergistically Enhances the Antileukemic Activity of Gilteritinib and MRX-2843 in Preclinical Models of FLT3-Mutated Acute Myeloid Leukemia. (PubMed, Cells)
Interestingly, the suppression of c-Myc enhances AZD5991-inudced cytochrome c release and the subsequent induction of apoptosis. AZD5991 enhances the antileukemic activity of the FLT3 inhibitors gilteritinib and MRX-2843 against FLT3-mutated AML in vitro, warranting further development.
Preclinical • Journal
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FLT3 (Fms-related tyrosine kinase 3) • MYC (V-myc avian myelocytomatosis viral oncogene homolog)
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FLT3-ITD mutation • FLT3 mutation
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Xospata (gilteritinib) • AZD5991 • MRX2843
2years
NA1-115-7, from Zygogynum pancheri, is a new selective MCL-1 inhibitor inducing the apoptosis of hematological cancer cells but non-toxic to normal blood cells or cardiomyocytes. (PubMed, Biomed Pharmacother)
Synthetic inhibitors targeting these proteins have been developed, and some hematological malignancies are now widely treated with a BCL-2 inhibitor (venetoclax)...Six MCL-1 inhibitors (S64315, AZD-5991, AMG-176, AMG-397, ABBV-467 and PRT1419) have been evaluated in clinical trials since 2016, but some were affected by safety issues and none are currently used clinically...Importantly, a similar treatment with NA1-115-7 was not toxic to erythrocytes, peripheral blood mononuclear cells, platelets, or cardiomyocytes. These results highlight the potential of natural products for use as specific BH3 mimetics non-toxic to normal cells, and they suggest that NA1-115-7 may be a promising tool for use in cancer treatment.
Journal • IO biomarker
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BCL2L1 (BCL2-like 1)
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MCL1 expression
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Venclexta (venetoclax) • AZD5991 • tapotoclax (AMG 176) • PRT1419 • ABBV-467 • MIK665 • murizatoclax (AMG 397)
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
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ABCB1 (ATP Binding Cassette Subfamily B Member 1) • BCL2L1 (BCL2-like 1) • BCL2L2 (BCL2 Like 2) • ANXA5 (Annexin A5)
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Venclexta (venetoclax) • Ninlaro (ixazomib) • carfilzomib • S63845 • A-1331852 • AZD5991
over2years
The combination of ruxolitinib and Bcl-2/Mcl-1 inhibitors has a synergistic effect on leukemic cells carrying a SPAG9::JAK2 fusion. (PubMed, Cancer Gene Ther)
Venetoclax (a BCL-2 inhibitor) or AZD5991 (an MCL-1 inhibitor) enhanced the effects of ruxolitinib on Ba/F3-SPAG9-JAK2 in vitro. These findings suggest that activation of the JAK2-STAT1-BCL-2/MCL-1 axis contributes to SPAG9::JAK2-related aberrant growth promotion. BCL-2 or MCL-1 inhibition is a potential therapeutic option for B-ALL with SPAG9::JAK2 fusion.
Journal • IO biomarker
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BCL2 (B-cell CLL/lymphoma 2) • JAK2 (Janus kinase 2) • STAT3 (Signal Transducer And Activator Of Transcription 3) • STAT1 (Signal Transducer And Activator Of Transcription 1) • SPAG9 (Sperm Associated Antigen 9)
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BCL2 expression • MCL1 expression • STAT3 mutation • JAK2 fusion • JAK2 rearrangement • STAT5A mutation
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Venclexta (venetoclax) • Jakafi (ruxolitinib) • AZD5991
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
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ABCB1 (ATP Binding Cassette Subfamily B Member 1) • BCL2L1 (BCL2-like 1) • BCL2L2 (BCL2 Like 2)
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Venclexta (venetoclax) • bortezomib • carfilzomib • S63845 • A-1331852 • AZD5991
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
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BCL2 (B-cell CLL/lymphoma 2) • BCL2L1 (BCL2-like 1)
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Venclexta (venetoclax) • S63845 • A-1331852 • AZD5991 • AZD0466 • AZD4320
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
Inhibition of MCL1 induces apoptosis in anaplastic large cell lymphoma and in primary effusion lymphoma. (PubMed, Sci Rep)
Antagonizing BH3 mimetics provide an option for medication, with venetoclax as the first drug applied for chronic lymphocytic leukemia and for acute myeloid leukemia. The combination of specific BH3 mimetics yielded synergistic effects, pointing to a novel strategy for the treatment of ALCL. The PI3K/mTOR inhibitor BEZ-235 could also efficiently be applied in combination with AZD-5991, offering an alternative to avoid thrombocytopenia which is associated with the use of BCLXL inhibitors.
Journal • IO biomarker
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BCL2 (B-cell CLL/lymphoma 2) • BCL2L1 (BCL2-like 1) • BCL2A1 (BCL2 Related Protein A1)
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BCL2 expression • MCL1 expression
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Venclexta (venetoclax) • dactolisib (RTB101) • AZD5991
almost3years
Activation of the STAT1-BCL-2/MCL-1 Axis in Leukemic Cells Carrying a SPAG9-JAK2 Fusion (ASH 2021)
Ba/F3 cells, which are IL-3 dependent murine pro B-ALL cells, were transduced with retroviral vector to establish Ba/F3 cells expressing SPAG9-JAK2 (Ba/F3-SPAG9-JAK2) under doxycycline (DOX) dependent manner...Treatment of Ba/F3-SPAG9-JAK2 cells with a combination of ruxolitinib and venetoclax or AZD5991 resulted in a significant reduction in the IC50 of ruxolitinib (p<0.01) [Fig...Activation of the JAK2-STAT1-BCL-2/MCL-1 axis contributes to aberrant growth promotion by SPAG9-JAK2. BCL-2 or MCL-1 inhibitors in combination with ruxolitinib shows efficacy against Ph-like ALL carrying the SPAG9-JAK2 fusion in vitro .
IO biomarker
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BCL2 (B-cell CLL/lymphoma 2) • JAK2 (Janus kinase 2) • MCL1 (Myeloid cell leukemia 1) • STAT1 (Signal Transducer And Activator Of Transcription 1)
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BCL2 expression • MCL1 expression • JAK2 mutation • JAK2 fusion
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Venclexta (venetoclax) • Jakafi (ruxolitinib) • AZD5991
3years
Cotargeting of Bcl-2 and Mcl-1 Shows Promising Antileukemic Activity against AML Cells Including those with Acquired Cytarabine Resistance. (PubMed, Exp Hematol)
Inhibition of Mcl-1 using another Mcl-1 selective inhibitor, AZD5991, also synergistically enhanced apoptosis induced by venetoclax in a caspase dependent manner. Importantly, S63845 in combination with venetoclax can effectively combat AML cells with acquired resistance to the standard chemotherapy drug cytarabine. Taken together, combined inhibition of Mcl-1 and Bcl-2 shows promise against AML cells, including relapse/refractory AML.
Journal
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BCL2 (B-cell CLL/lymphoma 2)
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Venclexta (venetoclax) • cytarabine • S63845 • AZD5991
3years
ASPP2k, a Dominant-Negative Splicing Variant of the Apoptosis-Stimulating Protein of p53-2 (ASPP2), Modulates Treatment Response Towards BCL-Signaling Inhibitors in Acute Myeloid Leukemia (ASH 2021)
Several compounds targeting BCL-2 signaling, which are under clinical investigation, were tested (BCL-2: venetoclax, BCL-2/Xl: AZD4320, MCL-1: AZD5991 and CDK9: AZD4573)...Priming with a hypomethylating agent (HMA, decitabine) resulted in additive (CI close to 1) to synergistic (CI 0.25 – 0.7) proapoptotic effects in isobologram analysis and led to a release of drug resistance in primary resistant cell lines...attenuation thereof after forcely expressing the dominant-negative splicing variant). To summarize, we show that inhibition of BCL-2 signaling is a promising approach to target acute leukemia – as a monoagent as well as in combination with HMA: Further, we provide a path for exploration of ASPP2k as a predictive tool as well as a therapeutic sensitizer of pro-apoptotic drugs, which will be addressed in future studies.
IO biomarker
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FLT3 (Fms-related tyrosine kinase 3) • NPM1 (Nucleophosmin 1)
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TP53 mutation
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Venclexta (venetoclax) • decitabine • AZD5991 • zemirciclib (AZD4573) • AZD4320
3years
Prediction of Venetoclax Sensitivity Based on BCL2 Protein-Protein Interaction for Acute Myeloid Leukemia Patients (ASH 2021)
Based on the EC50 data obtained through treatment with venetoclax and AZD5991, the sample was divided into a sensitive group (EC50300nM), which were highly responsive to BH3 mimetics, and the difference in PPI between the two groups was analyzed...Patient number BC7064 was classified as a high-BCL2 “responsive” group and was treated with venetoclax plus azacitidine...In conclusion, the combination diagnosis based on the BCL2 profile proposed by this research was made based on in vitro drug sensitivity, but it could also be applied to the actual clinical response results. In addition, this diagnostic method can sensitively track changes in the BCL2 profile throughout the AML treatment course, as seen in BC7064 case.
Clinical • IO biomarker
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BCL2 (B-cell CLL/lymphoma 2) • BCL2L1 (BCL2-like 1)
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BCL2 expression
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Venclexta (venetoclax) • azacitidine • AZD5991