AZD5991 / AstraZeneca - LARVOL DELTA

Potential novel interventions of oncohistones, epigenetic modifications, and RNA processing machinery in betel-nuts related HNSCC in Taiwan (AACR 2025) - "PI3K/AKT/mTOR interventions, ALK/IGF1R inhibitor, CDK4/6 inhibitor, BCl2 inhibitor, WEE1 inhibitor, ATR inhibitor, DNA-PK inhibitor, AT2AR inhibitor, Mcl-1 inhibitor, MEK1/2 inhibitor, JAK2 inhibitor, CXCR4 inhibitor, FAK inhibitor, p53 reactivator, MDM2 inhibitor, SHP2 inhibitor, PARP7 inhibitor, IAP inhibitor, GLS1 inhibitor, eribulin, & VEGFR2/ PDGFR/FGFR or VEGFR2/c-MET/Axl triple blockage might be effective on TW2.6 and reverse treatment refractoriness, through the inhibition of mesenchymal transformation, pRB, & PI3K/AKT /mTOR signaling and modulation of stemness & PD1/PDL1 pathway...Disrupting NSD1 in HNSCC cell lines led to CpG hypomethylation & enhanced cisplatin sensitivity. TW2.6 used to test (1)in vitro drug sensitivity to (a)Chemical Modulators of Splicing; (b)PRMT5 inhibitor; (c)CDK9 inhibitor, EZH2i, DNMT3i, BRD/BET4i, and HDACi; (d)NSD1/SETD2 inhibitor; (e)METTL3 inhibitor; (2)synergistic effects with other therapies by MTT assay, colony..."

IO biomarker • Head and Neck Cancer • Oncology • Squamous Cell Carcinoma of Head and Neck • AKT1 • ALK • ARID1B • ATM • AXL • BRD4 • CCND3 • CDK12 • CXCR4 • DDR2 • EPHB1 • FAT1 • FGF10 • FGFR • FLCN • HRAS • KDM5A • KDR • METTL3 • MITF • NSD1 • PDGFRB • PIK3CA • RICTOR • RPS6KB1 • SDHA • SETD2 • SOX9 • STK11 • TERT • TIPARP • TMB • TNFAIP3

Development and validation of a 16-gene T-cell- related prognostic model in non-small cell lung cancer. (PubMed, Front Immunol) - "High-risk patients responded better to AZD5991-1720, an MCL1 inhibitor, while low-risk patients showed improved responses to IGF1R-3801-1738, an IGF1R inhibitor, suggesting that risk stratification may help optimize treatment selection based on tumor-specific vulnerabilities...However, prospective validation is needed to confirm its clinical applicability. Potential limitations such as sample size and generalizability should be considered."

Biomarker • Journal • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • AKAP12 • BAIAP2 • CD69 • CKAP4 • CXCL13 • DSG2 • HOXC10 • KREMEN2 • LATS2 • LDHA • MAPK4 • PTX3

Genomic amplification of MCL1 as a therapeutic target for osteosarcoma (AACR 2025) - "The treatment for OS that combines surgery with chemotherapy, which consists of a four-drug combination of doxorubicin (DOX), cisplatin (CDDP), high-dose methotrexate (MTX), and ifosfamide, was established in 1970s, and it is still used as a standard therapy...Additionally, the combination of MIK665 with IGF-1R inhibitors, including OSI906, AEW541, and AZD3463, induced synergistic cell death by overcoming drug tolerance conferred by the activation of IGF signaling in OS cells...Moreover, the combination therapy of AZD5991 with OSI906 also reduced tumor growth in the NOS-10 xenograft model. These results suggest that genomic amplification of MCL1 in the 1q21.2-3 region, observed in nearly half of OS patients, may act as a predictive biomarker for combination therapy with an Mcl-1 inhibitor and an IGF1-R inhibitor."

Oncology • Osteosarcoma • Sarcoma • Solid Tumor • IGF1 • NOS1 • PIP5K1A

Functional apoptosis profiling reveals vulnerabilities in T-cell large granular lymphocytic leukemia. (PubMed, Ann Hematol) - "Accordingly, CD8 + T-LGLL cells from patients with enhanced MCL1 dependence significantly responded to AZD-5991 ex vivo while no response was observed in the remaining samples lacking enhanced MCL-1 dependence. Across clinically and genetically heterogeneous cases of T-LGLL, functional apoptosis profiling identified patients with CD8 + T-LGLL cells harboring a dominant dependence on MCL-1 as a potential therapeutic target."

Journal • Hematological Disorders • Hematological Malignancies • Leukemia • Oncology • T-Cell Large Granular Lymphocyte Leukemia • CD4 • CD8 • STAT3

Impact of Docirbrutinib (AS-1763) Treatment in CLL: Preclinical Data and Early Clinical Biomarkers (ASH 2024) - P1 | "Biological and biochemical effects were tested in treatment-naïve (TN with BTK-wild type) and relapsed/refractory (R/R with BTK and/or Bcl-2 mutant) CLL cells during in vitro investigations with 0.01, 0.1, and 1 µM docirbrutinib alone or with Bcl-2i (venetoclax) or Mcl-1i (AZD5991)...In TN CLL lymphocytes from 11 CLL pts, 72-hr incubation with docirbrutinib induced modest yet significant apoptosis which was comparable to ibrutinib or pirtobrutinib...In the dose-escalation trial, docirbrutinib treatment showed decreased BCR pathway biomarkers such as CCL3/CCL4 and phospho-BTK and PLCγ2. Updated data will be presented."

IO biomarker • Preclinical • Chronic Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Oncology • BCL2 • BCL2L1 • CCL3 • CD86 • CXCL12 • PLCG2

Structure-Based Discovery of a Series of Covalent, Orally Bioavailable, and Selective BFL1 Inhibitors. (PubMed, J Med Chem) - "The first article describes the hit identification from a covalent fragment library and the subsequent evolution from the hit to compound 6.22 This work reports the structure-based optimization of compound 6 into a series of BFL1 inhibitors selective over the other BCL2 family members, with low nanomolar cellular activity when combined with AZD5991, exemplified by compound 20. Compound 20 demonstrated a cell death phenotype in SUDHL1 and OCILY10 cell lines and in the in vivo study, BFL1 stabilization and cleaved caspase 3 activation were observed in a dose-dependent manner. In addition, the enzymatic turnover studies with the BFL1 protein showed that compound 20 stabilized the protein, extending the half-life to 10.8 h."

IO biomarker • Journal • Hematological Disorders • Hematological Malignancies • Oncology • BCL2 • CASP3

A PHASE 1 FIRST-IN-HUMAN STUDY OF THE MCL-1 INHIBITOR AZD5991 IN PATIENTS WITH RELAPSED/REFRACTORY HEMATOLOGIC MALIGNANCIES. (PubMed, Clin Cancer Res) - "Treatment with AZD5991 was associated with high incidence of laboratory troponin elevation and a low overall response rate."

Journal • P1 data • Acute Myelogenous Leukemia • Cardiovascular • Hematological Disorders • Hematological Malignancies • Infectious Disease • Leukemia • Myelodysplastic Syndrome • Oncology • Respiratory Diseases • Septic Shock

A PHASE 1 FIRST-IN-HUMAN STUDY OF THE MCL-1 INHIBITOR AZD5991 IN PATIENTS WITH RELAPSED/REFRACTORY HEMATOLOGIC MALIGNANCIES (Clin Cancer Res) - P1 | N=70 | NCT03218683 | Sponsor: AstraZeneca | "The most common (≥30%) adverse events (AEs) were diarrhea (59.0%), nausea (55.1%), and vomiting (47.4%). Four deaths occurred due to AEs: cardiac arrest, sepsis, tumor lysis syndrome (TLS), and acute respiratory failure; only TLS was related to AZD5991. Dose-limiting toxicities occurred in 5 patients. Three patients with MDS achieved an objective response: 1 marrow complete remission (mCR) without hematologic improvement, 1 partial remission with AZD5991 monotherapy, and 1 mCR with AZD5991+venetoclax."

P1 data • Acute Myelogenous Leukemia • Myelodysplastic Syndrome

FUNCTIONAL APOPTOSIS PROFILING REVEALS VULNERABILITIES IN T-CELL LARGE GRANULAR LYMPHOCYTIC LEUKEMIA (EHA 2024) - "Across clinically and genetically heterogeneous cases of T-LGL, functional apoptosis profiling identifiedpatients with dominant dependence on MCL-1 and provided a basis for a targeted therapeutic approach."

Hematological Disorders • Hematological Malignancies • Leukemia • Oncology • CD4 • CD8 • STAT3

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 • Endocrine Cancer • Melanoma • Oncology • Solid Tumor • Thyroid Gland Carcinoma • Thyroid Gland Papillary Carcinoma • BRAF • MCL1

KS18, an Mcl-1 inhibitor, triggers cell death and enhances the therapeutic efficacy of venetoclax in bortezomib-resistant multiple myeloma cells (AACR 2024) - "KS18 outperforms other Mcl-1 inhibitors such as S63845, VU661013, and AZD5991, according to the findings of our research, which shows that it is extraordinarily effective against MM cells that have become resistant to bortezomib. These intriguing findings highlight the potential value of KS18 as an adjunct to therapies aimed at overcoming bortezomib resistance in MM and other associated cancers. Bortezomib-resistant malignancies provide a challenge for patients, but additional research into the clinical value of KS18 holds the potential to improve treatment outcomes and broaden the range of therapeutic alternatives available to these patients."

Clinical • IO biomarker • Hematological Malignancies • Multiple Myeloma • Oncology • BCL2

Combined inhibition of MCL-1 and MEK reduces tumor growth in a triple-negative/inflammatory breast cancer, MEK-resistant xenograft mouse model (AACR 2024) - "Further, we treated resistant cells with MEKi AZD6244 and an MCL-1i (AZD5991) that confirmed restoration of MEK sensitivity in both resistant cell lines, resulting in decreased cell viability, colony formation and increased apoptosis. Our results suggest that MCL-1 is important for inducing acquired MEK resistance and combining an MCL-1i with a MEKi could improve treatment outcomes of patients with TNBC or IBC who have developed resistance to single-agent MEKi."

Preclinical • Breast Cancer • Hematological Malignancies • Leukemia • Mantle Cell Lymphoma • Oncology • Solid Tumor • Triple Negative Breast Cancer • ALDH1A1 • BBC3

Assessing cancer drug combination efficacy across 900+ PRISM cell lines in a multiplexed screening assay (AACR 2024) - "In the first combination, temozolomide+O6-benzylguanine (alkylating agent + MGMT inhibitor), we found that cell lines expressing MGMT were sensitized to temozolomide in the presence of O6-benzylguanine, thus illustrating synergy. In the second combination, we screened two anti-apoptosis compounds A-1331852+AZD5991 (BCL-xL + MCL1 inhibitor) and found that BCL-xL and MCL1 inhibition were also synergistic. In the third combination, ML210+ferrostatin-1 (GPX4 inhibitor inducing ferroptosis + ferroptosis inhibitor), we found that ferrostatin-1 antagonized the effects of ML210. Our analysis also reveals the importance of appropriate dose selection and analytical metrics for reliably measuring combined effects. In conclusion, the PRISM platform's multiplexed cell line screening is a robust method for characterizing rationally designed drug combinations, offering a systematic approach to enhance the precision of combination therapy development in cancer care."

Preclinical • Oncology • BCL2L1 • GPX4 • MGMT

AZD4573 in combination with CHOP increases combination benefit in preclinical peripheral T-cell lymphoma models (AACR 2024) - "Using MCL-1 inhibitor AZD5991, we showed statistically significant benefit in survival when combined with CHOP in MCL-1 dependent preclinical pTCL PDX models (Koch et al. CHOP treatment in vitro resulted in a decrease in c-MYC levels but not MCL-1, suggesting that combination benefit may be driven through c-MYC. This data suggests that treatment with AZD4573 as a monotherapy or in combination with CHOP regimen ­would be an effective therapeutic strategy in pTCL."

Combination therapy • IO biomarker • Preclinical • Cutaneous T-cell Lymphoma • Hematological Malignancies • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Peripheral T-cell Lymphoma • T Cell Non-Hodgkin Lymphoma • BCL2 • BCL2A1 • BCL2L1 • CASP3 • CASP7 • MYC

Beat AML: Study of Biomarker-Based Treatment of Acute Myeloid Leukemia (clinicaltrials.gov) - P1/2 | N=2000 | Recruiting | Sponsor: Beat AML, LLC | Trial completion date: Dec 2023 ➔ Dec 2026 | Trial primary completion date: Dec 2023 ➔ Dec 2026

Trial completion date • Trial primary completion date • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Oncology

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 • Acute Lymphocytic Leukemia • Acute Myelogenous Leukemia • Chronic Lymphocytic Leukemia • Hematological Disorders • Hematological Malignancies • Leukemia • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • T Acute Lymphoblastic Leukemia • BCL2 • BCL2L1

A selective MCL-1 inhibitor AZD5991 showed tumor regression in a triple-negative inflammatory breast cancer xenograft model (SABCS 2023) - "We are currently validating several significant targets to understand the biological mechanisms related to our candidate drug. Our long-term goal is to develop MCL-1 targeted therapy in combination with standard-of-care treatment for inflammatory and triple-negative breast cancers."

IO biomarker • Preclinical • Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • BAX • BCL2 • BCL2L1 • ER • HER-2 • RAD17

AZD4573 in Combination with CHOP Increases Combination Benefit in Preclinical Peripheral T-Cell Lymphomas Models (ASH 2023) - P2 | "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."

Combination therapy • IO biomarker • Preclinical • Cutaneous T-cell Lymphoma • Hematological Disorders • Hematological Malignancies • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Peripheral T-cell Lymphoma • T Cell Non-Hodgkin Lymphoma • BCL2 • BCL2A1 • BCL2L1 • CASP3 • CASP7 • MYC • TNFRSF8

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 • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Multiple Myeloma • Oncology • BCL2

Impact of the physical-chemical properties of poly(lactic acid)-poly(ethylene glycol) polymeric nanoparticles on biodistribution. (PubMed, J Control Release) - "Together, these techniques revealed a uniquely detailed picture of PNP size, surface structure, internal molecular architecture and the preferred site(s) of incorporation of the hydrophobic drug, AZD5991, properties which cannot be accessed via conventional characterization methodologies...We also demonstrate how, in this study, it is not practicable to validate the bioanalytical methodology for drug released in vivo due to the NP formulation properties, a process which is applicable for most small molecule-releasing nanomedicines. In conclusion, this work details a strategy for determining the effect of formulation variability on in vivo performance, thereby informing the translation of PNPs, and other NPs, from the laboratory to the clinic."

Journal

Potentiation of apoptosis in drug-resistant mantle cell lymphoma cells by MCL-1 inhibitor involves downregulation of inhibitor of apoptosis proteins. (PubMed, Cell Death Dis) - "In this study, we assessed the efficacy of the highly potent and selective MCL-1 inhibitor AZD5991 in various therapy-resistant MCL cell models. Supporting this notion, the IAP antagonist BV6 induced dramatic apoptosis in resistant MCL cells and sensitized the resistant MCL cells to venetoclax. Our study uncovered another unique route for MCL-1 inhibitor to trigger apoptosis, implying that the pro-apoptotic combination of IAP antagonists and apoptosis inducers could be further exploited for MCL patients with multiple therapeutic resistance."

Journal • Hematological Malignancies • Lymphoma • Mantle Cell Lymphoma • Oncology

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 • Chronic Lymphocytic Leukemia • Diffuse Large B Cell Lymphoma • Follicular Lymphoma • Hematological Malignancies • Leukemia • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • ANXA5 • BCL2 • BCL2L1 • BCL2L11 • BIRC3 • BRAF • CREBBP • EP300 • EZH2 • FBXW7 • KMT2D • KRAS • MLL2 • MYD88 • NOTCH1 • NRAS • SF3B1 • TP53

AZD 5991, a novel MCL-1-inhibitor, synergizes with hypomethylating agents (HMA) in acute myeloid leukemia (AML) models (DGHO 2023) - "Recent progress was made with the introduction of the BCL-2-inhibitor venetoclax (VEN) in AML therapy, which gained EMA approval in combination with HMA in 2021...Combination efficacy of AZD 5991 with decitabine was determined...A recent clinical trial, evaluating the combination of MCL-inhibition with VEN was terminated early due to toxicity – and novel strategies are urgently needed. Our data provide a rationale to further evaluate MCL-1 + HMA combinations in AML."

Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • ANXA5

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 • Brain Cancer • CNS Tumor • Glioblastoma • Oncology • Solid Tumor • EGFR

A PKPD Case Study: Achieving Clinically Relevant Exposures of AZD5991 in Oncology Mouse Models. (PubMed, AAPS J) - "Exposure-efficacy relationships were evaluated, demonstrating that dissimilar PK profiles result in differences in target engagement and efficacy outcomes. Thus, these data underscore the importance of accurately ascribing key PK metrics in the translational process to enable clinically meaningful predictions of efficacy."

Journal • Preclinical • Oncology