MIK665 / Servier, Novartis, HitGen - LARVOL DELTA

DEVELOPMENT OF SINGLE-MOLECULE ASSAYS FOR DETECTING BFL1 COMPLEXES TO ENABLE COMPREHENSIVE PROFILING OF THE APOPTOSIS PATHWAY (EHA 2025) - "Upon treatment with venetoclax (BCL2i), S64315 (MCL1i), and WEHI-539 (BCLxLi), either alone or in combination, we observed re-sequestration of BIM and BAK by BFL1, highlighting the dynamic interplay among BCL2-family proteins in response to inhibitor treatment. We developed highly sensitive assays to quantify BFL1 expression and its interactions with pro-apoptotic partners, providing a quantitative tool for investigating compound mechanisms of action. This SPID-based platform enables comprehensive profiling of anti-apoptotic protein rebalancing in response to BCL2-family inhibitors. Furthermore, it has potential applications in target engagement assays, supporting dose optimization and therapeutic development for apoptosis-targeting drugs."

IO biomarker • Hematological Malignancies • Oncology • BCL2L1 • CASP3 • MCL1

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

Combination of the ClpP agonist TR107 and the MCL1 inhibitor MIK665 enhances cytotoxicity in breast cancer cells [WITHDRAWN] (AACR 2025) - "Ongoing work involves testing the combination in vivo and investigating specific biomarkers that predict cell line sensitivity to the drug combination. In summary, we found strongly additive or synergistic therapeutic efficacy of a treatment combining TR-107 and MIK665 in multiple breast cancer cell lines."

IO biomarker • Breast Cancer • Estrogen Receptor Positive Breast Cancer • Hematological Malignancies • HER2 Breast Cancer • HER2 Positive Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Leukemia • Oncology • Solid Tumor • Triple Negative Breast Cancer • BCL2 • CLPP • ER • HER-2 • PGR

TP53 Inactivation Confers Resistance to the Menin Inhibitor Revumenib in Acute Myeloid Leukemia. (PubMed, bioRxiv) - "The MCL-1 inhibitor MIK665, but not venetoclax, preferentially sensitized TP53 -mutant AML cells to revumenib. These data identify mutant TP53 as a potential biomarker for de novo resistance to revumenib, and provide a rationale to evaluate MCL-1 and menin inhibitor combinations in patients KMT2A -rearranged leukemias with TP53 mutations."

IO biomarker • Journal • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • BCL2 • KMT2A • NPM1 • TP53

Src inhibition potentiates MCL-1 antagonist activity in acute myeloid leukemia. (PubMed, Signal Transduct Target Ther) - "The importance of MCL-1 in leukemogenesis has prompted development of MCL-1 antagonists e.g., S63845, MIK665. These findings argue that Src inhibitors such as SKI-606 potentiate MCL-1 antagonist anti-leukemic activity in vitro and in vivo by blocking MCL-1 antagonist-mediated cytoprotective MCL-1 accumulation by promoting degradative ubiquitination, disrupting STAT-3-mediated transcription, and inducing NOXA-mediated MCL-1 degradation. They also suggest that this strategy may improve MCL-1 antagonist efficacy in AML and potentially other malignancies."

Journal • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • Targeted Protein Degradation • BCL2L1 • CD34 • MYC

Predictors of Response and Rational Combinations for the Novel MCL-1 Inhibitor MIK665 in Acute Myeloid Leukemia (ASH 2024) - "Moreover, this work demonstrates that a combination of MIK665 with venetoclax can restore sensitivity in patient populations resistant to either of the single agents, a finding warranting further clinical evaluation. The value of this work lies in the discovery of biomarkers of response to MIK665, which can aid in the stratification of AML patients for MIK665-based treatments."

IO biomarker • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Mantle Cell Lymphoma • Oncology • ABCB1 • BCL2L1 • IL17A • IL17RA

S227928: A Novel Anti-CD74 ADC with MCL-1 Inhibitor Payload for the Treatment of Acute Myeloid Leukemia (AML) and Other Hematologic Malignancies (ASH 2024) - "Introduction Overexpression of MCL-1 is a well-known mechanism of resistance to venetoclax (ven), a BCL-2 inhibitor. Conclusion Given these promising data, S227928 should lead to an improved therapeutic index via more selective delivery of S64315 to CD74-expressing tumor cells. S227928 will be evaluated in a Phase 1/2 study as a single agent and in combination with ven for the treatment of patients with relapsed/refractory (R/R) AML or chronic myelomonocytic leukemia (CMML) who are no longer candidates for standard therapies."

IO biomarker • Acute Myelogenous Leukemia • Chronic Myelomonocytic Leukemia • Gastrointestinal Disorder • Hematological Disorders • Hematological Malignancies • Leukemia • Mantle Cell Lymphoma • Oncology • CD34 • CD74 • MIF

High-Throughput Drug Repurposing Identifies SN-38 As a Potent Inhibitor of AML with Synergistic Effects in Combination with PARP and BCL-2 Inhibitors for Treating KMT2A-Rearranged Leukemias (ASH 2024) - "Results : High Throughput Drug Screening identified the top five most active FDA-approved drugs across 6 AML cell lines : 1) SN-38 (a topoisomerase I inhibitor and the active metabolite of irinotecan), 2) Triplotide (an NF-κB inhibitor), 3) Mitoxantrone (a topoisomerase II inhibitor), 4) Idarubicin (a topoisomerase II inhibitor), and 5) Bortezomib (a proteasome inhibitor)...Drugs that exhibited greater selectivity, meaning greater responses in KMT2Ar cell lines, included : 1) Ingenol Mebutate (a PKC inhibitor), 2) a BET bromodomain inhibitor, 3) MIK665 (an MCL1 inhibitor), 4) Prexasertib (a CHK inhibitor), and 5) Crenolanib (an FLT3/PDGFR inhibitor)...Moreover, the observed synergy with PARP and BCL-2 inhibitors reveals strategies to overcome AML resistance mechanisms to SN-38. However, rigorous preclinical and clinical studies are essential to validate its efficacy, safety, and optimal dosing regimens."

Combination therapy • IO biomarker • Acute Lymphocytic Leukemia • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • Pediatrics • T Acute Lymphoblastic Leukemia • AFF1 • FLT3 • KMT2A • MLLT3

A First in Human Study of VOB560 in Combination with MIK665 in Patients with Relapsed/Refractory Non-Hodgkin Lymphoma, Acute Myeloid Leukemia, or Multiple Myeloma (ASH 2024) - P1 | "Patients who developed troponin increase underwent cardiac MRI, which showed no observable functional or structural changes to the heart.Conclusions : Early clinical data of VOB560 in combination with MIK665 reported an acceptable safety profile in patients with hematological malignancies. The observed activity in the AML patients supports the notion that targeting MCL1 and BCL2 is a promising approach in hematological malignancies."

Clinical • Combination therapy • P1 data • Acute Myelogenous Leukemia • Anemia • B Cell Lymphoma • Cardiovascular • Diffuse Large B Cell Lymphoma • Follicular Lymphoma • Hematological Disorders • Leukemia • Lymphoma • Metabolic Disorders • Multiple Myeloma • Nephrology • Neutropenia • Oncology • Renal Disease • Thrombocytopenia • BCL2

The tubulin polymerization inhibitor gambogenic acid induces myelodysplastic syndrome cell apoptosis through upregulation of Fas expression mediated by the NF-κB signaling pathway. (PubMed, Cancer Biol Ther) - "GNA combined with the MCL-1 inhibitor MIK665 potently suppressed the proliferation of MDS cells...GNA-induced apoptosis was attenuated in either p65 KO or Fas KO cells. These results demonstrate that GNA inhibited tubulin polymerization and induced apoptosis of MDS cells through upregulation of Fas expression mediated by the NF-κB signaling pathway, suggesting a chemotherapeutic strategy for MDS by microtubule dynamics disruption."

Journal • Hematological Malignancies • Myelodysplastic Syndrome • Oncology • CASP3 • CASP7

[PREPRINT] Predictors of Response and Rational Combinations for the Novel MCL-1 Inhibitor MIK665 in Acute Myeloid Leukemia (medRxiv) - "We observed that MIK665 sensitive samples had a more differentiated phenotype, whereas resistant samples displayed higher levels of ABCB1 (MDR1) and the anti-apoptotic protein BCL-XL. Further evaluation revealed that ABCB1 expression has good predictive performance in identifying MIK665 primary resistant samples. To induce sensitivity, we treated MIK665-resistant samples with ABCB1 inhibitor elacridar, BCL-XL inhibitor A1331852, or BCL-2 inhibitor venetoclax in combination with MIK665. While combinations with elacridar and A1331852 were not effective, the combination of MIK665 and venetoclax effectively eliminated AML blasts compared to either of the agents alone. Additionally, the combination restored sensitivity of samples with primary venetoclax resistance."

Preclinical • Preprint • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology

Identification of inhibitors of BCL2 family members and glucose metabolism as effective combination partners of belinostat in T-cell lymphoma (TCL) cell lines (EORTC-NCI-AACR 2024) - "Compounds identified from the screen and validated in the same cell lines by combination MTT experiments with increasing concentrations of belinostat were the BCL2 family inhibitor navitoclax, the NAMPT/GLUT inhibitor STF-31 (synergism in all cell lines), the EZH2 inhibitor tazemetostat (synergism: H9 and MAC1; additivity: FE-PD; no benefit: HH), the glucocorticoid agonist dexamethasone (synergism: HH, H9, FE-PD; no benefit: MAC1), the DHFR inhibitor pralatrexate (synergism: MAC1; additivity: H9, FE-PD; no benefit: HH), and the cereblon E3 ligase modulator lenalidomide (synergism: HH; no benefit: H9, FE-PD, MAC1). The robust combination efficacy of navitoclax with belinostat prompted us to test the MCL1 inhibitor MIK-665 (not present in the chemical library), which was synergistic with belinostat in all the cell lines...The epigenetic agent tazemetostat showed at least comparable efficacy to other agents combined with belinostat in the clinic (pralatrexate,..."

Preclinical • Hematological Malignancies • Lymphoma • Oncology • Peripheral T-cell Lymphoma • T Cell Non-Hodgkin Lymphoma • BCL2 • CRBN • DHFR • NAMPT

VOB560-MIK665 Combination First in Human Trial in Patients With Hematological Malignancies (Relapsed/Refractory Non-Hodgkin Lymphoma, Relapsed/Refractory Acute Myeloid Leukemia, or Relapsed/Refractory Multiple Myeloma) (clinicaltrials.gov) - P1 | N=37 | Terminated | Sponsor: Novartis Pharmaceuticals | Active, not recruiting ➔ Terminated; Business reasons

Combination therapy • Trial termination • Acute Myelogenous Leukemia • Hematological Disorders • Hematological Malignancies • Leukemia • Lymphoma • Multiple Myeloma • Non-Hodgkin’s Lymphoma • Oncology

Unveiling the Impact of Diffuse Intrinsic Pontine Glioma (DIPG) on Blood-Brain Barrier Integrity and Drug Penetration (EACR 2024) - "A more potent and selective MCL-1 inhibitor, S64315, also exhibited effects on BBB permeability in vitro, with significant changes to ZO-1 and claudin-5 expression...Toxicity studies have shown that repeated doses of S63845 with temsirolimus over 6 weeks is well tolerated...MCL-1 inhibitors may facilitate delivery of therapeutics by opening the BBB. This discovery has the potential to enhance the efficacy of anti-DIPG therapeutics."

Brain Cancer • CNS Tumor • Diffuse Intrinsic Pontine Glioma • Glioma • Oncology • Pediatrics • Solid Tumor • CLDN5 • TJP1

Phase I/II Trial of S64315 Plus Azacitidine in Acute Myeloid Leukaemia (clinicaltrials.gov) - P1/2 | N=17 | Completed | Sponsor: Institut de Recherches Internationales Servier | Active, not recruiting ➔ Completed | Trial completion date: Mar 2024 ➔ Aug 2023 | Trial primary completion date: Mar 2024 ➔ Aug 2023

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

SYNERGISTIC TARGETING OF BCL-2 AND MCL-1 IN RHABDOMYOSARCOMA (ASPHO 2024) - "The cells were treated with ABT-199, a known BCL-2 inhibitor, and MIK-665, a known MCL-1 inhibitor, both as single agents and in combination. Our findings indicate promising outcomes, particularly in specific subtypes of rhabdomyosarcoma cells, where simultaneous inhibition of BCL-2 and MCL-1 demonstrates synergy and increased cell death. These results could lead to further work with the possibility of new targeted treatment regimens for patients expressing these genetic changes with the hopes of improving patient outcomes. Resources: Kehr S, et.al., Cancer Letters, 2020 Oliveira RC, et."

IO biomarker • Mantle Cell Lymphoma • Oncology • Rhabdomyosarcoma • Sarcoma • Solid Tumor • BCL2

AMPK inhibition sensitizes acute leukemia cells to BH3 mimetic-induced cell death. (PubMed, Cell Death Differ) - "BH3 mimetics, including the BCL2/BCLXL/BCLw inhibitor navitoclax and MCL1 inhibitors S64315 and tapotoclax, have undergone clinical testing for a variety of neoplasms...Building on the observation that BH3 mimetic monotherapy induces AMP kinase (AMPK) activation in multiple acute leukemia cell lines, we report that the AMPK inhibitors (AMPKis) dorsomorphin and BAY-3827 sensitize these cells to navitoclax or MCL1 inhibitors...Conversely, dorsomorphin synergizes with navitoclax or the MCL1 inhibitor S63845 to induce cell death in primary acute leukemia samples ex vivo and increases the antitumor effects of navitoclax or S63845 in several xenograft models in vivo with little or no increase in toxicity in normal tissues. These results suggest that AMPK inhibition can sensitize acute leukemia to multiple BH3 mimetics, potentially allowing administration of lower doses while inducing similar antineoplastic effects."

IO biomarker • Journal • Hematological Disorders • Hematological Malignancies • Leukemia • Oncology • Thrombocytopenia • AMPK • BCL2 • BCL2L1 • BCL2L2

MCL1 inhibition targets Myeloid Derived Suppressors Cells, promotes antitumor immunity and enhances the efficacy of immune checkpoint blockade. (PubMed, Cell Death Dis) - "In this study, we show that the MCL1 inhibitor S64315 reduces melanoma tumor growth in an immune cell-dependent manner in mice...Together, this proof-of-concept study demonstrates the potential of combining an MCL1 inhibitor with anti-PD-1 in the treatment of melanoma. It justifies the further development of next generation MCL1 inhibitors to improve efficacy of ICIs in treating malignant melanoma."

Checkpoint block • Checkpoint inhibition • IO biomarker • Journal • Myeloid-derived suppressor cells • Cutaneous Melanoma • Hematological Disorders • Hematological Malignancies • Melanoma • Oncology • Solid Tumor • BCL2 • CD8

VOB560-MIK665 Combination First in Human Trial in Patients With Hematological Malignancies (Relapsed/Refractory Non-Hodgkin Lymphoma, Relapsed/Refractory Acute Myeloid Leukemia, or Relapsed/Refractory Multiple Myeloma) (clinicaltrials.gov) - P1 | N=37 | Active, not recruiting | Sponsor: Novartis Pharmaceuticals | Trial primary completion date: Dec 2023 ➔ Jun 2024

Combination therapy • Trial primary completion date • Acute Myelogenous Leukemia • Hematological Disorders • Hematological Malignancies • Leukemia • Lymphoma • Multiple Myeloma • Non-Hodgkin’s Lymphoma • Oncology

Dual targeting of Mcl-1 and Bcl-2 to overcome chemoresistance in cervical and colon cancer. (PubMed, Anticancer Drugs) - "This combination also prolonged overall survival compared with using S64315 or venetoclax alone. Our research highlights the therapeutic potential of inhibiting Mcl-1 and Bcl-2 simultaneously in chemoresistant cancers and provides a rationale for initiating clinical trials to investigate the combination of S64315 and venetoclax for the treatment of advanced colon and cervical cancer."

Journal • Cervical Cancer • Colon Cancer • Colorectal Cancer • Gastrointestinal Cancer • Leukemia • Lymphoma • Oncology • Solid Tumor • BCL2 • EIF4E

VOB560-MIK665 Combination First in Human Trial in Patients With Hematological Malignancies (Relapsed/Refractory Non-Hodgkin Lymphoma, Relapsed/Refractory Acute Myeloid Leukemia, or Relapsed/Refractory Multiple Myeloma) (clinicaltrials.gov) - P1 | N=37 | Active, not recruiting | Sponsor: Novartis Pharmaceuticals | Trial completion date: Dec 2023 ➔ Apr 2024

Combination therapy • Trial completion date • Acute Myelogenous Leukemia • Hematological Disorders • Hematological Malignancies • Leukemia • Lymphoma • Multiple Myeloma • Non-Hodgkin’s Lymphoma • Oncology

Phase I/II Trial of S64315 Plus Azacitidine in Acute Myeloid Leukaemia (clinicaltrials.gov) - P1/2 | N=17 | Active, not recruiting | Sponsor: Institut de Recherches Internationales Servier | Trial completion date: Nov 2023 ➔ Mar 2024 | Trial primary completion date: Nov 2023 ➔ Mar 2024

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

Phase I Dose Escalation Study of Intravenously Administered S64315 in Combination With Orally Administered Venetoclax in Patients With Acute Myeloid Leukaemia. (clinicaltrials.gov) - P1 | N=36 | Completed | Sponsor: Institut de Recherches Internationales Servier | Terminated ➔ Completed | Trial completion date: Nov 2022 ➔ May 2023 | Trial primary completion date: Nov 2022 ➔ May 2023

Combination therapy • Trial completion • Trial completion date • Trial primary completion date • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology

Simultaneous Inhibition of Mcl-1 and Bcl-2 Induces Synergistic Cell Death in Hepatocellular Carcinoma. (PubMed, Biomedicines) - "Therefore, we analyzed the efficacy of the two BH3-mimetics ABT-199 (Bcl-2 inhibitor) and MIK665 (Mcl-1 inhibitor) in HCC cell lines with differential expression levels of endogenous Bcl-2 and Mcl-1. Both drugs acted synergistically, highlighting the effectivity of this specific BH3-mimetic combination, particularly in HCC cell lines. These results indicate the potential of combining inhibitors of the BCL-2 family as new therapeutic options in HCC."

IO biomarker • Journal • Gastrointestinal Cancer • Hepatocellular Cancer • Oncology • Solid Tumor • BCL2

VOB560-MIK665 Combination First in Human Trial in Patients With Hematological Malignancies (Relapsed/Refractory Non-Hodgkin Lymphoma, Relapsed/Refractory Acute Myeloid Leukemia, or Relapsed/Refractory Multiple Myeloma) (clinicaltrials.gov) - P1 | N=37 | Active, not recruiting | Sponsor: Novartis Pharmaceuticals | Trial completion date: Sep 2024 ➔ Dec 2023 | Trial primary completion date: Sep 2024 ➔ Dec 2023

Combination therapy • Trial completion date • Trial primary completion date • Acute Myelogenous Leukemia • Hematological Disorders • Hematological Malignancies • Leukemia • Lymphoma • Multiple Myeloma • Non-Hodgkin’s Lymphoma • Oncology