MIK665 / Servier, Novartis, HitGen - LARVOL DELTA

A clinically translatable next-generation EVA strategy for glioblastoma: combining eltanexor and BH3-mimetics drives synergistic apoptosis. (EANO 2026) - "Background:Glioblastoma (GB) is characterized by marked aggressiveness, poor clinical outcome, and rapid development of resistance to currently available treatments. Replacing the original Venetoclax/A1210477 backbone with Navitoclax and a clinically advanced MCL-1 inhibitor resulted in substantially enhanced anti-glioblastoma activity and robust synergistic effects, with MIK665 showing superior performance compared with S63845 across experiments. These data support further development of Navitoclax and MIK665 as core components of a next-generation EVA strategy with strong translational potential."

Clinical • Brain Cancer • Glioblastoma • Oncology • Solid Tumor • BCL2 • BCL2L1 • BCL2L2 • CASP3

MCL-1 inhibition triggers a largely reversible cardiac stress signature in a humanised mouse model. (PubMed, Br J Pharmacol) - "Pharmacological MCL-1 inhibition induced a cardiac biomarker and transcriptional stress response characterised by troponin release and dynamic myocardial transcriptomic remodelling. Additional functional and histological analyses did not reveal overt systolic dysfunction, strain-detectable impairment, or increased fibrotic remodelling. These alterations are consistent with a largely reversible cardiac stress response rather than overt structural or functional cardiotoxicity. These findings support the use of refined, humanised preclinical models to improve translational cardiac safety assessment."

Journal • Preclinical • Cardiovascular • Fibrosis • Hematological Malignancies • Leukemia • Oncology

Phase 1 clinical trial of S64315, an intravenous MCL1 inhibitor, in patients with myeloid malignancies. (PubMed, Leuk Lymphoma) - P1 | "Exposure to S64315 increased in a dose-dependent manner between 50 and 500 mg. There were no objective responses to therapy."

Journal • P1 data • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Oncology

Therapeutic development of the clinically active compound ACT001 with Mcl-1 inhibitors for the treatment of paediatric diffuse midline glioma (ISPNO 2026) - P1 | "Mcl-1 inhibitors (MIK665 and AZD5991) showed the strongest synergy consistent with ACT001-mediated suppression of anti-apoptotic signalling...In vivo, ACT001, the Mcl-1 inhibitor S63845, and their combination each extended survival without evidence of synergy in orthotopic DMG models and reduced Ki67-positive tumour cells...Collectively, these findings indicate that ACT001 is a multi-targeted agent that disrupts NF-κB and apoptotic signalling while promoting oxidative stress and the unfolded protein response. Combining ACT001 with inhibitors of anti-apoptotic proteins represents a promising therapeutic strategy for patients with DMG."

Clinical • Brain Cancer • Diffuse Midline Glioma • Glioblastoma • Glioma • Pediatrics • Solid Tumor • NQO1 • RELA

Inhibition of MCL-1-mediated anti-apoptotic signalling as a potential therapeutic strategy for paediatric high-grade gliomas (ISPNO 2026) - P1/2 | "Selective MCL-1 inhibitors (S63845, MIK665, BRD-810) and the BCL-2 inhibitor venetoclax were screened in cytotoxicity assays, with MIK665 showing the greatest efficacy against both HGG and DMG cells. The discovery that MCL-1 inhibition restores H3K27me3 reveals a novel mechanistic link between apoptotic evasion and epigenetic dysregulation. The robust synergy with epigenetic inhibitor CBL-0137 provides a compelling rationale for further preclinical development in DMG and HGG tumours."

IO biomarker • Brain Cancer • CNS Tumor • Diffuse Midline Glioma • Glioma • High Grade Glioma • Mantle Cell Lymphoma • Pediatrics • Solid Tumor • ANXA5 • PDGFRA

The myeloid cell leukaemia-1 inhibitor MIK665 is a potent therapy in preclinical models of paediatric acute myeloid leukaemia. (PubMed, Br J Haematol) - "Bcl-2 homology domain 3 (BH3) mimetics, such as venetoclax (ABT-199), which targets BCL2, have shown promising activity in AML. Additionally, MIK665 showed significant activity against a subset of paediatric AML patient-derived xenografts (PDXs) in both ex vivo and in vivo experiments, with minimal impact on cardiac tissue pathophysiology. These findings strongly support the clinical advancement of MIK665 for paediatric AML treatment in a precision medicine approach."

Journal • Preclinical • Acute Myelogenous Leukemia • B Cell Lymphoma • Hematological Malignancies • Leukemia • Lymphoma • Oncology • Pediatrics • BCL2

Development and characterization of the venetoclax-resistant AML model to enable preclinical drug discovery (AACR 2026) - "Cell viability assays in these resistant cell lines demonstrated strong synergy between Venetoclax and two MCL-1 inhibitors, AMG-176 and MIK665. Interestingly, the MCL-1 inhibitor, MIK665 effectively overcame the resistance in the Ven-R-MV4-11 tumor model when used in combination with Venetoclax and Azacytidine. In conclusion, we have developed two Venetoclax-resistant AML models, which serve as a promising tool for mechanistic research and drug discovery aimed at overcoming the BCL2 inhibitor resistance."

IO biomarker • Preclinical • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology

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

Genome-wide CRISPR and drug screening reveal MCL1 as an actionable target in clear cell sarcoma (Sarcoma-RC 2026) - "The top hit was the BCL2 inhibitor venetoclax showing strong synergism with MIK665. Legal entity responsible for the study The authors. Funding Bayer."

Sarcoma • Solid Tumor • ATF1 • CHEK1 • CREB1 • EWSR1 • HSPA5 • SOX10

The development of ACT001 with Mcl-1 inhibitors as a novel combination therapy for the treatment of paediatric diffuse midline glioma (SNO 2025) - P1 | "Among the strongest were Mcl-1 inhibitors (Mcl1i-MIK665, Mcl1i-AZD5991) consistent with ACT001's mechanism of downregulating anti-apoptotic signaling...In vivo, single-drug treatment of ACT001 or Mcl1i-S63845 extended survival in orthotopic DMG models and significantly reduced the number of Ki67-positive tumor cells...Our findings suggest that ACT001 is a multi-targeted agent acting on NF-κB and apoptotic signalling while inducing oxidative stress. The combination of ACT001 with anti-apoptotic protein inhibitors represents a promising treatment strategy for DMG patients."

Combination therapy • IO biomarker • Brain Cancer • Diffuse Midline Glioma • Glioblastoma • Glioma • Pediatrics • Solid Tumor • BCL2 • NQO1 • SLC7A11 • SOD2

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

The development of ACT001 with Mcl-1 inhibitors as a novel combination therapy for the treatment of paediatric diffuse midline glioma (WFNOS 2025) - P1 | "Among the strongest were Mcl-1 inhibitors (Mcl1i-MIK665, Mcl1i-AZD5991) consistent with ACT001’s mechanism of downregulating anti-apoptotic signaling...In vivo, single-drug treatment of ACT001 or Mcl1i-S63845 extended survival in orthotopic DMG models and significantly reduced the number of Ki67-positive tumor cells...Our findings suggest that ACT001 is a multi-targeted agent acting on NF-κB and apoptotic signalling while inducing oxidative stress. The combination of ACT001 with anti-apoptotic protein inhibitors represents a promising treatment strategy for DMG patients."

Combination therapy • IO biomarker • Brain Cancer • Diffuse Midline Glioma • Glioblastoma • Glioma • Pediatrics • Solid Tumor • BCL2 • NQO1 • SLC7A11 • SOD2

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 Malignancies • Leukemia • Mantle Cell Lymphoma • Oncology • CD34 • CD74 • MIF

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 • First-in-human • P1 data • Acute Myelogenous Leukemia • Anemia • B Cell Lymphoma • Diffuse Large B Cell Lymphoma • Follicular Lymphoma • Hematological Disorders • Leukemia • Lymphoma • Metabolic Disorders • Multiple Myeloma • Nephrology • Neutropenia • Oncology • Renal Disease • Thrombocytopenia • BCL2

Inhibition of BCL-2 and MCL-1 disrupts mitochondrial respiration and overcomes radioresistance in choroidal melanoma. (PubMed, Biochem Biophys Res Commun) - "Combination therapy with venetoclax and the MCL-1 inhibitor MIK665 exhibited strong synergy, resulting in enhanced tumor regression and significantly prolonged survival. These findings demonstrate that dual inhibition of BCL-2 and MCL-1 effectively overcomes radioresistance in choroidal melanoma by disrupting mitochondrial function and promoting apoptosis."

IO biomarker • Journal • Choroidal Melanomas • Melanoma • Ocular Melanoma • Oncology • Solid Tumor • BCL2 • CASP3

Predictors of response and rational combinations for the novel MCL-1 inhibitor MIK665 in acute myeloid leukemia. (PubMed, Mol Oncol) - "To induce sensitivity, we treated MIK665-resistant samples with ABCB1 inhibitors elacridar or tariquidar, BCL-XL inhibitor A1331852, or BCL-2 inhibitor venetoclax in combination with MIK665. Additionally, the combination of MIK665 with venetoclax restored sensitivity in samples with primary venetoclax resistance. Overall, this study indicates that elevated ABCB1 expression is a potentially targetable resistance mechanism in the context of MIK665 resistance, and that a combination of MIK665 with venetoclax may be effective for overcoming resistance to either MCL-1 or BCL-2 inhibition."

IO biomarker • Journal • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • ABCB1 • BCL2L1

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

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

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