S63845

Our results elucidate quantitative pharmacodynamics of S63845, venetoclax, and cirtuvivint, an agent that is currently being evaluated with venetoclax to treat AML (NCT06484062). Compensatory increases in off-target Bim heterodimer levels in response to either S63845 or venetoclax offer a possible mechanism of clinical drug resistance.

Furthermore, single-agent treatment of S63845 resulted in significant suppression of tumor growth in patient-derived xenografts of SMARCA4/2-deficient NSCLC and SCCOHT. Collectively, our work uncovered MCL1 as a synthetic lethal target in SMARCA4/2-deficient cancers that may be exploited therapeutically.

In this study, we report the presence of residual drug-tolerant persister (DTP) and resistant lymphoma cells remaining within a highly immunogenic tumor microenvironment (TME) induced by the MCL-1 inhibitor (MCL-1i) S63845...Together, these findings highlight a synergistic, dual-pronged therapeutic strategy targeting both tumor-intrinsic survival pathways and the immunosuppressive TME. This combinatorial one-two-punch approach offers a promising path to eliminate DTP and residual disease, prevent relapse and pave the way for deep clinical remissions in aggressive B-cell lymphomas.

Cells were treated with VEN, the MCL-1 inhibitor S63845 and the mitogen-activated protein kinase (MEK) inhibitor trametinib (TRA), alone or in combination. The presented results highlight the role of MAPK-driven MCL-1 and BCL(x)L expression, which mediates VEN resistance. While dual inhibition of B-cell lymphoma 2 and MCL-1 is already effective, additional MEK inhibition may further improve outcomes in PTPN11-mutated AML.

Our findings provide new insights for combination therapy including Bcl-xL degradation for melanoma treatment.

Alterations in cellular metabolism have also accompanied the development of this resistance. We have shown that combining the Mcl-1 antagonist S63845 with various anticancer compounds can overcome the resistance of malignant cells to its action.

Pharmacological inhibition of MCL-1 with S63845 disrupts mitochondrial ultrastructure, leading to swollen mitochondria with disorganized cristae and destabilization of the OPA1-MICOS machinery that governs inner membrane architecture...Together, our findings identify MCL-1 as a modulator of cristae organization, linking lipid metabolism to neural progenitor fate. This work establishes mitochondrial inner membrane architecture as an instructive determinant of human neurogenesis and highlights the non-canonical MCL-1 functions as critical regulators of human brain development.

The FRET-HBTDS method was performed on the FRETscope with a 20× objective for the cells co-expressing CFP-Bcl-xL and YFP-Bak to assess the action of eight compounds (A1331852, S63845, AC, DSF/Cu, Met, REGO, SOFA, ABT199) on the interaction between Bcl-xL and Bak. Our data firmly demonstrate that A1331852 unlocks the binding state of Bcl-xL and Bak, while DSF/Cu modifies the structure of the Bcl-xL-Bak complex. These findings demonstrate that FRET-HBTDS can be used to assess the efficacy of a drug by revealing the binding state and complex molecular structure of the target proteins using FRET technology in living cells, which may be a potential targeted drug screening method.

Mnt deletion provoked the apoptosis of MLL::AF9 AML cells in vitro and increased apoptosis elicited by the BH3 (BCL-2 homology region 3) mimetic drugs S63845 (MCL-1 (Myeloid cell leukemia-1) specific), ABT-199/Venetoclax (BCL-2 (B-cell lymphoma-2) specific), and A-1331852 (BCL-XL (B-cell lymphoma-extra large) specific). Of note, inducing MNT deletion in a human MLL-rearranged AML cell line transplanted into NSG (NOD SCID Gamma) mice debulked established leukemia and significantly extended the survival of transplant recipients. Taken together with previous studies that demonstrated a critical role for MNT in the development and sustained expansion of B and T lymphomas, our results suggest that a small molecule inhibiting MNT function may be a valuable therapeutic agent for myeloid and lymphoid malignancies.

The results showed that ENKTL cells were more sensitive to BDA-366 than other small-molecule inhibitors, such as ABT-199, S63845 and Chidamide. In conclusion, as a BCL-2 BH4 domain antagonist, BDA-366 exhibited potent anti-tumor effect on ENKTL cells both in vitro and in vivo by triggering mitochondria-mediated apoptosis through suppressing NF-κB signaling pathway. Therefore, BDA-366 is a promising drug to treat ENKTL and overcome chemotherapy resistance.

The structural foundations for the design of MCL-1 inhibitors are revisited, the pharmacological profiles of the leading drugs (S63845, AZD5991, AMG 176) in advanced clinical development are summarized, and emerging strategies, such as combination therapies with inhibitors of anti-apoptotic proteins such as BCL-2, PROTAC strategies designed to degrade MCL-1, and reversible-binding chemotypes to maximize MCL-1 inhibition and minimize toxicity, are reviewed. The key to clinical success will be to carefully develop more intensive dosing regimens, rationally combine agents, and develop trial designs that prioritize the evaluation of new agents that maximize antitumor activity without the risk of off-target toxicities. Continued translational research and adaptive clinical trials are critical to fully realize the therapeutic potential of MCL-1 inhibition across various cancer contexts.

Combining the PAK4 inhibitor KPT-9274 with the MCL-1 antagonist S63845 induces synergistic lethality in AML cells. These findings provide the mechanistic insight of MYC stabilization in AML and establish a PAK4 inhibition-based targeted strategy as a promising therapeutic approach for AML treatment.