S63845

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.

We combined A-1331852 and S63845 with IKE or RSL3 (ferroptosis-inducing drugs). These data indicate that BCL-xL maintains ChRCC cell survival by suppressing apoptosis. The BCL-xL-specific PROTAC DT2216, currently in clinical trials, may provide an opportunity for ChRCC therapy.

Stress induced catecholamines confer S63845 resistance in AML through β-AR signaling. Critically, β2-AR blockade by propranolol downregulates MCL-1 expression, potentiating S63845 sensitivity in vitro and in vivo. Our findings establish pharmacological β-AR blockade as a promising strategy to overcome resistance in MCL-1-targeted therapy by abrogating compensatory MCL-1 upregulation.

Patients often develop resistance to next-generation hormonal therapies that target the AR-axis (e.g., abiraterone, enzalutamide)...Combinations targeting Bcl-xL (A-1331852 and navitoclax) and Mcl-1 (S63845) synergistically decreased cell viability and induced apoptotic activity via cleavage of PARP, caspase 3, and caspase 7 across AR-V7 expressing CRPC cell lines (LNCaP95, VCaP-CR, 22Rv1) and a patient-derived organoid model (LuCaP 167 CR)...We showed similar synergistic efficacy with the Bcl-xL targeting PROTAC in combination with S63845 in the 3D spheroid models. Our findings support further preclinical development of Bcl-xL and Mcl-1 inhibitors for mCRPC.

Parthenolide was used in combination with S63845, ABT-263 and ABT-199, BH3-mimetics targeting anti-/pro-apoptotic protein interactions. Mechanistically, parthenolide combined with S63845 reduces the protein level of MCL-1, upregulates pro-apoptotic NOXA, and prevents S63845-induced reduction of NOXA protein. Collectively, massive apoptosis induced synergistically by parthenolide combined with S63845 in trametinib-resistant melanoma cells displaying various phenotypes justifies exploring the potential of this strategy as a future treatment option for patients with melanoma resistant to therapies targeting MAPK signaling.

Venetoclax (Vtx) (as a model anticancer drug) is combined with an anticancer anthracycline drug, doxorubicin (Dox), or a myeloid cell leukemia-1 inhibitor drug (S63845) to form spherical, submicrometer-sized (∼200-1000 nm in diameter) particles, consisting predominantly of the drug molecules stabilized by hydrophobic interactions. Microscopy analysis of tumor tissues confirmed greater tissue damage and apoptosis induced by the NDs than those induced by the free drugs. The present findings highlight the potential of sono-driven assembled carrier-free systems in anticancer combination therapy, combining the advantages of a high surface area and slow-release particulate system with the synergistic action of multiple drugs to combat drug resistance.

While the effect of S63845 is mediated by both BAX and BAK in most cases, BAX, rather than BAK, acts as the primary mediator of BCLXLi in GC cells...Mechanistically, anti-mitotic chemotherapies induce MCL1 degradation via the ubiquitin-proteasome pathway mainly through FBXW7, whereas HER2-targeting drugs suppress MCL1 transcription via the STAT3/SRF axis. The combination of the STAT3 inhibitor and BCLXL inhibitor also exhibits synergistic killing, extending beyond HER2-amplified GC.

Furthermore, in vivo, combination of S63845, a selective Mcl-1 inhibitor, with tumor-nectrosis factor-related, apoptosis-induncing ligand (TRAIL) peptide reduces tumor growth, but only in tumors expressing VDAC2. Thus, we describe mitochondrial molecular fingerprint that discriminates liver from hepatocarcinoma and allows sparing normal tissue while targeting tumors.