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.

P1, N=6, Completed, University of Illinois at Chicago | Active, not recruiting --> Completed

All patients remained disease-free, with no events of measurable residual disease (MRD) positivity by flow cytometry or molecular analysis documented. These findings preliminarily confirm that venetoclax, cytarabine, and homoharringtonine-based cytoreductive therapy is a safe and effective bridging therapy for allo-HSCT in patients with refractory/relapsed AML and RUNX1::RUNX1T1 fusion gene.

Additionally, HHT inhibits NSCLC migration by modulating epithelial-mesenchymal transition (EMT) signaling. These findings highlight PDIA4 as a critical mediator of HHT efficacy against NSCLC, provide novel insights into PDIA4-associated therapy, and support the translational potential of HHT in NSCLC treatment.

P3, N=308, Not yet recruiting, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine

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.

Crucially, we demonstrate that gossypol binding reduces the overall flexibility of the binding site and that each binding state is characterized by a unique pattern of conformational stabilization across the four pockets. These findings provide an unprecedentedly detailed and dynamic roadmap of the gossypol-Bcl-2 interaction, offering crucial insights for the future structure-based design of next-generation inhibitors.

The combination enhanced the p53 expression. Our findings elucidate the mechanism underlying this synergistic interaction and underscore the potential of p53 status as a predictive biomarker for identifying patients most likely to benefit from HHT and gilteritinib combination therapy.

In luminal cells, EIF1A knockdown and the translation inhibitor homoharringtonine (HHT) both suppress HIF-1α translation and tumor growth, while promoting infiltration of anticancer immune cells including PD-1- T cells and CD163- macrophages...Collectively, this work defines conserved molecular features across PCa subtypes, providing promising insights for clinical management. This study was registered at Clinicaltrials.gov (NCT06834321).

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.

Collectively, these modulators demonstrate PPI druggability and provide chemical probes and lead scaffolds for therapeutic development in cancer, neurodegeneration, infectious disease, and immune disorders.

Herein, guided by the structural features of Sorafenib, the selective Bcl-2 inhibitor Venetoclax, and the selective Mcl-1 inhibitor AZD5991, we designed and synthesized a series of novel Sophocarpine-derived analogues bearing a pyridylethyl moiety via a molecular-hybridization strategy. In parallel, a 3D-QSAR (CoMFA) model was constructed to rationalize the structure-activity relationship and to inform further lead optimization. Collectively, these findings identify S6 as a promising Sophocarpine derivative with a putative dual Bcl-2/Mcl-1 targeting profile, with significant anti-HCC activity and potential for preclinical development.