P2, N=61, Not yet recruiting, First People's Hospital of Hangzhou

Moreover, Gossypol exhibited cytotoxic effects on human breast, prostate, and colorectal cancer cell lines, at least partially through downregulating the oncogenic substrates of targeted DUBs such as c-Myc, Mcl-1, MDM2, and Cyclin D1. Collectively, our findings position Gossypol as a promising small-molecule inhibitor targeting DUBs, especially USPs, and provide a rationale for further exploring its therapeutic potential in USP-driven cancers.

P2, N=35, Not yet recruiting, Second Affiliated Hospital, School of Medicine, Zhejiang University

KEGG analysis suggested that the toxic mechanisms may be linked to pathways involved in malignancy, the HIF-1 signaling pathway, proteoglycans in cancer, apoptosis, and others. Gossypol demonstrates a significant therapeutic effect against cervical cancer; however, its hepatotoxicity risk, mediated through multiple targets and pathways, requires further investigation.

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.