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.

P2, N=65, Completed, First Affiliated Hospital of Zhejiang University | Recruiting --> Completed | N=30 --> 65 | Trial primary completion date: Aug 2025 --> Apr 2025

The three natural products showed potent to significant activity, effectively inducing apoptosis in the HL-60 cell line. Hence, this study identifies three potential lead candidates for drug discovery against Bcl-2-related cancers after further mechanistic and pre-clinical studies.

Our study uncovers a "C1orf35-driven" energy metabolism model in MM cells, providing new insights into the pathogenesis of MM and a potential novel target for the treatment of cancer cells with a high"C1orf35-driven" anabolic metabolism. Schematic diagram of C1orf35 simultaneously promotes glycolysis and OXPHOS.

P=N/A, N=40, Not yet recruiting, the First Affiliated Hospital, Zhejiang University School of Medicine; The People's Hospital Affiliated to Ningbo University

SRSF2 mutations promoted DNR resistance through multiple mechanisms, and targeted combination therapy with PDGFB pathway inhibitors may represent a novel strategy to improve therapeutic outcomes in patients with mutations.

Pathway and perturbation analyses suggested that NCI-LYM-1 harbored a strong dependency on apoptotic pathways, which was confirmed by in vitro organoid testing with the BCL-2/BCL-xL inhibitor navitoclax (IC 50 : 0.27 µM) and the MCL-1 inhibitor AZD-5991 (IC 50 : 0.060 µM). Overall, NCI-LYM-1 recapitulates the clinical aggressiveness and heterogeneity of AVPC, providing a tractable platform to identify novel precision therapies.

P2 exhibited a ∼10-fold increase in antiproliferative potency against human leukemic cell lines compared to homoharringtonine (HHT)...Our findings provide valuable insights to guide the future structural optimization of harringtonine derivatives. Furthermore, P2 has been identified as a promising anti-leukemic candidate and warrants further development.

Drug sensitivity analysis indicated that H-R patients were more sensitive to Staurosporine and Sabutoclax, whereas L-R patients were more sensitive to dihydrorotenone and osimertinib. RT-qPCR validated differential mRNA expression between KIRC and normal cells. This six-LRPMR-based prognostic model provides valuable insights for prognosis assessment and personalized treatment selection in KIRC.

In vivo, the anti-leukemic efficacy of HHT was significantly diminished upon EWSR1 knockdown, demonstrating that EWSR1 was required for therapeutic response. Collectively, these findings uncover a phase separation-centric mechanism by which HHT exerts anti-AML activity, establish the EWSR1-YTHDF2-m6A axis as a critical regulator of leukemia progression, and position EWSR1 as both a functional target and a predictive biomarker for optimizing HHT-based therapies.

This study highlights the value of computational drug repurposing platforms for accelerating therapeutic discovery. Further preclinical investigations are warranted to evaluate HHT's in vivo efficacy and clinical applicability in RPF.

Our study demonstrates the utility of cancer organoids in drug discovery and identifies HHT as a promising therapeuticagent for ATC.