Venetoclax, navitoclax, and obatoclax represented significant advances in apoptosis-targeted therapy, with venetoclax emerging as the most clinically successful agent. However, resistance mechanisms and side effects were significant challenges, necessitating further preclinical and clinical studies to optimize the therapeutic potential of these agents.

Nine inhibitors (i.e., venetoclax, navitoclax; and seven previously prioritized BCL-2 hit inhibitors by our research group) are profiled across solvent systems, including neat DMSO, 10% DMSO, and a ternary matrix (S3: 10% DMSO, 90% sulfobutylether-β-cyclodextrin (SBE-β-CD) in saline). Comparisons with time-resolved fluorescence energy transfer (TR-FRET) analysis, in vitro assays, and MM/GBSA binding free energy results confirmed DSC's accuracy in detecting binding energetics. Collectively, these results position DSC as a robust, material-efficient tool for thermodynamic screening of BCL-2 ligands and other poorly soluble compounds, and as a practical complement to isothermal titration calorimetry when solubility or kinetic limitations prevail.

Drug sensitivity prediction indicated that high-risk patients may respond better to agents such as Tozasertib and Navitoclax. This study establishes a robust, demethylation-driven six-gene signature that effectively stratifies HCC patients into distinct prognostic groups. The model integrates multi-omic insights into tumor biology and therapeutic vulnerability, providing a clinically actionable framework for personalized risk assessment and treatment planning in hepatocellular carcinoma.

Inhibition of UBE3A combined with the senolytic agent ABT‑263 induced apoptosis and inhibited tumor growth. The UBE3A/mH2A1/TERT axis enhances the anti-senescence capacity of pancreatic cancer cells and drives malignant progression, suggesting that UBE3A may serve as a novel therapeutic target for pancreatic cancer.

cGAS-STING pathway can guide risk stratification and can be considered as a therapeutic target for ESCC patients, which provides novel insights into precision and personalized medicine for ESCC patients.

P1, N=24, Not yet recruiting, M.D. Anderson Cancer Center

These findings suggest that administration of venetoclax has the potential to enhance suppression of doxorubicin-exposed cancer cells, and that it may have potential as that of Bcl-xL-targeting agents. However, given the variable outcomes in the two triple-negative breast tumor cell lines, it becomes incumbent to identify the factors that confer susceptibility to Bcl- 2 targeting agents in anticipation of their potential utilization in the clinic for combination therapy in solid tumors.

Inflachromene, an inhibitor of the chromatin remodelers HMGB1/2, decoupled mitochondrial bioenergetics from senolytic susceptibility, yielding SASP-null/miR146a-negative senescent cancer cells that were completely resistant to ABT-263/navitoclax and A1331852 despite extensive mitochondrial reprogramming. Thus, the senolytic response is governed by a layered circuit in which mitochondrial bioenergetic heritage establishes the senolytic ceiling, TIS-acquired bioenergetic flexibility fine-tunes the amplitude of the senolytic response, and establishing a mitochondria-inflammatory SASP crosstalk is required for BH3-mediated senolysis. These results support using functional readouts that integrate mitochondrial metabolic flexibility and inflammatory SASP to predict and potentially enhance senolytic efficacy in TIS cancer cells.

These findings highlight a central role for CXCR2-mediated signaling in the development of radioresistance in HPV-negative HNSCC cells.

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

In this study, in addition to the induction of apoptosis, the use of PARPis (olaparib and niraparib) as maintenance therapies inhibited cell proliferation by causing cellular senescence to exert potent anticancer effects on Capan-1 (BRCA mutated) and PANC-1 (BRCA wild-type) cells...The inhibition of Bcl-2 through the sequence-dependent combination of navitoclax enhanced the anticancer effects of PARPis by removing senescent cells. Collectively, data from our study demonstrate that the clinical application of PARPis as maintenance therapy could be achieved through the induction of cellular senescence. Furthermore, sequence-dependent combination with senescence-targeting drugs can potentiate pancreatic cancer treatment effects of PARPis regardless of the BRCA status.

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.