navitoclax (ABT 263)

P1, N=17, Active, not recruiting, City of Hope Medical Center | Trial completion date: Apr 2026 --> Mar 2027 | Trial primary completion date: Apr 2026 --> Mar 2027

The CDK4/6 inhibitors abemaciclib and palbociclib have demonstrated promising results in patient-derived xenograft models of PM...While some cells showed sensitivity to Bcl-xL inhibitors, neither navitoclax nor the specific Bcl-xL inhibitor A-1331852, nor other BH3 mimetics targeting Bcl-2 (venetoclax) or Mcl-1 (S63845) increased cell death when combined with palbociclib...Therefore, we employed inhibitors of these pathways, such as dasatinib, momelotinib or Torin-1, which did not synergise with palbociclib to kill the cells...The differential effects of palbociclib and cisplatin on permanent growth arrest were verified by sorting PM cells based on size and β-galactosidase activity. Our findings underscore the importance of understanding the nature of therapy-induced senescence when assessing the effectiveness of senolytics in different tumour models.

This study identifies eight EMT-related prognostic genes in PTC and highlights their potential value as biomarkers for prognostic evaluation and therapeutic stratification.

Overall, ABT-263 therapy partially mitigates influenza severity in aged mice, primarily through dampening acute and chronic inflammation. Most of these effects were age-dependent, suggesting a role for pre-existing senescent cells.

A first milestone was the discovery of ABT-263 (navitoclax), a dual BCL-2/BCL-xL inhibitor. Building on this achievement, the development of venetoclax, a highly selective BCL-2 inhibitor, marked a major breakthrough, demonstrating potent pro-apoptotic activity and clinical efficacy in several leukaemia subtypes. Despite these advances, the design of inhibitors of BCL-2 family members remains challenging, largely due to the structural characteristics of the BH3-binding groove, which is both shallow and hydrophobic, complicating the identification of molecules with optimal binding affinity and selectivity. PROTACs targeting BCL-xL may represent a promising future strategy, potentially overcoming the intrinsic limitations of small molecule inhibitors.

Background: BH3 mimetics (such as venetoclax and navitoclax) are increasingly investigated in the context of the "one-two punch" anticancer strategy, wherein senescence-inducing therapies are combined with senolytic clearance. In FAERS, venetoclax combined with senescence-inducing chemotherapy shows stronger reporting signals for leukopenia and multi-lineage cytopenias and for several serious outcome categories compared with monotherapy. These reporting patterns highlight the need for further care in terms of clinical implementation of the currently investigated senolytics prior to the consideration of the "one-two punch" strategy.

Three parallel genome-wide CRISPR-Cas9 knockout screens were conducted in DDLPS cells to sensitize to palbociclib (CDK4 inhibitor), nutlin-3a (MDM2 inhibitor) or doxorubicin...Genetic perturbation of TDP2 or pharmacological inhibition of DNA-PKcs using peposertib synergized with prolonged administration of low-dose doxorubicin to induce cell cycle arrest and senescence, and subsequent senolytic treatment with Bcl2 inhibitor navitoclax triggered senescent cells to undergo apoptosis...These findings provide a rationale for targeting the NHEJ pathway to enhance the efficacy of low-dose doxorubicin in DDLPS, highlighting a potential therapeutic strategy exploiting p53-mediated cell cycle arrest and senescence. Furthermore, this study provides evidence of maintained baseline p53 activity in MDM2-amplified DDLPS.

Early "first-generation" senolytics, including navitoclax (ABT-263) and the dasatinib-quercetin (D + Q) combination, provided proof-of-concept that selective removal of SnCs can alleviate certain fibrotic, metabolic, and cardiovascular pathologies in preclinical studies. These approaches offer potentially more targeted and personalized therapeutic options but face significant challenges, including immunopathology, manufacturing complexity, off-target effects, and long-term safety concerns. The ongoing shift from broad inhibition to precision reprogramming represents a promising but preliminary step in the treatment of age-related diseases.

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.

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.

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.