Mar 16, 2023 · Multiple preclinical studies have confirmed the potent synergistic activity of combination BCL-2/MDM2 therapy in AML cells and xenograft models. Of note, these models typically employed p53 wildtype AML cells as functional p53 is considered critical for optimal MDM2 antitumor efficacy. 5, 6

Two clinical-stage anticancer drugs, the Bcl-2 inhibitor ABT-263 and the MDM2 inhibitor SAR405838 achieve complete tumor regression in animal models of leukemia but also induce acquired resistance.

Considering the important roles of BCL-2 and BCL-X L and MDM2 played in cancer, we design PROTACs by incorporation of MDM2 inhibitor into a BCL-2/X L inhibitor (e.g., ABT-263) via a linker. Such unique PROTACs may be capable of degrading BCL-X L and/or BCL-2 and meanwhile inhibiting MDM2 and stabilizing the p53 expression.

Nov 15, 2022 · Together, we provide strong evidence that concurrent targeting of MDM2-p53 binding and BCL2/BCLxL leads to potent and synergistic enhancement of apoptotic cell death in a range of high-risk ALL subtypes.

Apr 10, 2024 · Utilizing high-throughput combination screening of 1971 FDA-approved and clinically advanced compounds, we identified BCL-x L /BCL-2 inhibitor navitoclax as the most promising idasanutlin...

Given preclinical rationale, researchers tested the combination of Bcl-2 and MDM2 inhibition (by idasanutlin) in wildtype-AML to boost activity of venetoclax and prevent upfront resistance. Safety and efficacy of venetoclax and idasanutlin has been studied in 39 patients with relapsed refractory elderly AML patients.

Nov 29, 2018 · Drugs that showed pan-ALL efficacy included BCL-2 family inhibitors, idasanutlin (MDM2 inhibitor), luminespib (HSP90 inhibitor), daporinad (NMPRT inhibitor) and plicamycin (antineoplastic antibiotic).

Apr 14, 2016 · Identified by FP, ITC, and NMR spectroscopy, a compound 6e (zq-1) that directly binds to Mcl-1, Bcl-2, and MDM2 with balanced submicromolar affinities was obtained. Cell-based experiments demonstrated its antitumor ability through Bcl-2/MDM2 dual inhibition simultaneously.

Apr 10, 2024 · Here, we demonstrate the potent antileukemic activity of the MDM2 antagonist idasanutlin in high-risk and relapsed ex vivo coculture models of TP53 wildtype ALL (n = 40). Insufficient clinical responses to monotherapy MDM2 inhibitors in other cancers prompted us to explore optimal drugs for combination therapy.

Jun 1, 2015 · Purpose: Two clinical-stage anticancer drugs, the Bcl-2 inhibitor ABT-263, and the MDM2 inhibitor SAR405838 achieve complete tumor regression in animal models of leukemia but also induce acquired resistance.