9iv5

Publication Abstract from PubMed

Rational design of bromodomain (BD)-selective inhibitors could mitigate on-target toxicities associated with pan-BET inhibition but is challenging despite the availability of high-resolution structures. By simultaneously forming water bridges with BD1-specific residues in both the BC ring and the ZA channel, we identified a potent and orally bioavailable BET BD1-selective inhibitor DDO-8958, which exhibited a K(D) of 5.6 nM for BRD4 BD1 and a 214-fold selectivity for BRD4 BD1 over BD2. The cocrystal structure demonstrated a unique multi-water bridge mechanism involving BD1-specific residues K91- and D145-driven BD1 selectivity. DDO-8958 extensively influenced the oncogene expression and metabolic pathway, including oxidative phosphorylation in MIA PaCa-2. In vivo, DDO-8958 inhibited tumor growth and markedly augmented the therapeutic efficacy of the glycolysis inhibitor 2-DG. These findings illuminate that multi-water bridges enable design of BD1-selective inhibitors and a therapeutic strategy involving combined targeting of BD1-induced epigenetic reprogramming and glycolysis pathways for the management of pancreatic cancer.

Multi-Water Bridges Enable Design of BET BD1-Selective Inhibitors for Pancreatic Cancer Therapy.,Chen X, Kang W, Wu T, Cao D, Chen Y, Du Z, Yan L, Meng F, Wang X, You Q, Xiong B, Guo X, Jiang Z J Med Chem. 2025 Mar 13;68(5):5719-5735. doi: 10.1021/acs.jmedchem.4c03069. Epub , 2025 Feb 26. PMID:40011026^[3]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.