Bibliographic Details
| Title: |
Multi-Water Bridges Enable Design of BET BD1-Selective Inhibitors for Pancreatic Cancer Therapy |
| Authors: |
Chen, Xuetao, Kang, Wenjing, Wu, Tingting, Cao, Danyan, Chen, Yali, Du, Zhiyan, Yan, Leixin, Meng, Fanying, Wang, Xinyue, You, Qidong, Xiong, Bing, Guo, Xiaoke, Jiang, Zhengyu |
| Source: |
Journal of Medicinal Chemistry; 20250101, Issue: Preprints |
| Abstract: |
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 KDof 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-8958extensively influenced the oncogene expression and metabolic pathway, including oxidative phosphorylation in MIA PaCa-2. In vivo, DDO-8958inhibited 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. |
| Database: |
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