2. Academic Validation
  3. Multi-Water Bridges Enable Design of BET BD1-Selective Inhibitors for Pancreatic Cancer Therapy

Multi-Water Bridges Enable Design of BET BD1-Selective Inhibitors for Pancreatic Cancer Therapy

  • J Med Chem. 2025 Mar 13;68(5):5719-5735. doi: 10.1021/acs.jmedchem.4c03069.
Xuetao Chen 1 2,  Wenjing Kang 1 2,  Tingting Wu 1 2,  Danyan Cao 3,  Yali Chen 1 2,  Zhiyan Du 3,  Leixin Yan 1 2,  Fanying Meng 1 2,  Xinyue Wang 1 2,  Qidong You 1 2,  Bing Xiong 3,  Xiaoke Guo 1 2,  Zhengyu Jiang 1 2
Affiliations

Affiliations

  • 1 Jiang Su Key Laboratory of Drug Design and Optimization and State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China.
  • 2 Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China.
  • 3 Department of Medicinal Chemistry, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China.
PMID: 40011026 DOI: 10.1021/acs.jmedchem.4c03069
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 KD 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.

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