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

Area of Science:

• Biochemistry
• Molecular Biology
• Oncology

Background:

• Pan-BET inhibitors face challenges with on-target toxicities.
• Developing bromodomain (BD)-selective inhibitors is crucial for mitigating these toxicities.
• High-resolution structures are available but designing selective inhibitors remains difficult.

Purpose of the Study:

• To rationally design a potent and orally bioavailable BET BD1-selective inhibitor.
• To elucidate the mechanism enabling BD1 selectivity.
• To evaluate the therapeutic potential of the selective inhibitor in pancreatic cancer models.

Main Methods:

• Utilized a multi-water bridge mechanism involving BD1-specific residues (K91 and D145) for inhibitor design.
• Identified DDO-8958, a potent inhibitor with high selectivity for BRD4 BD1 over BD2.
• Assessed the effects of DDO-8958 on oncogene expression and metabolic pathways in MIA PaCa-2 cells.
• Evaluated in vivo anti-tumor efficacy and combination therapy with 2-DG.

Main Results:

• DDO-8958 demonstrated a K_D of 5.6 nM for BRD4 BD1 and 214-fold selectivity over BD2.
• The inhibitor influenced oncogene expression and oxidative phosphorylation in pancreatic cancer cells.
• In vivo studies showed DDO-8958 inhibited tumor growth and enhanced the efficacy of glycolysis inhibitor 2-DG.

Conclusions:

• Multi-water bridges are effective for designing BD1-selective inhibitors.
• Combined targeting of BD1-induced epigenetic reprogramming and glycolysis offers a novel therapeutic strategy for pancreatic cancer.
• DDO-8958 represents a promising candidate for pancreatic cancer management.