Discovery of Potent and Novel Dual PARP/BRD4 Inhibitors for Efficient Treatment of Pancreatic Cancer
- J Med Chem. 2021 Dec 9;64(23):17413-17435. doi: 10.1021/acs.jmedchem.1c01535.
- 1. State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, 211198 Nanjing, China.
- 2. Jiangsu Key Laboratory of Drug Design and Optimization, Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 210009, China.
Targeting poly(ADP-ribose) polymerase1/2 (PARP1/2) is a promising strategy for the treatment of pancreatic Cancer with breast Cancer susceptibility gene (BRCA) mutation. Inducing the deficiency of homologous recombination (HR) repair is an effective way to broaden the indication of PARP1/2 inhibitor for more patients with pancreatic Cancer. Bromodomain-containing protein 4 (BRD4) repression has been reported to elevate HR deficiency. Therefore, we designed, synthetized, and optimized a dual PARP/BRD4 Inhibitor III-16, with a completely new structure and high selectivity against PARP1/2 and BRD4. III-16 showed favorable synergistic antitumor efficacy in pancreatic Cancer cells and xenografts by arresting cell cycle progression, inhibiting DNA damage repair, and promoting autophagy-associated cell death. Moreover, III-16 reversed Olaparib-induced acceleration of cell cycle progression and recovery of DNA repair. The advantages of III-16 over Olaparib suggest that dual PARP/BRD4 inhibitors are novel and promising agents for the treatment of advanced pancreatic Cancer.