2. Academic Validation
  3. Discovery of Potent and Novel Dual PARP/BRD4 Inhibitors for Efficient Treatment of Pancreatic Cancer

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.
Shu-Ping Wang 1,  Yu Li 2,  Shi-Hui Huang 2,  Shi-Qi Wu 2,  Ling-Li Gao 2,  Qin Sun 2,  Qian-Wen Lin 2,  Lei Huang 2,  Liu-Qiong Meng 2,  Yi Zou 2,  Qi-Hua Zhu 2,  Yun-Gen Xu 1 2
Affiliations

Affiliations

  • 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.
PMID: 34813314 DOI: 10.1021/acs.jmedchem.1c01535
Abstract

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.

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