2. Academic Validation
  3. Structure-based design, synthesis, and evaluation of inhibitors with high selectivity for PARP-1 over PARP-2

Structure-based design, synthesis, and evaluation of inhibitors with high selectivity for PARP-1 over PARP-2

  • Eur J Med Chem. 2022 Jan 5;227:113898. doi: 10.1016/j.ejmech.2021.113898.
Jiang Yu 1,  Lingling Luo 2,  Tong Hu 3,  Yating Cui 2,  Xiao Sun 2,  Wenfeng Gou 2,  Wenbin Hou 4,  Yiliang Li 5,  Tiemin Sun 6
Affiliations

Affiliations

  • 1 Key Laboratory of Structure-Based Drug Design and Discovery, Shenyang Pharmaceutical University, Ministry of Education, Shenyang, 110016, China; Tianjin Key Laboratory of Radiation Medicine and Molecular Nuclear Medicine, Institute of Radiation Medicine, Peking Union Medical College & Chinese Academy of Medical Sciences, Tianjin, 300192, China.
  • 2 Tianjin Key Laboratory of Radiation Medicine and Molecular Nuclear Medicine, Institute of Radiation Medicine, Peking Union Medical College & Chinese Academy of Medical Sciences, Tianjin, 300192, China.
  • 3 Key Laboratory of Structure-Based Drug Design and Discovery, Shenyang Pharmaceutical University, Ministry of Education, Shenyang, 110016, China.
  • 4 Tianjin Key Laboratory of Radiation Medicine and Molecular Nuclear Medicine, Institute of Radiation Medicine, Peking Union Medical College & Chinese Academy of Medical Sciences, Tianjin, 300192, China. Electronic address: [email protected].
  • 5 Tianjin Key Laboratory of Radiation Medicine and Molecular Nuclear Medicine, Institute of Radiation Medicine, Peking Union Medical College & Chinese Academy of Medical Sciences, Tianjin, 300192, China. Electronic address: [email protected].
  • 6 Key Laboratory of Structure-Based Drug Design and Discovery, Shenyang Pharmaceutical University, Ministry of Education, Shenyang, 110016, China. Electronic address: [email protected].
PMID: 34656898 DOI: 10.1016/j.ejmech.2021.113898
Abstract

The poly (ADP-ribose) polymerase (PARP) inhibitors play a crucial role in Cancer therapy. However, most approved PARP inhibitors have lower selectivity to PARP-1 than to PARP-2, so they will inevitably have side effects. Based on the different catalytic domains of PARP-1 and PARP-2, we developed a strategy to design and synthesize highly selective PARP-1 inhibitors. Compounds Y17, Y29, Y31 and Y49 showed excellent PARP-1 inhibition, and their IC50 values were 0.61, 0.66, 0.41 and 0.96 nM, respectively. Then, Y49 (PARP-1 IC50 = 0.96 nM, PARP-2 IC50 = 61.90 nM, selectivity PARP-2/PARP-1 = 64.5) was proved to be the most selective inhibitor of PARP-1. Compounds Y29 and Y49 showed stronger inhibitory effect on proliferation in BRCA1 mutant MX-1 cells than in other Cancer cells. In the MDA-MB-436 xenotransplantation model, Y49 was well tolerated and showed remarkable single dose activity. The design strategy proposed in this paper is of far-reaching significance for the further construction of the next generation of selective PARP-1 inhibitors.

Keywords

Cancer; PARP-1 inhibitor; Rucaparib analogues; Selectivity; Structure based design.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-144642
    PARP-1 Inhibitor