5XSR

novel orally efficacious inhibitors complexed with PARP1

Summary for 5XSR

• Entry DOI: 10.2210/pdb5xsr/pdb
• Descriptor: Poly [ADP-ribose] polymerase 1, 6-fluoranyl-2-(4,5,6,7-tetrahydrothieno[2,3-c]pyridin-2-yl)-1~{H}-benzimidazole-4-carboxamide, SULFATE ION, ... (4 entities in total)
• Functional Keywords: complex structure, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Homo sapiens (Human)
• Cellular location: Nucleus : P09874
• Total number of polymer chains: 1
• Total formula weight: 40088.74

Authors

Liu, Q.,Xu, Y. (deposition date: 2017-06-15, release date: 2018-04-25, Last modification date: 2024-10-16)

Primary citation

Chen, X.,Huan, X.,Liu, Q.,Wang, Y.,He, Q.,Tan, C.,Chen, Y.,Ding, J.,Xu, Y.,Miao, Z.,Yang, C.
Design and synthesis of 2-(4,5,6,7-tetrahydrothienopyridin-2-yl)-benzoimidazole carboxamides as novel orally efficacious Poly(ADP-ribose)polymerase (PARP) inhibitors
Eur J Med Chem, 145:389-403, 2018

PubMed Abstract: The nuclear protein poly(ADP-ribose) polymerases-1/2 (PARP-1/2) are involved in DNA repair damaged by endogenous or exogenous process. And PARP-1/2 inhibitors have been proved to be clinically efficacious for DNA repair deficient tumors in the past decade. We have developed a series of 4,5,6,7-tetrahydrothienopyridin-2-yl benzimidazole carboxamides as novel and potent PARP-1/2 inhibitors. The best compound resulted from this series is compound 27 which displays excellent PARP-1 and PARP-2 inhibitory activity with IC of 18 nM and 42 nM, respectively. Furthermore, it can selectively kill BRCA2 deficient V-C8 cells with a CC of 920 nM. In the MDA-MB-436 (BRCA-1 mutant) xenograft model, this compound was well tolerated and showed single-agent activity. Based on the results above, compound 27 has been selected as a lead candidate targeting PARP-1/2 and its preclinical characterization is also underway.

PubMed: 29335205
DOI: 10.1016/j.ejmech.2018.01.018

Experimental method

X-RAY DIFFRACTION (2.3 Å)