Discovery of novel anti-tumor compounds targeting PARP-1 with induction of autophagy through and screening.

Front Pharmacol

Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research, International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of Ministry of Education (MOE) of China, Institute of Traditional Chinese Medicine and Natural Products, College of Pharmacy, Jinan University, Guangzhou, China.

Published: October 2022

Poly (ADP-ribose) polymerase 1 (PARP-1) is a critical enzyme involved in DNA damage repair and recombination, and shows great potential for drug development in the treatment of cancers with defective DNA repair. The anti-tumor activities of PARP-1 inhibitors are regulated by both inhibition activities and allosteric mechanisms of PARP-1, and may also be involved in an autophagy-mediated process. Screening PARP-1 inhibitors with potential allosteric mechanisms and induced autophagy process could achieve elevated potency toward cancer cell killing. In this study, we tried to discover novel anti-tumor compounds targeting PARP-1 by computer simulations and screening. In order to filter PARP-1 inhibitors that could affect the folding state of the helix domain (HD) on PARP-1, the free energy contribution of key residues on HD were systematically analyzed using the ligand-binding crystal structures and integrated into screening workflow for the selection of 20 pick-up compounds. Four compounds (Chemdiv codes: 8012-0567, 8018-6529, 8018-7168, 8018-7603) were proved with above 40% inhibitory ratio targeting PARP-1 under 20 μM, and further performed binding mode prediction and dynamic effect evaluation by molecular dynamics simulation. Further assays showed that compounds 8018-6529 and 8018-7168 could inhibit the growth of the human colorectal cancer cell (HCT-116) with IC50 values of 4.30 and 9.29 μM and were accompanied with an induced autophagy process. Taken together, we discover two novel anti-tumor compounds that target PARP-1 with an induced autophagy process and provide potential hit compounds for the anti-cancer drug development.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9638114PMC
http://dx.doi.org/10.3389/fphar.2022.1026306DOI Listing

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