Structure-based design, synthesis, and evaluation of inhibitors with high selectivity for PARP-1 over PARP-2.
Eur J Med Chem. 2022 Jan 05; 227:113898.EJ

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.

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Publisher Full Text (DOI)

Authors+Show Affiliations

Yu J

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.

Luo L

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.

Hu T

Key Laboratory of Structure-Based Drug Design and Discovery, Shenyang Pharmaceutical University, Ministry of Education, Shenyang, 110016, China.

Key Laboratory of Structure-Based Drug Design and Discovery, Shenyang Pharmaceutical University, Ministry of Education, Shenyang, 110016, China. Electronic address: suntiemin@syphu.edu.cn.

MeSH

Antineoplastic AgentsBRCA1 ProteinCell Line, TumorCell ProliferationDose-Response Relationship, DrugDrug DesignDrug Screening Assays, AntitumorHumansMolecular StructurePoly (ADP-Ribose) Polymerase-1Poly(ADP-ribose) Polymerase InhibitorsPoly(ADP-ribose) PolymerasesStructure-Activity Relationship

Pub Type(s)

Journal Article

Language

eng

PubMed ID

34656898

Citation

Yu, Jiang, et al. "Structure-based Design, Synthesis, and Evaluation of Inhibitors With High Selectivity for PARP-1 Over PARP-2." European Journal of Medicinal Chemistry, vol. 227, 2022, p. 113898.

Yu J, Luo L, Hu T, et al. Structure-based design, synthesis, and evaluation of inhibitors with high selectivity for PARP-1 over PARP-2. Eur J Med Chem. 2022;227:113898.

Yu, J., Luo, L., Hu, T., Cui, Y., Sun, X., Gou, W., Hou, W., Li, Y., & Sun, T. (2022). Structure-based design, synthesis, and evaluation of inhibitors with high selectivity for PARP-1 over PARP-2. European Journal of Medicinal Chemistry, 227, 113898. https://doi.org/10.1016/j.ejmech.2021.113898

Yu J, et al. 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. PubMed PMID: 34656898.

* Article titles in AMA citation format should be in sentence-case

TY - JOUR T1 - Structure-based design, synthesis, and evaluation of inhibitors with high selectivity for PARP-1 over PARP-2. AU - Yu,Jiang, AU - Luo,Lingling, AU - Hu,Tong, AU - Cui,Yating, AU - Sun,Xiao, AU - Gou,Wenfeng, AU - Hou,Wenbin, AU - Li,Yiliang, AU - Sun,Tiemin, Y1 - 2021/10/09/ PY - 2021/08/28/received PY - 2021/09/30/revised PY - 2021/10/01/accepted PY - 2021/10/18/pubmed PY - 2022/1/27/medline PY - 2021/10/17/entrez KW - Cancer KW - PARP-1 inhibitor KW - Rucaparib analogues KW - Selectivity KW - Structure based design SP - 113898 EP - 113898 JF - European journal of medicinal chemistry JO - Eur J Med Chem VL - 227 N2 - 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. SN - 1768-3254 UR - https://www.unboundmedicine.com/medline/citation/34656898/Structure_based_design_synthesis_and_evaluation_of_inhibitors_with_high_selectivity_for_PARP_1_over_PARP_2_ DB - PRIME DP - Unbound Medicine ER -

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Structure-based design, synthesis, and evaluation of inhibitors with high selectivity for PARP-1 over PARP-2.Eur J Med Chem. 2022 Jan 05; 227:113898.EJ