High affinity and low PARP-trapping benzimidazole derivatives as a potential warhead for PARP1 degraders.
Autor: | Peng X; Institute of Pharmacy and Pharmacology, Cooperative Innovation Center for Molecular Target New Drug Study, College of Pharmacy, Hengyang Medical School, University of South China, Hengyang, China., Li Y; Institute of Pharmacy and Pharmacology, Cooperative Innovation Center for Molecular Target New Drug Study, College of Pharmacy, Hengyang Medical School, University of South China, Hengyang, China., Qu J; Institute of Pharmacy and Pharmacology, Cooperative Innovation Center for Molecular Target New Drug Study, College of Pharmacy, Hengyang Medical School, University of South China, Hengyang, China., Jiang L; Institute of Pharmacy and Pharmacology, Cooperative Innovation Center for Molecular Target New Drug Study, College of Pharmacy, Hengyang Medical School, University of South China, Hengyang, China., Wu K; Department of Pharmacy, Ezhou Central Hospital, Ezhou, Hubei, China., Liu D; Institute of Pharmacy and Pharmacology, Cooperative Innovation Center for Molecular Target New Drug Study, College of Pharmacy, Hengyang Medical School, University of South China, Hengyang, China., Chen Y; Institute of Pharmacy and Pharmacology, Cooperative Innovation Center for Molecular Target New Drug Study, College of Pharmacy, Hengyang Medical School, University of South China, Hengyang, China., Peng J; Institute of Pharmacy and Pharmacology, Cooperative Innovation Center for Molecular Target New Drug Study, College of Pharmacy, Hengyang Medical School, University of South China, Hengyang, China., Guo Y; Institute of Pharmacy and Pharmacology, Cooperative Innovation Center for Molecular Target New Drug Study, College of Pharmacy, Hengyang Medical School, University of South China, Hengyang, China., Cao X; Institute of Pharmacy and Pharmacology, Cooperative Innovation Center for Molecular Target New Drug Study, College of Pharmacy, Hengyang Medical School, University of South China, Hengyang, China. Electronic address: caoxuancx@gmail.com. |
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Jazyk: | angličtina |
Zdroj: | European journal of medicinal chemistry [Eur J Med Chem] 2024 May 05; Vol. 271, pp. 116405. Date of Electronic Publication: 2024 Apr 25. |
DOI: | 10.1016/j.ejmech.2024.116405 |
Abstrakt: | PARPi have been explored and applied in the treatment of various cancers with remarkable efficacy, especially BRCA1/2 mutated ovarian, breast, prostate, and pancreatic cancers. However, PARPi renders inevitable drug resistance and showed high toxicity because of PARP-Trapping with long-term clinic tracking. To overcome the drug resistance and the high toxicity of PARPi, many novel methods have been developed including PROTACs. Being an event-driven technology, PROTACs needs a high affinity, low toxicity warhead with no steric hindrance in binding process. Veliparib shows the lowest PARP-Trapping effect but could hardly to be the warhead of PROTACs because of the strong steric hindrance. Other PARP1 inhibitors showed less steric hindrance but owns high PARP-Trapping effect. Thus, the development of novel warhead with high PARP1 affinity, low PARP1-Trapping, and no steric hindrance would be valuable. In this work, we reserved benzimidazole as the motif to reserve the low PARP1-Trapping effect and substituted the pyrrole by aromatic ring to avoiding the steric hindrance in PARP1 binding cave. Thus, a series of benzimidazole derivates were designed and synthesized, and some biological activities in vitro were evaluated including the inhibition for PARP1 enzyme and the PARP-Trapping effect using MDA-MB-436 cell line. Results showed that the compound 19A10 has higher PARP1 affinity(IC Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. (Copyright © 2024 Elsevier Masson SAS. All rights reserved.) |
Databáze: | MEDLINE |
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