Discovery of dual-targeted molecules based on Olaparib and Rigosertib for triple-negative breast cancer with wild-type BRCA.

Autor: Liu Z; Jiangsu Key Laboratory of Regional Specific Resource Pharmaceutical Transformation, Green Chemistry and Process Enhancement Technology, Huaiyin Institute of Technology, Huai'an 223003, China., Mao S; Jiangsu Key Laboratory of Regional Specific Resource Pharmaceutical Transformation, Green Chemistry and Process Enhancement Technology, Huaiyin Institute of Technology, Huai'an 223003, China., Dai L; Jiangsu Key Laboratory of Regional Specific Resource Pharmaceutical Transformation, Green Chemistry and Process Enhancement Technology, Huaiyin Institute of Technology, Huai'an 223003, China; School of Biological and Food Engineering, Huanghuai University, Zhumadian 463000, China., Huang R; Guangxi Key Laboratoryfor Pharmaceutical Molecular Discovery and Druggability Optimization, School of Pharmacy, Guilin Medicinal University, Guilin 541199, China., Hu W; Jiangsu Key Laboratory of Regional Specific Resource Pharmaceutical Transformation, Green Chemistry and Process Enhancement Technology, Huaiyin Institute of Technology, Huai'an 223003, China., Yu C; Jiangsu Key Laboratory of Regional Specific Resource Pharmaceutical Transformation, Green Chemistry and Process Enhancement Technology, Huaiyin Institute of Technology, Huai'an 223003, China., Yang Y; Jiangsu Key Laboratory of Regional Specific Resource Pharmaceutical Transformation, Green Chemistry and Process Enhancement Technology, Huaiyin Institute of Technology, Huai'an 223003, China., Cao G; Jiangsu Key Laboratory of Regional Specific Resource Pharmaceutical Transformation, Green Chemistry and Process Enhancement Technology, Huaiyin Institute of Technology, Huai'an 223003, China. Electronic address: CaoGuoxiu@126.com., Huang X; Jiangsu Key Laboratory of Regional Specific Resource Pharmaceutical Transformation, Green Chemistry and Process Enhancement Technology, Huaiyin Institute of Technology, Huai'an 223003, China. Electronic address: viphuangxc@126.com.
Jazyk: angličtina
Zdroj: Bioorganic & medicinal chemistry [Bioorg Med Chem] 2024 Nov 01; Vol. 113, pp. 117936. Date of Electronic Publication: 2024 Oct 05.
DOI: 10.1016/j.bmc.2024.117936
Abstrakt: PARP inhibitors (PARPis) demonstrate significant potential efficacy in the clinical treatment of BRCA-mutated triple-negative breast cancer (TNBC). However, a majority of patients with TNBC do not possess BRCA mutations, and therefore cannot benefit from PARPis. Previous studies on multi-targeted molecules derived from PARPis or disruptors of RAF-RAF pathway have offered an alternative approach to develop novel anti-TNBC agents. Hence, to broaden the application of PARP inhibitors for TNBC patients with wild-type BRCA, a series of dual-targeted molecules were constructed via integrating the key pharmacophores of Olaparib (Ola) and Rigosertib into a single entity. Subsequent studies exhibited that the resulting compounds 13a-14c obtained potential anti-proliferative activity against BRCA-defected or wild-type TNBC cells. Among them, an optimal compound 13b showed good inhibitory activity toward PARP-1, displayed approximately 34-fold higher inhibitory activity than that of Ola in MDA-MB-231 cells, and exerted multi-functional mechanisms to induce apoptosis. Moreover, 13b displayed superior antitumor efficacy (TGI, 61.3 %) than the single administration of Ola (TGI, 38.5 %), 11b (TGI, 51.8 %) or even their combined administration (TGI, 56.7 %), but did not show significant systematic toxicity. These findings suggest that 13b may serve as a potential candidate for BRCA wild-type TNBC.
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 Ltd. All rights reserved.)
Databáze: MEDLINE
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