Chemistry

Synthesis and evaluation of 2,5-substituted pyrimidines as small-molecule gankyrin binders

Document Type

Article

Abstract

Background: Gankyrin is an ankyrin-repeat protein that promotes cell proliferation, tumor development and cancer progression when overexpressed. Aim: To design and synthesize a novel series of gankyrin-binding small molecules predicated on a 2,5-pyrimidine scaffold. Materials & methods: The synthesized compounds were evaluated for their antiproliferative activity, ability to bind gankyrin and effects on cell cycle progression and the proteasomal degradation pathway. Results: Compounds 188 and 193 demonstrated the most potent antiproliferative activity against MCF7 and A549 cells, respectively. Both compounds also demonstrated the ability to effectively bind gankyrin, disrupt proteasomal degradation and inhibit cell cycle progression. Conclusion: The 2,5-pyrimidine scaffold exhibits a novel and promising strategy for binding gankyrin and inhibiting cancer cell proliferation. © 2024 Future Medicine Ltd.. All rights reserved.

Publication Title

Future Medicinal Chemistry

Publication Date

3-1-2024

Volume

16

Issue

3

First Page

239

Last Page

251

ISSN

1756-8919

DOI

10.4155/fmc-2023-0124

Keywords

breast cancer, gankyrin, lung cancer, protein-protein interactions, tumor suppressor proteins

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