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

Author:

Kanabar Dipti1ORCID,Kane Emma I2ORCID,Chavan Tejashri1ORCID,Laflamme Taylor M2,Suarez Ethan1,Goyal Mimansa1,Gupta Vivek1ORCID,Spratt Donald E2ORCID,Muth Aaron1ORCID

Affiliation:

1. Department of Pharmaceutical Sciences, College of Pharmacy & Health Sciences, St. John's University, Queens, NY 11439, USA

2. Gustaf H. Carlson School of Chemistry & Biochemistry, Clark University, Worcester, MA 01610, USA

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.

Funder

National Institute of General Medical Sciences

Publisher

Future Science Ltd

Subject

Drug Discovery,Pharmacology,Molecular Medicine

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