Chemistry

Small-Molecule Gankyrin Inhibition as a Therapeutic Strategy for Breast and Lung Cancer

Document Type

Article

Abstract

Gankyrin is an oncoprotein responsible for the development of numerous cancer types. It regulates the expression levels of multiple tumor suppressor proteins (TSPs) in liver cancer; however, gankyrin's regulation of these TSPs in breast and lung cancers has not been thoroughly investigated. Additionally, no small-molecule gankyrin inhibitor has been developed which demonstrates potent anti-proliferative activity against gankyrin overexpressing breast and lung cancers. Herein, we are reporting the structure-based design of gankyrin-binding small molecules which potently inhibited the proliferation of gankyrin overexpressing A549 and MDA-MB-231 cancer cells, reduced colony formation, and inhibited the growth of 3D spheroids in an in vitro tumor simulation model. Investigations demonstrated that gankyrin inhibition occurs through either stabilization or destabilization of its 3D structure. These studies shed light on the mechanism of small-molecule inhibition of gankyrin and demonstrate that gankyrin is a viable therapeutic target for the treatment of breast and lung cancer.

Publication Title

Journal of Medicinal Chemistry

Publication Date

7-14-2022

Volume

65

Issue

13

First Page

8975

Last Page

8997

ISSN

0022-2623

DOI

10.1021/acs.jmedchem.2c00190

Keywords

assays, cancer, cell physiology, cells, peptides and proteins

Cross Post Location

Student Publications

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