A Novel Inhibitor L755507 Efficiently Blocks C-Myc-MAX Heterodimerization and Induces Apoptosis in Cancer Cells

Overview

Journal J Biol Chem

Specialty Biochemistry

Date 2021 Jun 22

PMID 34157284

Citations 11

Authors

Ashutosh Singh

Ankur Kumar

Prateek Kumar

Namyashree Nayak

Taniya Bhardwaj

Rajanish Giri

Neha Garg

Affiliations

Soon will be listed here.

Abstract

c-Myc is a transcription factor that plays a crucial role in cellular homeostasis, and its deregulation is associated with highly aggressive and chemotherapy-resistant cancers. After binding with partner MAX, the c-Myc-MAX heterodimer regulates the expression of several genes, leading to an oncogenic phenotype. Although considered a crucial therapeutic target, no clinically approved c-Myc-targeted therapy has yet been discovered. Here, we report the discovery via computer-aided drug discovery of a small molecule, L755507, which functions as a c-Myc inhibitor to efficiently restrict the growth of diverse Myc-expressing cells with low micromolar IC values. L755507 successfully disrupts the c-Myc-MAX heterodimer, resulting in decreased expression of c-Myc target genes. Spectroscopic and computational experiments demonstrated that L755507 binds to the c-Myc peptide and thereby stabilizes the helix-loop-helix conformation of the c-Myc transcription factor. Taken together, this study suggests that L755507 effectively inhibits the c-Myc-MAX heterodimerization and may be used for further optimization to develop a c-Myc-targeted antineoplastic drug.

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