Development of VPC-70619, a Small-Molecule N-Myc Inhibitor as a Potential Therapy for Neuroendocrine Prostate Cancer.

Anh-Tien Ton,Jane Foo,Helene Morin,Fuqiang Ban,Anastasia Kalyta,Eric Leblanc,Artem Cherkasov,Joseph Lee,Nada Lallous,Kriti Singh,Carl Perez

doi:10.3390/ijms23052588

Abstract

The Myc family of transcription factors are involved in the development and progression of numerous cancers, including prostate cancer (PCa). Under the pressure of androgen receptor (AR)-directed therapies resistance can occur, leading to the lethal form of PCa known as neuroendocrine prostate cancer (NEPC), characterized among other features by N-Myc overexpression. There are no clinically approved treatments for NEPC, translating into poor patient prognosis and survival. Therefore, there is a pressing need to develop novel therapeutic avenues to treat NEPC patients. In this study, we investigate the N-Myc-Max DNA binding domain (DBD) as a potential target for small molecule inhibitors and utilize computer-aided drug design (CADD) approaches to discover prospective hits. Through further exploration and optimization, a compound, VPC-70619, was identified with notable anti-N-Myc potency and strong antiproliferative activity against numerous N-Myc expressing cell lines, including those representing NEPC.

Highlights

The Myc protein family are transcription factors regulating communication networks within cells by binding to DNA and modulating the expression of numerous genes involved in cell growth and division
We identified a potent compound, VPC-70619, characterized by the same 4cyano-2-(trifluoromethyl)phenyl-benzohydrazide scaffold which anchors the compound into the hydrophobic core of the N-Myc-Max DNA binding domain (DBD) pocket, as well as a 2-chlorobenzonitrile group which clashes with the DNA E-box binding to N-Myc-Max
We determined that N’-[4-Cyano-2-(trifluoromethyl)phenyl]benzohydrazide derivatives developed by computer-aided drug design (CADD) modelling synergized with experimental validation are potent and selective N-Myc inhibitors

Summary

Introduction

The Myc protein family are transcription factors regulating communication networks within cells by binding to DNA and modulating the expression of numerous genes involved in cell growth and division. Dysregulation of Myc, especially N-Myc, is strongly associated with the development of the most resistant malignancies, including neuroendocrine prostate cancer (NEPC) [1–4] for which efficient therapeutic options are limited [5,6]. Development of novel molecules targeting N-Myc onco-driver has a great potential as therapeutic intervention for NEPC [7]. Myc has always been considered a difficult target and often classified as undruggable, due to its intrinsically disordered nature and the lack of distinct binding pockets on its surface [8–11]. Directly blocking Myc transcription might trigger unwanted side effects because of its central role in controlling gene expression in cells [12]. Deployment of cutting-edge computer-aided drug design (CADD) approaches and refined experimental methodologies have been critical in recent years to overcome the challenges of targeting

Methods

Discussion

Conclusion