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

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.

Automated summary

The Myc family of transcription factors plays a crucial role in the development and progression of various cancers, including prostate cancer. Neuroendocrine prostate cancer, a lethal form of PCa, lacks effective treatment options. Therefore, there is an urgent need to explore new therapeutic approaches for treating patients with neuroendocrine prostate cancer. In this study, a potential small molecule inhibitor targeting the N-Myc-Max DNA binding domain was discovered through computer-aided drug design, showing promising anti-N-Myc and antiproliferative activities.