Our Science

MYC proteins play a key role in up to 70% of all human cancers and are implicated in tumorigenesis and therapeutic resistance mechanisms. Specifically, the heterodimer of MYC and related transcription factor MAX regulates several downstream genes primarily involved in the cell cycle. Silencing or inhibition of MYC thus results in resensitization of tumors to extant therapies. Despite the enormous promise of MYC- targeting cancer treatments, there exist no direct small-molecule MYC inhibitors in the
clinic.

Several conceptual and practical difficulties, including MYC’s lack of defined binding “pockets” and potential toxicity to normal tissues have led many to regard MYC as an “undruggable” target. Nevertheless, our team is leveraging evolving computational strategies with unique insights into MYC protein binding and function, in combination with in vivo screening to rapidly identify and evaluate potential inhibitors.

Small-Molecule MYC Inhibitors Suppress Tumor Growth and Enhance Immunotherapy

Summary

Small molecules that directly target MYC and are also well tolerated in vivo will provide invaluable chemical probes and potential anti-cancer therapeutic agents. We developed a series of small-molecule MYC inhibitors that engage MYC inside cells, disrupt MYC/MAX dimers, and impair MYC-driven gene expression. The compounds enhance MYC phosphorylation on threonine-58, consequently increasing proteasome-mediated MYC degradation. The initial lead, MYC inhibitor 361 (MYCi361), suppressed in vivo tumor growth in mice,

A MYC inhibitor selectively alters the MYC and MAX cistromes and modulates the epigenomic landscape to regulate target gene expression

Introduction

MYC functions as a transcription factor that regulates a diverse set of gene networks including ribosome biogenesis, mRNA translation, microRNA regulation, cell cycle progression, DNA replication and repair, immune response, metabolism, and apoptosis (1–3). Dysregulated MYC expression is strongly implicated in tumorigenesis and is a hallmark of various types of cancer (4–6); however, therapeutic targeting of MYC has been challenging due to the difficulty of generating high-quality small-molecule inhibitors for what is an intrinsically disordered protein.

14-3-3 Proof of Concept and Possibilities

Natural compounds, such as the fungal metabolite Fusicoccin-A, are known to stabilize 14-3-3:client interactions and have inspired the creation of synthetic stabilizers that are able to constitute the same effect. These efforts resulted in a systematic understanding of the 14-3-3:client interface. Small-molecule drugs based on various chemotypes — from complex natural products to molecular fragments — can now be deployed to stabilize a range of these complexes. Our team has leveraged its deep understanding of 14-3-3 structure and protein-protein interactions to create a modular platform for discovering these compounds.