Chemical Rewiring of Oncogenic Transcription

Many cancers are driven by mutations affecting transcription regulation. Through cancer genome sequencing studies, we understand that these aberrations are pervasive through many layers of gene control. Yet, with few exceptions, this knowledge has not precipitated in effective treatments since pharmacologic inhibition of transcription is often infeasible or functionally inconsequential.To address this limitation, I want to innovate chemical strategies that move beyond loss of function (LOF) approaches. Gene control is organized at the level of proximity. Hence, I hypothesize that transcriptional regulators can be chemically rewired by neomorphic small molecules that recruit functionally opposing gene-regulatory effectors, thereby prompting an acute, deep, and sustained disruption of oncogenic transcriptional circuits. The identification, characterization, and translation of such Neomorphic Transcriptional Compounds (NeoTraCs) will be the subject of the GE|NEomorph proposal. We will focus on NeoTraCs to rewire the repressive PRC2 complex, the p400 chromatin regulator complex, and the non-canonical BAF complex. While these targets have established roles in various cancers, inhibitors are not available or have limited functional impact.To identify NeoTraCs that address these limitations, we will implement a diverse discovery approach that incorporates hypothesis-driven design with phenotypic strategies geared to co-opt undrugged transcriptional effectors via bivalent NeoTraCs, and unligandable effectors via molecular glue-like NeoTraCs. Identified hits will be characterized via multi-omics approaches. Through careful mechanistic investigation, we will deduce general mechanistic principles, understand their impact on oncogenic transcription and investigate associated translational opportunities.GE|NEomorph will significantly advance our ability to understand and disrupt transcriptional dysregulation in cancer and pave the way for novel innovative therapies.