Prof. Angela N Koehler

The Koehler Laboratory builds chemical tools and methods for studying proteins that are dysregulated in cancer, especially those residing within transcriptional regulatory networks. Transcription factors that become overactive in disease are promising yet untested targets for therapeutics. These proteins mediate the excessive transcription of genes whose products are required for tumor growth and metastasis. Unlike enzymes, directly modulating transcription factor function requires specific disruption or recruitment of DNA-protein or protein-protein interactions. The discovery or design of small molecules that disrupt or promote these interactions has thus far proven challenging and the protein class is often perceived to be ‘undruggable.’ While a few successes have been published, the chemical biology community has yet to develop general strategies for directly modulating the function of transcription factors with drug-like small molecules.

Koehler’s team explores a variety of strategies to identify small molecules capable of modulating or degrading transcription factors, often involving remodeling of transcriptional complexes on chromatin. They use newly discovered probes to study the roles of specific oncogenic transcription factors, address therapeutic hypotheses in cancer, and develop selected probes into imaging agents, diagnostic tools, or therapeutic leads. The team is extending their small-molecule approach to other cancer-relevant targets, including RNA-binding proteins and cytokines.