The Koehler lab is focused on building chemical tools and methods for studying temporal aspects of transcriptional regulation in development and disease with a focus on cancer. The lab pursues these goals by discovering and developing direct small-molecule probes of proteins involved in transcriptional regulation such as transcription factors and chromatin modifying enzymes.
Transcription factors that become overactive in disease are promising yet untested targets for therapeutics. For example, these proteins mediate the excessive transcription of genes whose products are required for tumor growth and metastasis. Unlike enzymes, directly modulating the function of a transcription factor requires specific disruption or recruitment of DNA-protein or protein-protein interactions. The discovery or design of small molecules that specifically disrupt or promote these interactions has thus far been a significant challenge and the protein class is often perceived to be ‘undruggable.’ While a handful of successes have been published, the chemical biology community has yet to develop general and systematic strategies for directly modulating the function of transcription factors in cells using small molecules. Our team is developing a general approach to small-molecule probe discovery for transcription factors by coupling direct binding assays with functional assays involving transcriptional and other phenotypic readouts. Examples of probe discovery targets include several proteins involved in regulating MYC-driven transcription, transcription factors such as HOXB13 and FOXA1 that particpate in remodeling the androgen receptor cistrome in metastatic prostate cancer, and oncogenic fusion proteins involving transcription factors such as MYB-NFIB, a gene fusion linked to adenoid cystic carcinoma (ACC), or PAX3-FOXO1, a fusion protein with clinical significance in rhabdomyosarcoma (RMS).
The group also seeks to identify small-molecule probes of enzymes that regulate the acetylation status of these oncogenic transcription factors. Several transcription factors are non-histone substrates of chromatin modifying enzymes. The mechanistic consequences of acetylation status for transcription factors is not well understood but evidence suggests that these marks affect protein half-life and stable association with chromatin, among other functions. We have an interest in identifying small-molecule probes that distinguish between histone and non-histone substrates for deacetylases. We use a variety of biochemical and cellular approaches to identify compounds that serve as selective probes of function for specific HDACs or that selectively alter acetylation status of specific transcription factors in cells. Specifically, we have an interest in identifying allosteric probes of functions distinct from enzymatic activities, such as protein-protein interactions involving cofactors or other members of the transcriptional machinery.
The interdisciplinary nature of the projects in our group enables training in several disciplines relevant to cancer chemical biology. Each project provides opportunities for training in organic chemistry, biochemistry, cell biology, and pharmacology. Some projects also provide opportunities to learn about high-throughput screening and informatics (bio- and chem-). Interested trainees should contact Dr. Koehler directly at firstname.lastname@example.org. Current postdoctoral fellow openings in the lab are focused on synthetic and medicinal chemistry, chemical biology, and cell biology. Interested fellows should send a copy of their CV and cover letter summarizing previous training experiences and future training goals.
High-throughput screens involve known bioactives, FDA-approved drugs, natural products, and products of diversity-oriented synthesis.
"Midsummer Nights' Science: Tackling the "Undruggable""
Broad Institute Midsummer Nights' Science series, Broad Institute, 2013.