Assistant Professor of Biological Engineering
KI Research Areas of Focus:
"Our laboratory focuses on building chemical tools and methods for studying deregulated transcription in cancer. We discover and develop small molecules that directly bind and modulate ‘undruggable’ transcription factors or their protein partners. We also aim to develop modulators of enzymes that regulate the post-translational modifications that govern transactivation or protein stability of these factors. These small-molecule probes may be used to address specific therapeutic questions, and where applicable, selected probes are developed into diagnostic tools or therapeutic leads."
Professor Koehler is an assistant professor of biological engineering at MIT and an intramural member of the Koch Institute. She is also an associate member of the Broad Institute, and a member of the MIT Center for Precision Cancer Medicine. Koehler earned her bachelor’s degree in biochemistry and molecular biology from Reed College in 1997. In 2003, she finished her doctorate in chemistry from Harvard University and became an institute fellow at the Broad Institute, where she served as the director of transcriptional chemical biology in the Chemical Biology Program. She was also a project leader in the NCI Cancer Target Discovery and Development Center at the Broad Institute aimed at targeting causal cancer genes with small molecules. Professor Koehler joined the Koch Institute in 2014, where she serves as faculty co-director of the Swanson Biotechnology Center High-Throughput Screening Facility. Koehler also serves on the Chemistry in Cancer Research Working Group steering committee for the American Association for Cancer Research. Her recent awards include the Novartis Lectureship in Chemistry, the Ono Pharma Breakthrough Science Initiative Award, and being named a Genome Technology Young Investigator.
Research in the Koehler laboratory is focused on building chemical tools and methods for studying temporal aspects of transcriptional regulation in development and cancer. 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 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 proven challenging 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 with drug-like small molecules.
Koehler’s team is developing a general approach to direct and indirect small-molecule probe discovery for transcription factors by coupling direct binding assays with functional assays involving transcriptional and other phenotypic readouts. They use newly discovered probes to study the precise roles of specific oncogenic transcription factors and to address therapeutic hypotheses in cancer. Selected probes may be developed into imaging agents, diagnostic tools, or therapeutic leads.
Richters A, Koehler AN. 2017. Epigenetic Modulation using Small Molecules - Targeting Histone Acetyltransferases in Disease. Curr Med Chem.
Boskovic ZV, Kemp MM, Freedy AM, Viswanathan VS, Pop MS, Fuller JH, Martinez NM, Figueroa Lazú SO, Hong JA, Lewis TA, et al. 2016. Inhibition of Zinc-Dependent Histone Deacetylases with a Chemically Triggered Electrophile. ACS Chem Biol 11: 1844–1851.
Pop MS, Wassaf D, Koehler AN. 2014. Probing small-molecule microarrays with tagged proteins in cell lysates. Curr Protoc Chem Biol 6: 209–220.
Casalena DE, Wassaf D, Koehler AN. 2012. Ligand discovery using small-molecule microarrays. Methods Mol Biol 803: 249–263.
Kemp MM, Weïwer M, Koehler AN. 2012. Unbiased binding assays for discovering small-molecule probes and drugs. Bioorg Med Chem 20: 1979-1989.
Kemp MM, Wang Q, Fuller JH, West N, Martinez NM, Morse EM, Weïwer M, Schreiber SL, Bradner JE, Koehler AN. 2011. A novel HDAC inhibitor with a hydroxy-pyrimidine scaffold. Bioorg Med Chem Lett 21: 4164–4169.
Vegas AJ, Koehler AN. 2010. Detecting protein-small molecule interactions using fluorous small-molecule microarrays. Methods Mol Biol 669: 43–55.
Schmitz K, Haggarty SJ, McPherson OM, Clardy J, Koehler AN. 2007. Detecting binding interactions using microarrays of natural product extracts. J Am Chem Soc 129: 11346–11347.
Bradner JE, McPherson OM, Koehler AN. 2006. A method for the covalent capture and screening of diverse small molecules in a microarray format. Nat Protoc 1: 2344–2352.
Bradner JE, McPherson OM, Mazitschek R, Barnes-Seeman D, Shen JP, Dhaliwal J, Stevenson KE, Duffner JL, Park SB, Neuberg DS, et al. 2006. A robust small-molecule microarray platform for screening cell lysates. Chem Biol 13: 493–504.
Tackling the "Undruggable": Koehler’s presentation at the 2012 edition of the Midsummer Nights’ Science at the Broad Institute series.