Samuel A. Goldblith Professor of Applied Biology
Associate Professor of Biological Engineering
Institute Member, Broad Institute of MIT and Harvard
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. We use approaches rooted in biology, chemistry, and engineering to achieve our research goals and collaborate routinely with physician scientists."
Professor 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. She is also a co-director of the MIT biomedical engineering undergraduate program and a member of the committee on pre-health advising at MIT. She has served on the Chemists in Cancer Research Executive Advisory Board for AACR. Awards include being named a Genome Technology Young Investigator and a Broad Institute Merkin Fellow. She has also received the Ono Pharma Foundation Breakthrough Science Award, the Novartis Lectureship in Chemistry, the AACR-Bayer Innovation and Discovery Award, and NSF CAREER Award, and the Junior Bose Award for Excellence in Teaching. Professor Koehler is a founder of Ligon Discovery and Kronos Bio, is a member of the scientific advisory board of MS2Array, and has served as an advisor to several other pharmaceutical or biotechnology companies.
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.
Struntz NB, Chen A, Deutzmann A, Wilson RM, Stefan E, Evans HL, Ramirez MA, Liang T, Caballero F, Wildschut MH, Neel DV, Pop MS, McConkey M, Muller S, Curtin BH, Tseng H, Frombach KR, Freeman DB, Butty VL, Levine SS, Feau S, Elmiligy S, Hong JA, Lewis TA, Vetere A, Clemons PA, Malstrom SA, Ebert BL, Lin CY, Felsher DW, Koehler AN, 2019. Stabilization of the Max homodimer with a small molecule attenuates Myc-driven transcription. Cell Chem Biol, published online March 14, 2019, doi: 10.1016/j.chembiol.2019.02.009.
Freeman DB, Richters A, Pop MS, Struntz NB, and Koehler AN. 2018. Emerging non-canonical small-molecule inhibitors of Androgen Receptor (AR) and AR interactome partners for the treatment of castrate-resistant prostate cancer. Medicinal Chemistry Reviews. Vol. 3, Chapter 14, 2018.
Leifer BS, Doyle SK, Richters A, Evans HL, Koehler AN. 2018. An array-based ligand discovery platform for proteins with short half-lives. Methods in Enzymology 610: 191-218.
Richters A, Koehler AN. 2017. Epigenetic Modulation using Small Molecules - Targeting Histone Acetyltransferases in Disease. Curr Med Chem. 24: 4121-4150
Boskovic ZV, Kemp MM, Freedy AM, Viswanathan VS, Pop MS, Fuller JH, Martinez NM, Figueroa Lazú SO, Hong JA, Lewis TA, Calarese D, Love JD, Vetere A, Almo SC, Schreiber SL, Koehler AN. 2016. Inhibition of Zinc-Dependent Histone Deacetylases with a Chemically Triggered Electrophile. ACS Chem Biol 11: 1844–1851.
Yang Z, Koehler AN, Wang L. 2016. A novel small molecule activator of nuclear receptor SHP inhibits HCC cell migration via suppressing Ccl2. Mol Cancer Ther 15: 2294-2301.
Pop MS, Stransky N, Garvie CW, Theurillat JP, Lewis TA, Zhong C, Culyba EK, Lin F, Daniels DS, Pagliarini R, Ronco L, Koehler AN, Garraway LA. 2014. A small molecule that binds and inhibits the ETV1 transcription factor oncoprotein. Mol Cancer Ther. 6: 1492-1502.
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.
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.
Tackling the "Undruggable": Koehler’s presentation at the 2012 edition of the Midsummer Nights’ Science at the Broad Institute series.