Karl Van Tassel (1925) Career Development Assistant Professor of Biological Engineering
Ph.D. 2003, Harvard University
KI Research Areas of Focus:
Current Cancer Area of Interest:
B-cell lymphomas, Glioblastoma, Lung cancer, Prostate cancer, Deregulation of transcription in cancer
"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. Can small molecules be used to adjust overactive transcription factors back to activities observed in untransformed cells? Will inactivation of master regulator transcription factors (e.g. c-Myc or NF-kappaB) be an effective approach to treating a broad swath of cancers in which the oncoprotein is aberrantly active and a driver of the malignant phenotype? Or is inhibition of a master regulator too toxic? Will alternative approaches focused on targeting upstream ‘druggable’ signaling enzymes or indirectly modulating transcription of the genes encoding these oncoproteins prove to be more suitable? Where applicable, selected probes are developed into diagnostic tools or therapeutic leads."
Angela Koehler is an Assistant Professor of Biological Engineering at MIT. She received her B.A. in biochemistry and molecular biology from Reed College in 1997 and her Ph.D. in chemistry from Harvard University in 2003. Previously, Koehler was 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.
Research in Koehler’s lab 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.
Izhack Cherny, Maria Korolev, Angela N. Koehler, Michael H. Hecht. “Proteins from an unevolved library of de novo designed sequences bind a range of small molecules.” ACS Synth. Biol., 1, 130-138, 2012.
Melissa M. Kemp, Michel Weïwer, Angela N. Koehler. “Unbiased binding assays for discovering small-molecule probes and drugs.” Bioorg. Med. Chem., 20, 1979-1989, 2012.
Melissa M. Kemp, Qiu Wang, Jason H. Fuller, Nathan West, Nicole Martinez, Elizabeth M. Morse, Michel Weïwer, Stuart L. Schreiber, James E. Bradner, Angela N. Koehler, “A novel HDAC inhibitor with a hydroxy-pyrimidine scaffold.” Bioorg. Med. Chem. Lett., 21, 4164-4169, 2011.
Myung-Soo Kang, Eun Kyung Lee, Vishal Soni, Timothy A. Lewis, Angela N. Koehler, Viswanathan Srinivasana, Elliott Kieff. ‘Roscovitine inhibits EBNA1 Serine 393 phosphorylation, nuclear localization, transcription, and episome maintenance.” J. Virol. 85, 2859-2868, 2011.
Jermont M. Chen, Anne H. Armstrong, Angela N. Koehler, Michael H. Hecht. “Small-molecule microarrays enable the discovery of compounds that bind the Alzheimer’s Abeta peptide and reduce its cytotoxicity.” J. Am. Chem. Soc., 132, 17015-17022, 2010.
Angela N. Koehler. “A complex task? Direct modulation of transcription factors with small molecules.” Curr. Opin. Chem. Biol. 14, Curr. Opin. Chem. Biol., 14, 331-340, 2010.
Arturo J. Vegas, Angela N. Koehler. “Detecting protein-small molecule interactions using fluorous small- molecule microarrays.” Methods Mol. Biol., 669, 43-55, 2010.
Carlos Tassa, Jay L. Duffner, Timothy A. Lewis, Ralph Weissleder, Stuart L. Schreiber, Angela N. Koehler, Stanley Y. Shaw. “Binding affinity and kinetic analysis of targeted small molecule-modified nanoparticles.” Bioconjugate Chemistry, 21, 14-19, 2010.
Katja Schmitz, Stephen J. Haggarty, Olivia M. McPherson, Jon Clardy, Angela N. Koehler. “Detecting binding interactions using microarrays of natural product extracts.” J. Am. Chem. Soc., 129, 11346-11347, 2007.
James E. Bradner, Olivia M. McPherson, Angela N. Koehler. “A method for the covalent capture and screening of diverse small molecules in a microarray format.” Nature Protocols, 1, 2344-2352, 2006.
Search PubMed for Koehler Lab publications
Articles and Media
Tackling the "Undruggable": Koehler’s presentation at the 2012 edition of the Midsummer Nights’ Science at the Broad Institute series.