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The Chemical Biology Initiative provides molecular solutions to problems posed by cancer, fostering basic biological discoveries and the translation of these discoveries into new drugs for cancer patients.
The scientific programs of Chemical Biology Initiative's core investigators focus on:
Members of the Chemical Biology Initiative have numerous collaborations with investigators from other Dana-Farber integrative centers, Harvard-affiliated hospitals, and the Broad Institute. Our team includes:
Nathanael Gray, PhDLab WebsitePubMed
The Gray Laboratory is focused on developing inhibitors for mutant forms of protein kinases often found in cancer. Using kinase-focused libraries designed by structure-guided methods, coupled with kinome-wide selectivity profiling, the Gray lab develops first-in-class chemical inhibitors. They form collaborative teams with cell biologists and translational researchers in the Longwood Medical area and beyond, to further the development of their molecules.
Michael Eck, MD, PhDLab WebsitePubMed
Michael Eck and his laboratory employ biochemical and structural methods, including X-ray crystallography to define the molecular interactions that underlie cytoplasmic signal transduction. They are especially interested in determining the structure of signaling complexes that underlie cancer, and in use structural approaches to facilitate development of anti-cancer drugs.
Active areas of investigation include the structural biology of integrins, focal adhesion kinase (FAK), and Src-family kinases in the regulation of cytoskeletal rearrangements. The Eck Lab also studies the cytoplasmic signaling interactions that control antigen-dependent T-cell activation, and the interactions of the transcription factor Tcf4 with beta-catenin, a driving force in the development of colon cancer.
Loren Walensky, MD, PhDLab WebsitePubMed
The Walensky Laboratory studies deregulated apoptotic and transcriptional pathways in cancer. They develop 'stapled peptides' that preserve the structure of biologically active proteins as chemical probes to target the BCL2 family. Using this approach with structural studies, biochemical and cellular assays they have identified the trigger site on BAX and characterized the activation mechanism of BAK. They are conducting structure-function studies to understand the role BCL2 family member proteins play in chemoresistance.
Haribabu Arthanari, PhDPubMed
Protein-Protein Interactions (PPIs) is the Holy Grail of therapeutic intervention, offering a plethora of unique structural landscapes as potential targets. Research in the Arthanari group uses structure-guided approaches to characterize and validate these interactions in the context of disease models. We utilize a combination of techniques including NMR spectroscopy, NMR-based fragment and high throughput screening, and biophysical and cell-based assays to map hotspots in the interaction interface, to further understand the molecular mechanisms orchestrated by these interactions, and to identify disruptive inhibitors that may be developed into treatments for the related pathologies. Current areas of focus include:
Sara Buhrlage, PhDLab WebsitePubMed
Researchers in the Buhrlage group are focused on the development of novel inhibitors and prototype drugs for deubiquitinylases (DUBs). DUBs are involved in the maintenance of protein homeostasis, and several DUB family members have been shown to rescue oncogenic proteins from degradation. The Buhrlage Lab finds new DUB inhibitors, screens them for anti-cancer activity and validates their mechanism of action. They collaborate extensively with biochemists, synthetic chemists, cell biologists, and structural biologists.
Eric Fischer, PhDLab WebsitePubMed
Eric Fischer and his trainees use structural biology, cell biology, and biochemical approaches to investigate the molecular mechanisms of multi-component ubiquitin ligases and their role in cancer. Armed with this knowledge, the Fischer Lab seeks to propose and test new avenues of therapeutic intervention.
Jun Qi, PhDPubMed
The Qi group designs and synthesizes novel small molecule inhibitors of epigenetic chromatin modification and transcriptional activation, which are dysregulated in cancer. Using a multidisciplinary approach that includes synthetic and medicinal chemistry, chemical biology, and biology, the group seeks understanding of the biological relevance of these epigenetic targets in cancer – with the goal of developing tool and lead compounds to establish rationale for human clinical investigation.
Justin Kim, PhD
Research in the Kim laboratory is focused on the development of new chemical tools for chemical biology and total synthesis applications. In particular, the Kim lab explores the development of chemical agents that can be activated specifically in microenvironments unique to tumor cells without interfering with native biochemical processes. The development of these modular, environmentally-responsive components should have far-ranging applications to the development of intracellular probes for imaging and drugs against cancer.
View a selection of recent publications from investigators in the Chemical Biology Initiative:
Nishikawa JL, Boeszoermenyi A, Vale-Silva LA, Torelli R, Posteraro B, Sohn YJ, Ji F, Gelev V, Sanglard D, Sanguinetti M, Sadreyev RI, Mukherjee G, Bhyravabhotla J, Buhrlage SJ, Gray NS, Wagner G, Näär AM, Arthanari H. Inhibiting fungal multidrug resistance by disrupting an activator-Mediator interaction. Nature 2016 Feb 25; 530(7591):485-9. PMID: 26886795.
Cavadini, S., Fischer, E.S., Bunker, R.D., Potenza, A., Lingaraju, G.M., Goldie, K.N., Mohamed, W.I., Faty, M., Petzold, G., Beckwith, R.E.J., Tichkule, R., Hassiepen, U., Abdulrahman, W., Pantelic, R.S., Matsumoto, S., Sugasawa, K., Stahlberg, H., Thomä, N.H. Cullin-RING ubiquitin E3 ligase regulation by the COP9 signalosome. Nature 2016; 531(7596):598-603.
Tan L, Akahane K, McNally R, Reyskens KM, Ficarro SB, Liu S, Herter-Sprie GS, Koyama S, Pattison MJ, Labella K, Johannessen L, Akbay EA, Wong KK, Frank DA,
Marto JA, Look TA, Arthur JS, Eck MJ, Gray NS. Development of Selective Covalent Janus Kinase 3 Inhibitors. J Med Chem. 2015 Aug 27; 58(16):6589-606. PubMed PMID: 26258521; PubMed Central PMCID: PMC4777322.
Barclay LA, Wales TE, Garner TP, Wachter F, Lee S, Guerra RM, Stewart ML,
Braun CR, Bird GH, Gavathiotis E, Engen JR, Walensky LD. Inhibition of
Pro-apoptotic BAX by a noncanonical interaction mechanism. Mol Cell. 2015 Mar
5; 57(5):873-86 PubMed PMID: 25684204; PubMed Central PMCID: PMC4384643.
Ritorto MS, Ewan R, Perez-Oliva AB, Knebel A, Buhrlage SJ, Wightman M, Kelly
SM, Wood NT, Virdee S, Gray NS, Morrice NA, Alessi DR, Trost M. Screening of DUB
activity and specificity by MALDI-TOF mass spectrometry. Nat Commun. 2014 Aug
27; 5:4763. PubMed PMID: 25159004; PubMed Central PMCID: PMC4147353.
Filippakopoulos P, Qi J, Picaud S, Shen Y, Smith WB, Fedorov O, Morse EM, Keates T, Hickman TT, Felletar I, Philpott M, Munro S, West N, Cameron MJ, Heightman TD, Thangue NL, Kung AL, French CA, Wiest O, Knapp S, Bradner JE. Selective inhibition of BET bromodomains. Nature, 2010; 468, 1067-1073. PMCID: PMC3010259
If you are interested in collaborating with our Chemical Biology investigators — or in finding out more about the research being conducted by the Chemical Biology Initiative — please contact Nathanael Gray, PhD, at firstname.lastname@example.org.
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