Chemical biology of deregulated apoptotic and transcriptional pathways in cancer.
Mayer Building, Room 664
450 Brookline Avenue
Boston, MA 02215
Lab Size: 15-20
The Walensky laboratory focuses on the chemical biology of deregulated apoptotic and transcriptional pathways in cancer. Our goal is to develop an arsenal of new compounds-a “chemical toolbox”-to investigate and block protein interactions that cause cancer and other diseases. To achieve these objectives, we take a multidisciplinary approach that employs synthetic chemistry, structural biology, and biochemistry, cell biology, and mouse modeling to systematically dissect the pathologic signaling pathways of interest. We have applied a chemical strategy, termed hydrocarbon stapling, to generate highly specific and stable peptidic compounds that preserve the structure of bioactive peptides, maximizing their potential as therapeutic reagents and as novel tools to elucidate biological pathways in normal and diseased tissues. For example, we have synthesized and deployed “stapled” peptides to structurally define the elusive activation sites and trigger mechanisms of essential executioner proteins of the apoptotic pathway, reactivate the p53 tumor suppressor pathway in chemoresistant solid tumors, overcome the apoptotic blockades of chemoresistant hematologic cancer cells, and advance a novel proteomic technology to capture alpha-helical targets and define their interaction sites. We believe that the development of stapled peptides will extend the potential for discovery of novel and unforeseen protein interactions and how they impact health and disease. Indeed, the constructs used to dissect disease pathways can be applied to interrogate them in a cellular context and provide the templates for next generation therapeutics.
Our studies emphasize the chemical, structural, and cellular biology of BCL-2 family proteins. These proteins are master regulators of programmed cell death and, when deregulated, can contribute to a host of human diseases characterized by pathologic cell survival or premature cell death. We believe that by dissecting the protein interactions of this pathway and probing the functional consequences of chemical modulation of the signaling network, new therapeutic strategies will emerge for enhancing or subverting cell survival for therapeutic benefit.
My laboratory is comprised of a diverse group of predoctoral and postdoctoral talent, whose expertise includes chemistry, structural biology, biochemistry, cell biology, immunology, hematopathology, pharmacology, mouse modeling, preclinical testing, and clinical oncology. By attacking clinically-relevant research challenges using a cache of techniques drawn from diverse basic disciplines, we hope to break new ground in our understanding of the protein interactions that govern the critical balance between cellular life and death.
Gavathiotis E, Suzuki M, Davis ML, Pitter K, Bird GH, Katz SG, Tu HC, Kim H, Cheng EH, Tjandra N, Walensky LD. BAX activation is initiated at a novel interaction site. Nature. 2008 Oct 23; 455(7216):1076-81.
Stewart ML, Fire E, Keating AE, Walensky LD. The MCL-1 BH3 helix is an exclusive MCL-1 inhibitor and apoptosis sensitizer. Nat Chem Biol. 2010 Aug; 6(8):595-601.
Bernal F, Wade M, Godes M, Davis TN, Kung AL, Wahl GM, Walensky LD. A stapled p53 Helix overcomes HDMX-mediated suppression of p53. Cancer Cell, 2010, Nov 16; 18: 411-22.
Labelle JL, Katz SG, Bird GH, Gavathiotis E, Stewart ML, Lawrence C, Fisher JK, Godes M, Pitter K, Kung AL, Walensky LD. A stapled BIM peptide overcomes apoptotic resistance in hematologic cancers. J Clin Invest. 2012 Jun 1; 122(6):2018-31.
Gavathiotis E, Reyna DE, Bellairs JA, Leshchiner ES, Walensky LD. Direct and selective small-molecule activation of proapoptotic BAX. Nat Chem Biol. 2012 Jul;8(7):639-45.