Photo of Loren D. Walensky,  MD, PhD

Loren D. Walensky, MD, PhD

Dana-Farber Cancer Institute

Dana-Farber Cancer Institute
Phone: (617) 632-6307
Fax: (617) 632-6401

Loren D. Walensky, MD, PhD

Dana-Farber Cancer Institute


  • Associate Professor, Pediatrics, Harvard Medical School
  • Assistant Professor, Pediatric Oncology, Dana-Farber Cancer Institute


Research Abstract

The Walensky laboratory focuses on the chemical biology of deregulated apoptotic and transcriptional pathways in cancer. Our goal is to create an arsenal of new compounds-a “chemical toolbox”-to investigate and block protein interactions that cause cancer. To achieve these objectives, we take a multidisciplinary approach that employs synthetic chemistry techniques, structural biology analyses, and biochemical, cellular, and mouse modeling experiments to systematically dissect the pathologic signaling pathways of interest.

We develop and apply new approaches to chemically stabilize natural peptides so that their shape, and therefore their anti-cancer activities can be restored. Optimizing natural peptides in this way provides alternative compounds to study protein interactions and manipulate biological pathways within cells to treat human disease. For example, we have used a chemical strategy, termed “hydrocarbon-stapling,” to synthesize a panel of pro-apoptotic peptides with markedly improved pharmacological properties. We have demonstrated that the stapled peptides retain their natural shape, are resistant to degradation, and can enter and kill leukemia cells by neutralizing their survival proteins. When administered to mice with leukemia, a stapled peptide modeled after the BH3 death domain of a BCL-2 family protein successfully blocked cancer growth and prolonged the lives of treated animals.

In ongoing studies, we broadly apply the new peptide-stapling strategy to produce a diversity of cancer biology discovery tools, in order to study and deactivate aberrant apoptotic and transcriptional pathways in a variety of human tumors. We emphasize the structural basis for ligand-protein interactions, validation of intracellular targets, characterization of novel protein interactors, analysis of ligand-mediated alteration of signaling pathways in cellular and murine models of disease, in vivo imaging technologies, and clinical translation.


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  • Edwards AL, Wachter F, Lammert M, Huhn AJ, Luccarelli J, Bird GH, Walensky LD. Cellular uptake and ultrastructural localization underlie the pro-apoptotic activity of a hydrocarbon-stapled BIM BH3 peptide. ACS Chem Biol 2015. PubMed
  • Zhang T, Barclay L, Walensky LD, Saghatelian A. Regulation of mitochondrial ceramide distribution by members of the BCL-2 family. J Lipid Res 2015. PubMed
  • Carpio MA, Michaud M, Zhou W, Fisher JK, Walensky LD, Katz SG. BCL-2 family member BOK promotes apoptosis in response to endoplasmic reticulum stress. Proc Natl Acad Sci U S A 2015; 112:7201-6. PubMed
  • Zhang T, Walensky LD, Saghatelian A. A Nonapoptotic Role for BAX and BAK in Eicosanoid Metabolism. ACS Chem Biol 2015. PubMed
  • 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; 57:873-86. PubMed
  • Leshchiner ES, Parkhitko A, Bird GH, Luccarelli J, Bellairs JA, Escudero S, Opoku-Nsiah K, Godes M, Perrimon N, Walensky LD. Direct inhibition of oncogenic KRAS by hydrocarbon-stapled SOS1 helices. Proc Natl Acad Sci U S A 2015; 112:1761-6. PubMed
  • Ljubicic S, Polak K, Fu A, Wiwczar J, Szlyk B, Chang Y, Alvarez-Perez JC, Bird GH, Walensky LD, Garcia-Ocaña A, Danial NN. Phospho-BAD BH3 mimicry protects 硫 cells and restores functional 硫 cell mass in diabetes. Cell Rep 2015; 10:497-504. PubMed
  • Perry JA, Kiezun A, Tonzi P, Van Allen EM, Carter SL, Baca SC, Cowley GS, Bhatt AS, Rheinbay E, Pedamallu CS, Helman E, Taylor-Weiner A, McKenna A, DeLuca DS, Lawrence MS, Ambrogio L, Sougnez C, Sivachenko A, Walensky LD, Wagle N, Mora J, de Torres C, Lavarino C, Dos Santos Aguiar S, Yunes JA, Brandalise SR, Mercado-Celis GE, Melendez-Zajgla J, Cárdenas-Cardós R, Velasco-Hidalgo L, Roberts CW, Garraway LA, Rodriguez-Galindo C, Gabriel SB, Lander ES, Golub TR, Orkin SH, Getz G, Janeway KA. Complementary genomic approaches highlight the PI3K/mTOR pathway as a common vulnerability in osteosarcoma. Proc Natl Acad Sci U S A 2014; 111:E5564-73. PubMed
  • Reynolds C, Roderick JE, LaBelle JL, Bird G, Mathieu R, Bodaar K, Colon D, Pyati U, Stevenson KE, Qi J, Harris M, Silverman LB, Sallan SE, Bradner JE, Neuberg DS, Look AT, Walensky LD, Kelliher MA, Gutierrez A. Repression of BIM mediates survival signaling by MYC and AKT in high-risk T-cell acute lymphoblastic leukemia. Leukemia 2014. PubMed
  • Bird GH, Gavathiotis E, Labelle JL, Katz SG, Walensky LD. Distinct BimBH3 (BimSAHB) Stapled Peptides for Structural and Cellular Studies. ACS Chem Biol 2014; 9:831-7. PubMed
  • Katz SG, Labelle JL, Meng H, Valeriano RP, Fisher JK, Sun H, Rodig SJ, Kleinstein SH, Walensky LD. Mantle cell lymphoma in cyclin D1 transgenic mice with Bim-deficient B cells. Blood 2014; 123:884-93. PubMed
  • Szlyk B, Braun CR, Ljubicic S, Patton E, Bird GH, Osundiji MA, Matschinsky FM, Walensky LD, Danial NN. A phospho-BAD BH3 helix activates glucokinase by a mechanism distinct from that of allosteric activators. Nat Struct Mol Biol 2014; 21:36-42. PubMed
  • Kim W, Bird GH, Neff T, Guo G, Kerenyi MA, Walensky LD, Orkin SH. Targeted disruption of the EZH2-EED complex inhibits EZH2-dependent cancer. Nat Chem Biol 2013; 9:643-50. PubMed
  • Edwards AL, Gavathiotis E, LaBelle JL, Braun CR, Opoku-Nsiah KA, Bird GH, Walensky LD. Multimodal interaction with BCL-2 family proteins underlies the proapoptotic activity of PUMA BH3. Chem Biol 2013; 20:888-902. PubMed
  • Hilgendorf KI, Leshchiner ES, Nedelcu S, Maynard MA, Calo E, Ianari A, Walensky LD, Lees JA. The retinoblastoma protein induces apoptosis directly at the mitochondria. Genes Dev 2013; 27:1003-15. PubMed
  • Walensky LD. Playing FullBAK. Cell Cycle 2013. PubMed
  • Leshchiner ES, Braun CR, Bird GH, Walensky LD. Direct activation of full-length proapoptotic BAK. Proc Natl Acad Sci U S A 2013; 110:E986-95. PubMed
  • Walensky LD. Protein-protein interactions: A PUMA mechanism unfolds. Nat Chem Biol 2013; 9:141-3. PubMed
  • Cohen NA, Stewart ML, Gavathiotis E, Tepper JL, Bruekner SR, Koss B, Opferman JT, Walensky LD. A competitive stapled peptide screen identifies a selective small molecule that overcomes MCL-1-dependent leukemia cell survival. Chem Biol 2012; 19:1175-86. PubMed
  • Takada K, Zhu D, Bird GH, Sukhdeo K, Zhao JJ, Mani M, Lemieux M, Carrasco DE, Ryan J, Horst D, Fulciniti M, Munshi NC, Xu W, Kung AL, Shivdasani RA, Walensky LD, Carrasco DR. Targeted disruption of the BCL9/硫-catenin complex inhibits oncogenic Wnt signaling. Sci Transl Med 2012; 4:148ra117. PubMed
  • Walensky LD. Interview with Loren D Walensky. Future Med Chem 2012; 4:1537-9. PubMed
  • Gavathiotis E, Reyna DE, Bellairs JA, Leshchiner ES, Walensky LD. Direct and selective small-molecule activation of proapoptotic BAX. Nat Chem Biol 2012; 8:639-45. PubMed
  • Walensky LD. Stemming danger with Golgified BAX. Mol Cell 2012; 46:554-6. PubMed
  • 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; 122:2018-31. PubMed
  • Gavathiotis E, Walensky LD. Tracking BAX once its trigger is pulled. Cell Cycle 2011. PubMed
  • Braun CR, Mintseris J, Gavathiotis E, Bird GH, Gygi SP, Walensky LD. Photoreactive stapled BH3 peptides to dissect the BCL-2 family interactome. Chem Biol 2010; 17:1325-33. PubMed
  • Bernal F, Wade M, Godes M, Davis TN, Whitehead DG, Kung AL, Wahl GM, Walensky LD. A stapled p53 helix overcomes HDMX-mediated suppression of p53. Cancer Cell 2010; 18:411-22. PubMed
  • Gavathiotis E, Reyna DE, Davis ML, Bird GH, Walensky LD. BH3-triggered structural reorganization drives the activation of proapoptotic BAX. Mol Cell 2010; 40:481-92. PubMed
  • Bird GH, Madani N, Perry AF, Princiotto AM, Supko JG, He X, Gavathiotis E, Sodroski JG, Walensky LD. Hydrocarbon double-stapling remedies the proteolytic instability of a lengthy peptide therapeutic. Proc Natl Acad Sci U S A 2010; 107:14093-8. PubMed
  • 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; 6:595-601. PubMed
  • 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; 455:1076-81. PubMed
  • Danial NN, Walensky LD, Zhang CY, Choi CS, Fisher JK, Molina AJ, Datta SR, Pitter KL, Bird GH, Wikstrom JD, Deeney JT, Robertson K, Morash J, Kulkarni A, Neschen S, Kim S, Greenberg ME, Corkey BE, Shirihai OS, Shulman GI, Lowell BB, Korsmeyer SJ. Dual role of proapoptotic BAD in insulin secretion and beta cell survival. Nat Med 2008; 14:144-53. PubMed
  • Bird GH,Bernal F,Pitter K,Walensky LD. Synthesis and biophysical characterization of stabilized alpha-helices of BCL-2 domains. Methods Enzymol 2008; 446:369-86. PubMed
  • Pitter K,Bernal F,Labelle J,Walensky LD. Dissection of the BCL-2 family signaling network with stabilized alpha-helices of BCL-2 domains. Methods Enzymol 2008; 446:387-408. PubMed
  • Verdine GL, Walensky LD. The challenge of drugging undruggable targets in cancer: lessons learned from targeting BCL-2 family members. Clin Cancer Res 2007; 13:7264-70. PubMed
  • Bernal F, Tyler AF, Korsmeyer SJ, Walensky LD, Verdine GL. Reactivation of the p53 Tumor Suppressor Pathway by a Stapled p53 Peptide [J. Am. Chem. Soc. 2007, 129, 2456-2457]. J Am Chem Soc 2007; 129:5298. PubMed
  • Oh KJ, Barbuto S, Pitter K, Morash J, Walensky LD, Korsmeyer SJ. A membrane-targeted BID BH3 peptide is sufficient for high potency activation of BAX in vitro. J Biol Chem 2006; 281:36999-7008. PubMed
  • Walensky LD, Pitter K, Morash J, Oh KJ, Barbuto S, Fisher J, Smith E, Verdine GL, Korsmeyer SJ. A stapled BID BH3 helix directly binds and activates BAX. Mol Cell 2006; 24:199-210. PubMed
  • Walensky LD. BCL-2 in the crosshairs: tipping the balance of life and death. Cell Death Differ 2006; 13:1339-50. PubMed
  • Walensky LD, Kung AL, Escher I, Malia TJ, Barbuto S, Wright RD, Wagner G, Verdine GL, Korsmeyer SJ. Activation of apoptosis in vivo by a hydrocarbon-stapled BH3 helix. Science 2004; 305:1466-70. PubMed
  • Letai A, Bassik MC, Walensky LD, Sorcinelli MD, Weiler S, Korsmeyer SJ. Distinct BH3 domains either sensitize or activate mitochondrial apoptosis, serving as prototype cancer therapeutics. Cancer Cell 2002; 2:183-92. PubMed