Picture of Sara
Sara Buhrlage, Ph.D.
Assistant Professor of Biological Chemistry and Molecular Pharmacology

The mission of our group is to develop first-in-class inhibitors and prototype drugs for DUBs that can be utilized to pharmacologically validate members of the gene family as new targets for cancer treatment and other diseases.

 Research:

Degradation of cancer causing proteins

The number of biologically validated cancer drug targets far outnumbers the number of pharmacologically and clinically validated drug targets.  A large reason for this disparity is that many cancer targets require modulation of protein-protein interactions typically considerable ‘undruggable.'  To address this problem we identify novel targets and compounds that promote specific degradation of such targets.  Proteins are tagged for degradation post-translationally by the addition of ubiquitin chains, which encode for proteosomal and lysosomal degradation.  Addition and removal of ubiquitin tags on substrates are coordinated by the action of ubiquitin activating, conjugating, and ligating enzymes (E1, E2, E3) and deubiquitylating enzymes (DUB).  A growing number of DUB family members have been shown to rescue oncoproteins from degradation using genetic methods however a lack of potent and selective small molecule inhibitors has hindered pharmacological and clinical validation of DUBs.   DUBs are proteases, a class of enzymes for which clinical stage inhibitors of non-DUB members exist.  The mission of our group is to develop first-in-class inhibitors and prototype drugs for DUBs that can be utilized to pharmacologically validate members of the gene family as new targets for cancer treatment and other diseases. Our approach is to: 1) Execute target, gene family and peptidomimetic approaches to achieve new DUB inhibitors; 2) Screen DUB inhibitor libraries for anti-cancer activities; and 3) Pursue validation and mechanistic work for selected DUBs and compounds.  We are also committed to developing technologies that accelerate ubiquitin system and especially DUB research.  To accomplish these goals we work as a collaborative team of synthetic chemists, biochemists, cell biologists and structural biologists.

Address: 

Dana-Farber Cancer Institute

Longwood Center-3311

450 Brookline Ave

Boston, MA 02215

Publications View
Evaluation of ERK as a therapeutic target in acute myelogenous leukemia.
Authors: Authors: Weisberg E, Meng C, Case A, Sattler M, Tiv HL, Gokhale PC, Buhrlage S, Wang J, Gray N, Stone R, Liu S, Bhagwat SV, Tiu RV, Adamia S, Griffin JD.
Leukemia
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Comparison of effects of midostaurin, crenolanib, quizartinib, gilteritinib, sorafenib and BLU-285 on oncogenic mutants of KIT, CBL and FLT3 in haematological malignancies.
Authors: Authors: Weisberg E, Meng C, Case AE, Sattler M, Tiv HL, Gokhale PC, Buhrlage SJ, Liu X, Yang J, Wang J, Gray N, Stone RM, Adamia S, Dubreuil P, Letard S, Griffin JD.
Br J Haematol
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Deubiquitinases Maintain Protein Homeostasis and Survival of Cancer Cells upon Glutathione Depletion.
Authors: Authors: Harris IS, Endress JE, Coloff JL, Selfors LM, McBrayer SK, Rosenbluth JM, Takahashi N, Dhakal S, Koduri V, Oser MG, Schauer NJ, Doherty LM, Hong AL, Kang YP, Younger ST, Doench JG, Hahn WC, Buhrlage SJ, DeNicola GM, Kaelin WG, Brugge JS.
Cell Metab
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Conformational flexibility and inhibitor binding to unphosphorylated interleukin-1 receptor-associated kinase 4 (IRAK4).
Authors: Authors: Wang L, Ferrao R, Li Q, Hatcher JM, Choi HG, Buhrlage SJ, Gray NS, Wu H.
J Biol Chem
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Discovery of a First-In-Class Covalent Allosteric Inhibitor of SUMO E1 Activating Enzyme.
Authors: Authors: Magin RS, Doherty LM, Buhrlage SJ.
Cell Chem Biol
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Genome-scale CRISPR-Cas9 screen identifies druggable dependencies in TP53 wild-type Ewing sarcoma.
Authors: Authors: Stolte B, Iniguez AB, Dharia NV, Robichaud AL, Conway AS, Morgan AM, Alexe G, Schauer NJ, Liu X, Bird GH, Tsherniak A, Vazquez F, Buhrlage SJ, Walensky LD, Stegmaier K.
J Exp Med
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BTKCys481Ser drives ibrutinib resistance via ERK1/2 and protects BTKwild-type MYD88-mutated cells by a paracrine mechanism.
Authors: Authors: Chen JG, Liu X, Munshi M, Xu L, Tsakmaklis N, Demos MG, Kofides A, Guerrera ML, Chan GG, Patterson CJ, Meid K, Gustine J, Dubeau T, Severns P, Castillo JJ, Hunter ZR, Wang J, Buhrlage SJ, Gray NS, Treon SP, Yang G.
Blood
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Structure-Guided Development of a Potent and Selective Non-covalent Active-Site Inhibitor of USP7.
Authors: Authors: Lamberto I, Liu X, Seo HS, Schauer NJ, Iacob RE, Hu W, Das D, Mikhailova T, Weisberg EL, Engen JR, Anderson KC, Chauhan D, Dhe-Paganon S, Buhrlage SJ.
Cell Chem Biol
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Crystal structure of human IRAK1.
Authors: Authors: Wang L, Qiao Q, Ferrao R, Shen C, Hatcher JM, Buhrlage SJ, Gray NS, Wu H.
Proc Natl Acad Sci U S A
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Identification of an allosteric benzothiazolopyrimidone inhibitor of the oncogenic protein tyrosine phosphatase SHP2.
Authors: Authors: LaRochelle JR, Fodor M, Ellegast JM, Liu X, Vemulapalli V, Mohseni M, Stams T, Buhrlage SJ, Stegmaier K, LaMarche MJ, Acker MG, Blacklow SC.
Bioorg Med Chem
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