Photo of Sara Buhrlage,  PhD

Sara Buhrlage, PhD

Dana-Farber Cancer Institute

Dana-Farber Cancer Institute
Phone: (617) 632-1963


saraj_buhrlage@dfci.harvard.edu

Sara Buhrlage, PhD

Dana-Farber Cancer Institute

EDUCATIONAL TITLES

  • Assistant Professor, Biological Chemistry and Molecular Pharmacology, Harvard Medical School
  • Assistant Professor, Cancer Biology, Dana-Farber Cancer Institute

DF/HCC PROGRAM AFFILIATION

Research Abstract

Dr. Sara Buhrlage is an Assistant Professor in Dana-Farber’s Cancer Biology Department and HMS’s Biological Chemistry and Molecular Pharmacology Department. Sara completed a Ph.D. in organic chemistry in 2008, under the direction of Prof. Anna Mapp, from the University of Michigan where she successfully designed, synthesized and characterized small molecules that bind the transcriptional co-activator CBP and upregulate transcription when tethered to DNA. Following completion of her Ph.D. Sara trained for two years in medicinal chemistry at the Broad Institute. There she led a team of 6 chemists performing lead optimization on a macrocycle inhibitor of the hedgehog protein which resulted in analogs with superior potency, improved metabolic stability, excellent in vivo pharmacokinetics and no in vitro safety liabilities. In 2010 she joined the medicinal chemistry core at Dana-Farber Cancer Institute as a staff scientist where she quickly advanced from an entry level position to Lead Scientist, the highest non-academic track position within the Institute, before accepting a faculty appointment. In the core group Sara collaborated with cancer biologists and clinicians to pharmacologically validate novel targets of disease in vitro and in vivo and study mechanisms of disease and drug resistance. During her time in this group, Sara co-authored 12 publications and wrote 10 funded grant applications allowing the medicinal chemistry core to be financially independent less than four years after opening. In sum, Sara has established herself as leader in inhibiting ‘undruggable’ cancer targets using both direct and indirect methods. In her independent position she is using this expertise to study the regulation of proteostasis via the ubiquitin proteasome system, with a focus on deubiquitylating enzymes (DUBs) and cancer oncoproteins.

Publications from Harvard Catalyst Profiles

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  • Varca AC, Casalena D, Auld D, Buhrlage SJ. Identification of deubiquitinase inhibitors via high-throughput screening using a fluorogenic ubiquitin-rhodamine assay. STAR Protoc 2021; 2:100896. PubMed
  • Chan WC, Sharifzadeh S, Buhrlage SJ, Marto JA. Chemoproteomic methods for covalent drug discovery. Chem Soc Rev 2021; 50:8361-8381. PubMed
  • Yang J, Weisberg EL, Liu X, Magin RS, Chan WC, Hu B, Schauer NJ, Zhang S, Lamberto I, Doherty L, Meng C, Sattler M, Cabal-Hierro L, Winer E, Stone R, Marto JA, Griffin JD, Buhrlage SJ. Small molecule inhibition of deubiquitinating enzyme JOSD1 as a novel targeted therapy for leukemias with mutant JAK2. Leukemia 2021. PubMed
  • Varca AC, Casalena D, Chan WC, Hu B, Magin RS, Roberts RM, Liu X, Zhu H, Seo HS, Dhe-Paganon S, Marto JA, Auld D, Buhrlage SJ. Identification and validation of selective deubiquitinase inhibitors. Cell Chem Biol 2021. PubMed
  • Magin RS, Liu X, Felix A, Bratt AS, Chan WC, Buhrlage SJ. Small molecules as tools for functional assessment of deubiquitinating enzyme function. Cell Chem Biol 2021. PubMed
  • Koduri V, Duplaquet L, Lampson BL, Wang AC, Sabet AH, Ishoey M, Paulk J, Teng M, Harris IS, Endress JE, Liu X, Dasilva E, Paulo JA, Briggs KJ, Doench JG, Ott CJ, Zhang T, Donovan KA, Fischer ES, Gygi SP, Gray NS, Bradner J, Medin JA, Buhrlage SJ, Oser MG, Kaelin WG. Targeting oncoproteins with a positive selection assay for protein degraders. Sci Adv 2021. PubMed
  • Ray A, Du T, Song Y, Buhrlage SJ, Chauhan D, Anderson KC. Targeting ubiquitin-specific protease-7 in plasmacytoid dendritic cells triggers anti-myeloma immunity. Leukemia 2021. PubMed
  • Bushman JW, Donovan KA, Schauer NJ, Liu X, Hu W, Varca AC, Buhrlage SJ, Fischer ES. Proteomics-Based Identification of DUB Substrates Using Selective Inhibitors. Cell Chem Biol 2021; 28:78-87.e3. PubMed
  • Yang G, Wang J, Tan L, Munshi M, Liu X, Kofides A, Chen JG, Tsakmaklis N, Demos MG, Guerrera ML, Xu L, Hunter ZR, Che J, Patterson CJ, Meid K, Castillo JJ, Munshi NC, Anderson KC, Cameron M, Buhrlage SJ, Gray NS, Treon SP. The HCK/BTK inhibitor KIN-8194 is active in MYD88 driven lymphomas and overcomes mutated BTKCys481 ibrutinib resistance. Blood 2021. PubMed
  • Donovan KA, Ferguson FM, Bushman JW, Eleuteri NA, Bhunia D, Ryu S, Tan L, Shi K, Yue H, Liu X, Dobrovolsky D, Jiang B, Wang J, Hao M, You I, Teng M, Liang Y, Hatcher J, Li Z, Manz TD, Groendyke B, Hu W, Nam Y, Sengupta S, Cho H, Shin I, Agius MP, Ghobrial IM, Ma MW, Che J, Buhrlage SJ, Sim T, Gray NS, Fischer ES. Mapping the Degradable Kinome Provides a Resource for Expedited Degrader Development. Cell 2020; 183:1714-1731.e10. PubMed
  • Hatcher JM, Yang G, Wang L, Ficarro SB, Buhrlage S, Wu H, Marto JA, Treon SP, Gray NS. Discovery of a Selective, Covalent IRAK1 Inhibitor with Antiproliferative Activity in MYD88 Mutated B-Cell Lymphoma. 2020; 11:2238-2243. PubMed
  • Schauer NJ, Liu X, Magin RS, Doherty LM, Chan WC, Ficarro SB, Hu W, Roberts RM, Iacob RE, Stolte B, Giacomelli AO, Perera S, McKay K, Boswell SA, Weisberg EL, Ray A, Chauhan D, Dhe-Paganon S, Anderson KC, Griffin JD, Li J, Hahn WC, Sorger PK, Engen JR, Stegmaier K, Marto JA, Buhrlage SJ. Selective USP7 inhibition elicits cancer cell killing through a p53-dependent mechanism. Sci Rep 2020; 10:5324. PubMed
  • Weisberg E, Meng C, Case AE, Tiv HL, Gokhale PC, Buhrlage SJ, Yang J, Liu X, Wang J, Gray N, Adamia S, Sattler M, Stone R, Griffin JD. Effects of the multi-kinase inhibitor midostaurin in combination with chemotherapy in models of acute myeloid leukaemia. J Cell Mol Med 2020; 24:2968-2980. PubMed
  • Yang J, Meng C, Weisberg E, Case A, Lamberto I, Magin RS, Adamia S, Wang J, Gray N, Liu S, Stone R, Sattler M, Buhrlage S, Griffin JD. Inhibition of the deubiquitinase USP10 induces degradation of SYK. Br J Cancer 2020. PubMed
  • Weisberg E, Meng C, Case AE, Tiv HL, Gokhale PC, Toure AA, Buhrlage S, Liu X, Wang J, Gray N, Stone R, Adamia S, Winer E, Sattler M, Griffin JD. The combination of FLT3 and SYK kinase inhibitors is toxic to leukaemia cells with CBL mutations. J Cell Mol Med 2020; 24:2145-2156. PubMed
  • Munshi M, Liu X, Chen JG, Xu L, Tsakmaklis N, Demos MG, Kofides A, Guerrera ML, Jimenez C, Chan GG, Hunter ZR, Palomba ML, Argyropoulos KV, Meid K, Keezer A, Gustine J, Dubeau T, Castillo JJ, Patterson CJ, Wang J, Buhrlage SJ, Gray NS, Treon SP, Yang G. SYK is activated by mutated MYD88 and drives pro-survival signaling in MYD88 driven B-cell lymphomas. Blood Cancer J 2020; 10:12. PubMed
  • Schauer NJ, Magin RS, Liu X, Doherty LM, Buhrlage SJ. Advances in Discovering Deubiquitinating Enzyme (DUB) Inhibitors. J Med Chem 2019. PubMed
  • 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. Evaluation of ERK as a therapeutic target in acute myelogenous leukemia. Leukemia 2019. PubMed
  • 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. Comparison of effects of midostaurin, crenolanib, quizartinib, gilteritinib, sorafenib and BLU-285 on oncogenic mutants of KIT, CBL and FLT3 in haematological malignancies. British Journal of Haematology 2019. PubMed
  • Wang L, Ferrao R, Li Q, Hatcher JM, Choi HG, Buhrlage SJ, Gray NS, Wu H. Conformational flexibility and inhibitor binding to unphosphorylated interleukin-1 receptor-associated kinase 4 (IRAK4). J Biol Chem 2019; 294:4511-4519. PubMed
  • 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. Deubiquitinases Maintain Protein Homeostasis and Survival of Cancer Cells upon Glutathione Depletion. Cell Metab 2019. PubMed
  • 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. Genome-scale CRISPR-Cas9 screen identifies druggable dependencies in wild-type Ewing sarcoma. J Exp Med 2018; 215:2137-2155. PubMed
  • Chen JG, Liu X, Munshi M, Xu L, Tsakmaklis N, Demos MG, Kofides A, Guerrera ML, Chan GG, Patterson CJ, Meid KE, Gustine J, Dubeau T, Severns P, Castillo JJ, Hunter ZR, Wang J, Buhrlage SJ, Gray NS, Treon SP, Yang G. BTKdrives ibrutinib resistance via ERK1/2, and protects BTKMYD88 mutated cells by a paracrine mechanism. Blood 2018. PubMed
  • 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. Structure-Guided Development of a Potent and Selective Non-covalent Active-Site Inhibitor of USP7. Cell Chem Biol 2017; 24:1490-1500.e11. PubMed
  • Wang L, Qiao Q, Ferrao R, Shen C, Hatcher JM, Buhrlage SJ, Gray NS, Wu H. Crystal structure of human IRAK1. Proc Natl Acad Sci U S A 2017; 114:13507-13512. PubMed
  • Weisberg EL, Schauer NJ, Yang J, Lamberto I, Doherty L, Bhatt S, Nonami A, Meng C, Letai A, Wright R, Tiv H, Gokhale PC, Ritorto MS, De Cesare V, Trost M, Christodoulou A, Christie A, Weinstock DM, Adamia S, Stone R, Chauhan D, Anderson KC, Seo HS, Dhe-Paganon S, Sattler M, Gray NS, Griffin JD, Buhrlage SJ. Inhibition of USP10 induces degradation of oncogenic FLT3. Nat Chem Biol 2017. PubMed
  • Weisberg EL, Puissant A, Stone R, Sattler M, Buhrlage SJ, Yang J, Manley PW, Meng C, Buonopane M, Daley JF, Lazo S, Wright R, Weinstock DM, Christie AL, Stegmaier K, Griffin JD. Characterization of midostaurin as a dual inhibitor of FLT3 and SYK and potentiation of FLT3 inhibition against FLT3-ITD-driven leukemia harboring activated SYK kinase. 2017; 8:52026-52044. PubMed
  • Paolella BR, Gibson WJ, Urbanski LM, Alberta JA, Zack TI, Bandopadhayay P, Nichols CA, Agarwalla PK, Brown MS, Lamothe R, Yu Y, Choi PS, Obeng EA, Heckl D, Wei G, Wang B, Tsherniak A, Vazquez F, Weir BA, Root DE, Cowley GS, Buhrlage SJ, Stiles CD, Ebert BL, Hahn WC, Reed R, Beroukhim R. Copy-number and gene dependency analysis reveals partial copy loss of wild-type SF3B1 as a novel cancer vulnerability. Elife 2017. PubMed
  • Sun Y, Alberta JA, Pilarz C, Calligaris D, Chadwick EJ, Ramkissoon SH, Ramkissoon LA, Garcia VM, Mazzola E, Goumnerova L, Kane M, Yao Z, Kieran MW, Ligon KL, Hahn WC, Garraway LA, Rosen N, Gray NS, Agar NY, Buhrlage SJ, Segal RA, Stiles CD. A brain-penetrant RAF dimer antagonist for the noncanonical BRAF oncoprotein of pediatric low-grade astrocytomas. 2017. PubMed
  • LaRochelle JR, Fodor M, Ellegast JM, Liu X, Vemulapalli V, Mohseni M, Stams T, Buhrlage SJ, Stegmaier K, LaMarche MJ, Acker MG, Blacklow SC. Identification of an allosteric benzothiazolopyrimidone inhibitor of the oncogenic protein tyrosine phosphatase SHP2. Bioorg Med Chem 2017; 25:6479-6485. PubMed
  • Wu H, Hu C, Wang A, Weisberg EL, Chen Y, Yun CH, Wang W, Liu Y, Liu X, Tian B, Wang J, Zhao Z, Liang Y, Li B, Wang L, Wang B, Chen C, Buhrlage SJ, Qi Z, Zou F, Nonami A, Li Y, Fernandes SM, Adamia S, Stone RM, Galinsky IA, Wang X, Yang G, Griffin JD, Brown JR, Eck MJ, Liu J, Gray NS, Liu Q. Discovery of a BTK/MNK dual inhibitor for lymphoma and leukemia. Leukemia 2016; 30:173-81. PubMed
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