Dysregulation of protein homeostasis drives many types of cancer, infection and neurodegeneration. The mission of our group is to develop first-in-class inhibitors and prototype drugs for deubiquitylating enzymes, a class of enzymes responsible for regulating proteostasis, that can be utilized to pharmacologically validate members of the gene family as new targets for cancer treatment and other diseases.
Longwood Center, LC3311
360 Longwood Ave.
Boston, MA 02215
Lab Size: Between 5-10
Summary: Proper regulation of protein homeostasis is required for nearly every aspect of cell life including DNA repair, cell cycle regulation, innate immunity and transcription. Dysregulation of proteostasis drives many types of cancer, infection and neurodegeneration. The ubiquitin system performs a central role in maintenance of proteostasis through reversible post-translational addition of (poly)ubiquitin to proteins, a mark that: 1) tags substrates for destruction by the proteasome or lysosome and 2) functions as a switch for gene expression through ubiquitylation of histone lysine sidechains. Ubiquitylation is coordinated by the action of ubiquitin activating, conjugating, ligating (E1, E2, E3) and deubiquitylating enzymes (DUB). The mission of our group is to develop first-in-class inhibitors and prototype drugs for DUBs that can utilized to pharmacologically validate members of the gene family as new targets for cancer treatment and other diseases.
DUBs have garnered significant attention as potential therapeutic targets in the field of oncology due to their removal of degradative ubiquitin marks from cancer causing proteins. For example, the DUBs USP1, USP2, USP7, USP8 and USP12 have been shown to rescue oncogenes ID1, cyclin D1, MDM2, EGFR and Androgen receptor, respectively, from degradation in multiple cancers using primarily genetic methods. It has been demonstrated for a limited number of DUBs that small molecule inhibition of DUB protease activity can promote degradation of substrate oncoproteins. For example we developed a novel USP1 inhibitor and demonstrated in collaboration with Professor Alan D’Andrea that pharmacological inhibition of USP1 promotes degradation of the transcription factor ID1 in acute myeloid leukemia. At present, there are approximately 95 recognized human DUB enzymes belonging to 5 distinct families.
Our approach to DUB inhibitor development and target validation 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.
Ritorto, M. S.; Ewan, R.; Perex-Oliva, A.; Knebel, A.; Buhrlage, S. J.; Wightman, M.; Kelly, S. M.; Wood, N. T.; Gray, N. S.; Morrice, N. A.; Alessi, D. R.; Trost, M. ‘Screening of DUB activity and specificity by MALDI-TOF mass spectrometry,’ Nat. Comm., 2014, 5, 4763.
Mistry, H.; Hsieh, G.; Buhrlage, S. J.; Huang, M.; Park, E.; Cuny, G. D.; Galinsky, I.; Stone, R.; Gray, N.; D’Andrea, A. D.; Parmar, K. ‘Small molecule inhibitors of USP1 target ID1 degradation in leukemic cells,’ Mol. Can.Ther., 2013, 12, 2651-2662.
Yang, G.; Zhou, Y.; Liu, X.; Xu, L.; Cao, Y.; Manning, R. J.; Patterson, C. J.; Buhrlage, S. J.; Gray, N.S.; Tai, Y.; Anderson, K. C.; Hunter, Z. R. Treon, S. P. ‘A mutation in MYD88 (L265P) supports the survival of lymphoplasmacytic cells by activation of Bruton’s Tyrosine Kinase in Waldenstrom’s Macroglobulinemia,’ Blood, 2013, 122, 1222-1232.
Buhrlage, S. J.; Bates, C. A.; Rowe, S. P.; Minter, A. R.; Brennan, B. B.; Majmudar, C. Y.; Wemmer, D. E.; Al-Hashimi, H.; Mapp, A. K. ‘Amphipathic small molecules mimic the binding mode and function of endogenous transcription factors,’ NMR Investigation of Small Molecule Transcriptional Activator Interactions with Protein Targets,’ ACS Chem. Biol. 2009, 4, 335-344.
Buhrlage, S. J.; Brennan, B. B.; Minter, A. R.; Mapp, A. K. ‘Stereochemical Promiscuity in Artificial Transcription Activators,’ J. Am. Chem. Soc. 2005, 12, 12456-12457.