Target Class Approach to Develop DUB Inhibitors

ASPIRE Award (2019-2020)

Sara Buhrlage, PhD (Principal) and Jarrod Marto, PhD, Dana-Farber Cancer Institute

Deubiquitinases (DUBs) catalyze the removal of ubiquitin from proteins. Proteins tagged with ubiquitin are marked for shuttling to the cell’s waste disposal system, known as the proteasome. Inactivation of specific DUBs could, therefore, lead to the degradation of proteins that keep cancer cells alive. DUBs function as part of the ubiquitin-proteasome system (UPS), and although they represent a class of highly specific protein targets whose inhibition could be therapeutic, there are currently no approved DUB-targeting drugs. Dr. Sara Buhrlage of the Dana-Farber Cancer Institute is working with her team on a target class approach to develop tool molecules and drug candidates that inhibit DUBs, utilizing novel chemoproteomic methods to characterize a focused library of covalent probe compounds. Non-specific drugs targeting the UPS have worked in lymphoma and multiple myeloma, both of which have approved UPS-based drugs. However, these inhibitors target the broader function of the UPS and often lead to toxicity. Targeting specific DUBs could provide the desired therapeutic benefit while alleviating toxic side effects. This work will also provide a framework for future target class approaches to inhibiting other types of enzymes.

published research

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.