Abstract 1728: Discovery of highly selective DUB inhibitors with in vivo pre-clinical anti-tumor activity

Ubiquitin proteasome pathways are emerging as a growing source for novel anti-cancer therapeutics. In this respect, by depleting a number of deubiquitylating enzymes (DUBs) through a combination of synthetic lethality screens and isogenic cell line models, MISSION has identified several novel DUBs essential for a range of different tumor types, including platinum-resistant ovarian cancers, DNA damage response (DDR) pathway deficient tumors (e.g. ATM, ATR or BRCA2 defective) and haematological tumors such as multiple myeloma. Illustrating the diversity of DUBs as oncology targets we identified USP11 and UCHL1 using our target validation platform. USP11 was identified as essential for proliferation of platinum-resistant cells but not platinum-sensitive tumor cells in an isogenic model derived from patient tumors before and after development of resistance. In addition, USP11 depletion displayed synthetic lethality in isogenic models of BRCA2 or ATR loss, supporting USP11's previously identified association with homologous recombination proteins as well as the importance such processes in platinum resistance mechanisms. UCHL1 on the other hand is a prototypical oncogene target that selectively drives proliferation in many tumor types, such as multiple myeloma and lung cancer. UCHL1 depletion leads to selective killing of a number of tumors whose proliferation is driven by UCHL1. Validation of targets like USP11 or UCHL1 for the selective treatment of cancer bearing genetic deficiencies or resistant to standard-of-care supports the rationale of developing DUB inhibitors for cancers with unmet medical need. A broad drug discovery platform combining unique biochemical, cellular, biophysical and structural assays was designed by MISSION to identify and optimise potent and selective DUB inhibitors. Early selective DUB hits, developed for USP11 and UCHL1, are successfully recapitulating target validation biology, including synthetic lethality in matched isogenic backgrounds. Lead optimisation of chemical series has recently been translated into compounds with adequate properties for in vivo proof-of-concept studies. The challenges and advances in demonstrating in vivo DUB target engagement will be discussed. MISSION's integrated drug discovery methodologies exemplify the tractability of DUBs to pharmacologic intervention and the potential scope for DUB inhibitors in a number of cancer types, including those characterised by DDR deficiencies. Citation Format: Xavier