Chemical Optimization of a novel class of USP inhibitor for cancer treatment

DESCRIPTION provided by applicant Numerous regulatory proteins are tightly controlled by ubiquitin conjugation and deconjugation and deviations from this dynamic process are manifested in clinical disorders such as cancer inflammation neurodegenerative disorders and metabolic diseases The deubiquitylase DUB USP plays multiple regulatory roles all of which are pro survival antiapoptotic One of its most intriguing roles is the furtherance of immune evasion whereby tumors employ various mechanisms to escape detection and killing by the host defense T and NK cell mediated immune system Abrogation of tumor tolerance induction has become a leading anticancer strategy as it should in principle work on a broad spectrum of cancers Clinical activity of antibodies to two receptors that trigger suppression of T cell defens CTLA and PD has led to USFDA approval of three biologicals for treating melanoma While the strategy is valid opportunities for improvement of the therapeutic index exist in the areas of mechanism multiple mechanisms can lead to tolerance suggesting that combination therapies will be needed for maximum efficacy and treatment cost a serious issue especially with biologicals The involvement of USP in sustaining immune evasion immediately suggests a therapeutic strategy inhibitors of USP destabilize the transcription factor Foxp which is needed to activate a population of Tcells Tregs that limit activation of tumoricidal T effector Teff cells Thus a USP inhibitor should break Treg induced tolerance allowing Teff cells to kill the tumor In Phase I Progenraandapos s selective USP inhibitor P was confirmed to diminish Foxp stability and eliminate Treg cellsandapos ability to induce tolerance by down regulating Teff cells as predicted Moreover P mediated anti tumor activity in the AE mesothelioma syngeneic tumor model only in immunocompetent mice thus suppressing tumor growth in this model by inhibiting T cell anergy and not by direct cytotoxic effects of the kind observed in other models Also in Phase I the potency and drug like properties of P were improved by the generation of a series of compounds with EC nM while maintaining selectivity and efficacy in cellular and in vivo proof of concept models In Phase II lead optimization will focus on further improvement of pharmacological properties PK toxicology and efficacy studies will guide chemical synthesis The goal is to identify potent and selective compounds with efficacy against lung cancer and other tumor models with the ultimate commercial goal of initiating clinical development PUBLIC HEALTH RELEVANCE Immuno oncology based treatment of cancer promises to increase effectiveness of cancer therapy by harnessing the patientandapos s own immune system to remove the invading tumor rather than by directly killing tumor cells and other cells of the body leading to harmful side effects Several classes of drug may be needed to achieve the maximum activation of the immune defense and the proposed project continues the development of a class of molecule that has enabled T cells to eradicate tumors in animal models either singly or in combination with other immuno oncology agents The project will identify a clinical candidate s