Discovery and development of RRx-001, a novel nitric oxide and ROS mediated epigenetic modulator

Abstract

Methods to find compounds that interact favorably with anti-cancer biological targets typically start from a limited set of structural types and focus on target-based approaches resulting in limited breakthroughs, mostly incremental improvements, and many structurally similar compounds that fall into ‘me too’ or ‘me better’ categories. Due to the very low success rate for drug development in oncology, different, ʼnon-me too’ approaches that utilize novel chemotypes together with phenotypic discovery approaches are required to provide truly novel treatments. The defense and aerospace industry offers a huge resource of largely untapped chemical diversity that lends itself to a phenotypic approach to drug discovery. Herein we describe a novel program focused on discovering drug candidates from energetic materials that arose from a unique partnership between a defense contractor specializing in the research and utilization of energetic materials and an academic institution, under the umbrella of a start-up and with an innovative funding and organizational structure. We describe the most advanced compound, RRx-001, the first of a new class of NO-mediated epigenetic anticancer agents that bind hemoglobin and drive RBC-mediated redox reactions under hypoxia.