CHAPTER 7: Discovery of the Serenex Hsp90 Inhibitor, SNX5422
Published:23 Oct 2013
SNX 5422 is a synthetic orally bioavailable inhibitor of Hsp90 discovered by the biotechnology company Serenex Inc. (Durham NC, USA) using the chemoproteomic platform proteome mining. The molecule is derived from an indoline scaffold and is therefore structurally distinct from all other known Hsp90 inhibitors reported in the literature. The molecule also inhibits with nM potency the related heat-shock proteins GRP94 and TRAP-1, although it has yet to be established to what extent these actions contribute to its biological effects in vivo. SNX5422 is a pro-drug with oral bioavailability and is hydrolyzed to the active parent compound SNX2112 upon uptake. In cell-based and initial animal studies, and subsequent full pre-clinical work-up, SNX5422 exhibited all the hallmarks of a bona fide Hsp90 inhibitor (i.e. degradation of the expected portfolio of Hsp90-dependent clients, induction of Hsp70, tumor growth arrest). In general, the compound was well tolerated in animals, and showed potent efficacy in a variety of xenograph models of human cancer, both alone and in combination with other existing anticancer agents. The compound was therefore advanced to Phase I safety studies. At the time of writing SNX5422 had completed two Phase I clinical trials conducted by the National Cancer Institutes (Bethesda, MD, USA) and Pfizer (who acquired Serenex in 2008). Chapter 7 covers the discovery and development of SNX5422 and summarizes its biological activities in vivo.