Hypoxia-inducible factors (HIFs) are members of the basic helix-loop-helix superfamily of transcription factors that play a central role in regulating oxygen homeostasis. Aberrant signaling through HIF-2α in particular has been implicated as a driver of certain cancers, most notably in clear cell renal cell carcinoma due to the loss of function of the von Hippel-Lindau tumor suppressor. The identification of a ligandable cavity within the PAS-B domain of HIF-2α by Gardner and Bruick revealed an opportunity to inhibit the transcriptional activity of the dimeric complex formed with HIF-1β. This opportunity has gone on to stimulate a number of groups to identify HIF-2α inhibitors targeting the cavity within the PAS-B domain, cumulating most recently in the identification of belzutifan.<br/><br/>We will describe our experiences from the application of multiple hit-finding approaches targeting the fully-enclosed lipophilic cavity within the PAS-B domain of HIF-2α which identified a number of relatively lipophilic and apolar starting points. Of these levamisole, originally developed as an antiparasitic agent, was prioritized for further evaluation due to the presence of the ionizable 5,5-ring system that offered the possibility for improved physical properties. Further evolution of the levamisole hit led to the discovery of novel spirocyclic analogs with improved HIF-2α inhibitory activity and which preserved the weakly-basic pKa of the isothiourea core.

Identification of spirocyclic inhibitors of the transcription factor HIF-2α: Soluble ligands targeting a lipophilic binding site

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