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Drug discovery and development

Another major focus of my laboratory is to translate the mechanistic findings and the chemical biology tools into treatment strategies. These efforts encompass a large spectrum of activities such as lead compound discovery and development, medicinal chemistry, computational analyses, assay development, pharmacokinetic and pharmacodynamic studies, in vivo efficacy studies, biomarker discovery, diagnostic assay development, combination therapy studies, intellectual property development, and commercialization strategies.

The Chiosis lab has significant expertise in drug discovery and development and in taking discoveries from bench to bedside, as exemplified by four successful INDs, over 350 patents and patent applications, and successful out-licensing to move drug candidates and diagnostics ahead in the clinic. We have shown that a safe and effective way to target HSP90 is to differentiate HSP90 incorporated into the epichaperome (stable, multi-partner complexes effected by strong interactions) from HSP90 as part of physiological complexes (dynamic complexes effected by weak interactions with a limited number of partners). One way to differentiate such complexes is by regulating the kinetic binding of an inhibitor. By addressing the kinetics of binding, we have developed an HSP90 inhibitor, PU-H71, with preference for HSP90 when this chaperone is incorporated into the epichaperome. PU-H71 dissociates from epichaperomes much slower (i.e. days) than it does from other HSP90 pools (i.e. minutes), and this difference in the koff (dissociation constant) is what provides it with selectivity. Our lab has developed methods to synthesize, scale-up and characterize PU-H71. It has extensively studied the mechanism of action of this agent in cancer. It has taken the agent from the ligand design stage to IND-enabling studies and Phase 1 clinical evaluation (in collaboration with the NCI). We then spun out a small biotechnology company, Samus Therapeutics, to move the agent through the next clinical steps. PU-H71 is currently in clinic being studied in multiple indications in cancer.

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