CHAPTER 9: Discovery and Selection of NVP-HSP990 as a Clinical Candidate
Published:23 Oct 2013
T. D. Machajewski, D. Menezes, and Z. Gao, in Inhibitors of Molecular Chaperones as Therapeutic Agents, ed. T. D. Machajewski and Z. Gao, The Royal Society of Chemistry, 2013, pp. 241-258.
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This chapter describes the discovery of NVP-Hsp990, a potent, orally bioavailable Hsp90 inhibitor currently in early clinical development. The program strategy for the discovery of Hsp990 is detailed from hit identification to in vivo pre-clinical evaluation. This approach relied heavily on the application of structure-based drug design to rapidly optimize biochemical potency, and identify opportunities for fine-tuning the in vitro and in vivo properties. A significant protein rearrangement is described, which enabled the identification of a highly potent inhibitor series. PK/PD/efficacy relationships are described that guided dose and schedule optimization for the clinical candidate.