CHAPTER 9: Discovery and Selection of NVP-HSP990 as a Clinical Candidate

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.