Development of Hsp90 Inhibitors for the Treatment of HER-2 Positive Solid Cancers

BIIB021 (4), an Hsp90 inhibitor discovered through SAR studies, was investigated through phase II clinical trials for the treatment of HER-2 positive solid cancers. The medicinal chemistry route used to make the API for the initial clinical trials was developed to overcome the rapid API decomposition in the salt formation step and to control impurity levels in the API. The development resulted in a two-stage process that was used to produce ~200 kg of the API in > 99.90% purity (no impurity > 0.06%) to support the clinical trials. Further medicinal chemistry investigations led to the discovery of BIIB028, an inhibitor with improved stability, enhanced solubility that enabled an intravenous formulation, and greater potency for in-hospital chemotherapy trials. Improvements to the three-stage medicinal chemistry route permitted the synthesis of 12 kg of API at 99.6% purity in support of the phase I clinical trials.