Timothy P LaBranche, Lucian DiPietro, Natasja Brooijmans, Doug Wilson, Nicholas Lydon, Timothy Guzi, Kevin Wilson, Oleg Schmidt-Kittler, Michael C Heinrich, Yemarshet K Gebreyohannes, Joseph L Kim, Christoph Lengauer, Adam Shutes, Alexandra K Gardino, Nancy Kohl, Patrick Schöffski, Xing Julia Zhu, Alison Davis, Erica K Evans, Andy Boral, Yulian Zhang, Agnieszka Wozniak, Daniel J DeAngelo, Stephen Miller, Brian L Hodous, Beni Wolf
Targeting oncogenic kinase drivers with small-molecule inhibitors can have marked therapeutic benefit, especially when administered to an appropriate genomically defined patient population. Cancer genomics and mechanistic studies have revealed that heterogeneous mutations within a single kinase can result in various mechanisms of kinase activation. Therapeutic benefit to patients can best be optimized through an in-depth understanding of the disease-driving mutations combined with the ability to match these insights to tailored highly selective drugs. This rationale is presented for BLU-285, a clinical stage inhibitor of oncogenic KIT and PDGFRA alterations, including activation loop mutants that are ineffectively treated by current therapies. BLU-285, designed to preferentially interact with the active conformation of KIT and PDGFRA, potently inhibits activation loop mutants KIT D816V and PDGFRA D842V with subnanomolar potency and also inhibits other well-characterized disease-driving KIT mutants both in vitro and in vivo in preclinical models. Early clinical evaluation of BLU-285 in a phase 1 study has demonstrated marked activity in patients with diseases associated with KIT (aggressive systemic mastocytosis and gastrointestinal stromal tumor) and PDGFRA (gastrointestinal stromal tumor) activation loop mutations.