TY - JOUR
T1 - A precision therapy against cancers driven by KIT/PDGFRA mutations
AU - Evans, Erica K.
AU - Gardino, Alexandra K.
AU - Kim, Joseph L.
AU - Hodous, Brian L.
AU - Shutes, Adam
AU - Davis, Alison
AU - Zhu, Xing Julia
AU - Schmidt-Kittler, Oleg
AU - Wilson, Doug
AU - Wilson, Kevin
AU - DiPietro, Lucian
AU - Zhang, Yulian
AU - Brooijmans, Natasja
AU - LaBranche, Timothy P.
AU - Wozniak, Agnieszka
AU - Gebreyohannes, Yemarshet K.
AU - Schöffski, Patrick
AU - Heinrich, Michael C.
AU - DeAngelo, Daniel J.
AU - Miller, Stephen
AU - Wolf, Beni
AU - Kohl, Nancy
AU - Guzi, Timothy
AU - Lydon, Nicholas
AU - Boral, Andy
AU - Lengauer, Christoph
PY - 2017/11/1
Y1 - 2017/11/1
N2 - 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.
AB - 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.
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U2 - 10.1126/scitranslmed.aao1690
DO - 10.1126/scitranslmed.aao1690
M3 - Article
C2 - 29093181
AN - SCOPUS:85032840410
SN - 1946-6234
VL - 9
JO - Science translational medicine
JF - Science translational medicine
IS - 414
M1 - eaao1690
ER -