Overcoming myelosuppression due to synthetic lethal toxicity for FLT3-targeted acute myeloid leukemia therapy
Alexander A Warkentin,
Michael S Lopez,
Elisabeth A Lasater,
Kimberly Lin,
Bai-Liang He,
Anskar YH Leung,
Catherine C Smith,
Neil P Shah,
Kevan M Shokat
Affiliations
Alexander A Warkentin
Department of Cellular and Molecular Pharmacology, Howard Hughes Medical Institute, University of California, San Francisco, San Francisco, United States
Michael S Lopez
Department of Cellular and Molecular Pharmacology, Howard Hughes Medical Institute, University of California, San Francisco, San Francisco, United States
Elisabeth A Lasater
Division of Hematology and Oncology, University of California, San Francisco, San Francisco, United States
Kimberly Lin
Division of Hematology and Oncology, University of California, San Francisco, San Francisco, United States
Bai-Liang He
Division of Haematology, Department of Medicine, Li Ka Shing Faculty of Medicine, University of Hong Kong, Pokfulam, Hong Kong
Anskar YH Leung
Division of Haematology, Department of Medicine, Li Ka Shing Faculty of Medicine, University of Hong Kong, Pokfulam, Hong Kong
Catherine C Smith
Division of Hematology and Oncology, University of California, San Francisco, San Francisco, United States
Neil P Shah
Division of Hematology and Oncology, University of California, San Francisco, San Francisco, United States
Kevan M Shokat
Department of Cellular and Molecular Pharmacology, Howard Hughes Medical Institute, University of California, San Francisco, San Francisco, United States
Activating mutations in FLT3 confer poor prognosis for individuals with acute myeloid leukemia (AML). Clinically active investigational FLT3 inhibitors can achieve complete remissions but their utility has been hampered by acquired resistance and myelosuppression attributed to a ‘synthetic lethal toxicity’ arising from simultaneous inhibition of FLT3 and KIT. We report a novel chemical strategy for selective FLT3 inhibition while avoiding KIT inhibition with the staurosporine analog, Star 27. Star 27 maintains potency against FLT3 in proliferation assays of FLT3-transformed cells compared with KIT-transformed cells, shows no toxicity towards normal human hematopoiesis at concentrations that inhibit primary FLT3-mutant AML blast growth, and is active against mutations that confer resistance to clinical inhibitors. As a more complete understanding of kinase networks emerges, it may be possible to define anti-targets such as KIT in the case of AML to allow improved kinase inhibitor design of clinical agents with enhanced efficacy and reduced toxicity.
