Overcoming myelosuppression due to synthetic lethal toxicity for FLT3-targeted acute myeloid leukemia therapy

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Abstract

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 to 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.

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Alexander A Warkentin

Department of Cellular and Molecular Pharmacology, Howard Hughes Medical Institute, University of California, San Francisco, San Francisco, United States

Competing interests
The authors declare that no competing interests exist.
Michael S Lopez

Department of Cellular and Molecular Pharmacology, Howard Hughes Medical Institute, University of California, San Francisco, San Francisco, United States

Competing interests
The authors declare that no competing interests exist.
Elisabeth A Lasater

Division of Hematology, University of California, San Francisco, San Francisco, United States

Competing interests
The authors declare that no competing interests exist.
Kimberly Lin

Division of Hematology, University of California, San Francisco, San Francisco, United States

Competing interests
The authors declare that no competing interests exist.
Bai-Liang He

Division of Haematology, Department of Medicine, Li Ka Shing Faculty of Medicine, University of Hong Kong, Pokfulam, Hong Kong

Competing interests
The authors declare that no competing interests exist.
Anskar Y H Leung

Division of Haematology, Department of Medicine, Li Ka Shing Faculty of Medicine, University of Hong Kong, Pokfulam, Hong Kong

Competing interests
The authors declare that no competing interests exist.
Catherine C Smith

Division of Hematology, University of California, San Francisco, San Francisco, United States

Competing interests
The authors declare that no competing interests exist.
Neil P Shah

Division of Hematology, University of California, San Francisco, San Francisco, United States

Competing interests
The authors declare that no competing interests exist.
Kevan M Shokat

Department of Cellular and Molecular Pharmacology, Howard Hughes Medical Institute, University of California, San Francisco, San Francisco, United States

For correspondence
Kevan.Shokat@ucsf.edu

Competing interests
The authors declare that no competing interests exist.

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This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.