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

Alexander A Warkentin,Neil P Shah,Catherine C Smith,Bai-Liang He,Elisabeth A Lasater,Michael S Lopez,Anskar Yh Leung,Kevan M Shokat,Kimberly Lin

doi:10.7554/elife.03445

Alexander A Warkentin, Neil P Shah + Show 7 more

Open Access

https://doi.org/10.7554/elife.03445

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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 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.

Highlights

Kinase inhibitors are among the fastest growing new class of therapeutics for treating cancer, with 25 new kinase inhibitors approved by the FDA in the last 14 years (Mullard, 2014)
The findings demonstrate that when it comes to drug development, it is sometimes as important to avoid certain molecular targets as it is to hit others
We have recently proposed that a Type I inhibitor, which binds to the active kinase conformation, would circumvent these mutations that confer resistance to AC220 (Smith et al, 2012)

Summary

Introduction

Kinase inhibitors are among the fastest growing new class of therapeutics for treating cancer, with 25 new kinase inhibitors approved by the FDA in the last 14 years (Mullard, 2014). Since these agents almost exclusively target a kinase's highly conserved ATP binding pocket, achieving selectivity is problematic. The key question, in light of the complex kinase networks in all cells, is which anti-targets should be avoided, in order to limit toxicity in normal tissues. By understanding the synthetic lethal effects on normal cells and developing selective inhibitors which avoid even a small number of ‘off-target’ kinases, we believe that clinical agents with an improved therapeutic index can be developed

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