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

• Published in: eLife Vol. 3
• Main Authors: Warkentin, Alexander A, Lopez, Michael S, Lasater, Elisabeth A, Lin, Kimberly, He, Bai-Liang, Leung, Anskar Yh, Smith, Catherine C, Shah, Neil P, Shokat, Kevan M
• Format: Journal Article
• Language: English
• Published: England eLife Sciences Publications Ltd 22-12-2014; eLife Sciences Publications, Ltd
• Subjects: Acute myeloid leukemia; Animals; Antineoplastic Agents - chemistry; Antineoplastic Agents - therapeutic use; Antineoplastic Agents - toxicity; Biochemistry; Bone Marrow Diseases - chemically induced; Cancer therapies; Cell Line, Tumor; Cell proliferation; chemical synthesis; Cytotoxicity; Embryos; Enzyme inhibitors; FLT3; fms-Like Tyrosine Kinase 3 - drug effects; fms-Like Tyrosine Kinase 3 - genetics; Hematology; Human Biology and Medicine; Humans; Kinases; Leukemia; Leukemia, Myeloid, Acute - drug therapy; Microscopy; Models, Biological; Mutation; Myeloid leukemia; Myelosuppression; protein kinase; Staurosporine; Structure-Activity Relationship; Toxicity; Transformed cells; Zebrafish; United States > US; California; chemical synthesis; human biology; leukemia; staurosporine; FLT3; KIT; biochemistry; medicine; zebrafish; protein kinase
• ISSN: 2050-084X; 2050-084X
• DOI: 10.7554/eLife.03445

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.