Star27 overcomes synthetic lethal toxicity for FLT3-targeted therapy against acute myeloid leukemia


Fms-like tyrosine kinase 3 (FLT3) is a receptor tyrosine kinase (RTK) mediating hematopoietic differentiation and is the most frequently mutated gene in acute myeloid leukemia (AML), an aggressive fatal blood cancer. However, the current clinical kinase targeted drugs are not only inhibit FLT3, but also KIT, another member of the class III family of RTKs, causing the reduction of lymphoid progenitors and postnatal lethality, called "synthetic lethal toxicity". To solve this problem, Warkentin et al. reported a staurosporine analog, Star27, that enable to inhibit FLT3 while avoiding KIT inhibition. The article was published in Elife.


Researchers found Star27 strongly suppress proliferation of FLT3-transformed cells compared to KIT-dependent cells. At concentrations that enable to inhibit growth of primary FLT3-mutant AML, Star27 does not provide toxicity to normal human hematopoiesis, and shows considerable benefits against the resistance to clinical inhibitors. This study demonstrated a more complete understanding of kinase networks for defining antitargets in the case of AML or other cancers to improve design of clinical strategy with higher efficiency and lower toxicity. 


Elife. 2014 Dec 22;3. doi: 10.7554/eLife.03445.