BGS-2456: A Selective FLT3 Inhibitor with No Myelosuppressive Effects and High Potency Against AML

The text discusses a class of enzymes known as Class III receptor tyrosine kinases, highlighting FLT3 as a common mutation in AML. It notes that while there are KIT TKIs that do not affect FLT3, FLT3 TKIs have not been successful in avoiding KIT inhibition. Preclinical findings indicate that inhibiting both FLT3 and KIT could lead to myelosuppression, which may hinder treatment. A non-myelosuppressive FLT3 TKI could potentially improve outcomes, as seen with BCR::ABL1 TKIs in Ph+ ALL. The text introduces FF-10101, a covalent inhibitor of FLT3, which was active against FLT3 and resistant mutants but did not selectively inhibit KIT, leading to myelosuppression and discontinuation of its development.

The study then focuses on BGS-2456, a covalent FLT3 inhibitor, which was tested for its activity and selectivity. Experiments with Cys → Ser substitutions in FLT3-ITD revealed that C695 substitution led to a loss of activity, and a compound without the covalent group (BGS-2457) was significantly less potent. Cell viability assays were conducted on AML and GIST-T1 cell lines to evaluate BGS-2456's properties and its selectivity for FLT3 over KIT. Additionally, CFU assays were used to assess myelosuppressive effects, and the compound's activity against drug-resistant FLT3-ITD mutants was tested.

The results confirmed BGS-2456 as a potent and selective FLT3 inhibitor, with high potency and minimal hematologic toxicity. It was found to be effective against drug-resistant mutants without causing myelosuppression even at high concentrations. The text concludes that BGS-2456 has potential as a leading TKI for treating FLT3-mutant AML, and research is ongoing to understand its high selectivity.