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.
How to Use Synapse Database to Search and Analyze Translational Medicine Data?
The transational medicine section of the Synapse database supports searches based on fields such as drug, target, and indication, covering the T0-T3 stages of translation. Additionally, it offers a historical conference search function as well as filtering options, view modes, translation services, and highlights summaries, providing you with a unique search experience.

Taking obesity as an example, select "obesity" under the indication category and click search to enter the Translational Medicine results list page. By clicking on the title, you can directly navigate to the original page.

By clicking the analysis button, you can observe that GLP-1R treatment for obesity has gained significant attention over the past three years, with preclinical research still ongoing in 2023. Additionally, there are emerging potential targets, such as GDF15, among others.

Click on the image below to go directly to the Translational Medicine search interface.
