Acute myeloid leukemia (AML) is highly aggressive cancer that affects the blood and bone marrow. Many studies had revealed that FLT3 plays a key role in the development of AML and poor prognosis. FLT3 is aberrantly expressed in most patients with AML, and about one third of patients have a mutation in FLT3. The two major types of FLT3 mutations are internal tandem duplications (FLT3/ITDs) and tyrosine kinase domain point mutations (FLT3/TKDs). These mutations give a constitutive activation in FLT3 signaling, which is associated with a poor prognosis in AML. We had previously reported that thieno[2,3-d]pyrimidine derivatives showed inhibitory activity against FLT3 and mutant FLT3. Among them, compound 1 exhibited best antiproliferative activity against human leukemia cell lines which harbor FLT3 or mutant FLT3 than AC220, which is a well-known FLT3 inhibitor, and has good microsomal stability. However, compound 1 had poor solubility (2.96 uM in 100 mM pH 7.4 phosphate buffered saline; PBS) due to a bulky moiety at the C6 position. Therefore we performed structural modification at the C2 and C6 position utilizing compound 1 as a starting point. As a result of optimization, we developed compound 13b with a thiazole moiety at the C2 position. It exhibited much better growth inhibition activity against human leukemia cell lines than compound 1 and showed desirable drug-like properties including moderate microsomal stability and increased solubility. Therefore, we concluded that compound 13b is suitable for being a structural basis for further modification and as well as a promising potential FLT3 inhibitor for AML treatment.

Improving solubility of thieno[2,3-d]pyrimidine based FLT3 inhibitor via structural modifications at the C2 and C6 position

254th National Meeting (2017)

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.