Rational Design and Development of Novel CDK9 Inhibitors for the Treatment of Acute Myeloid Leukemia

CDK9 is an essential drug target correlated to the development
of acute myeloid leukemia (AML). Starting from the hit compound 10, which was discovered through a screening of our in-house
compound library, the structural modifications were carried out based
on the bioisosterism and scaffold hopping strategies. Consequently,
compound 37 displayed the optimal CDK9 inhibitory activity
with an IC50 value of 5.41 nM, which was nearly 1500-fold
higher than compound 10. In addition, compound 37 exhibited significant antiproliferative activity in broad
cancer cell lines. Further investigation of in vivo properties demonstrated that compound 37 could be orally
administrated with an acceptable bioavailability (F = 33.7%). In MV-4-11 subcutaneous xenograft mouse model, compound 37 (7.5 mg/kg) could significantly suppress the tumor progression
with a T/C value of 27.80%. Compound 37 represents a
promising lead compound for the development of a novel class of CDK9
inhibitors for the treatment of acute myeloid leukemia.