Discovery of Novel 2-Aminopyridine-Based and 2-Aminopyrimidine-Based Derivatives as Potent CDK/HDAC Dual Inhibitors for the Treatment of Refractory Solid Tumors and Hematological Malignancies

Co-inhibition of histone deacetylase (HDAC) and cyclin-dependent kinase (CDK) synergizes to produce enhanced antitumor effects and potentially overcomes the drug resistance. In this work, we discovered a series of novel CDK9/HDACs dual inhibitors. Among them, compound <b>8e</b> was identified to show potent CDK9 and HDAC1 inhibitory activities, with IC₅₀ values at 88.4 and 168.9 nM, respectively, and exhibited antiproliferative capacities against hematological and solid tumor cells. Meanwhile, <b>8e</b> showed high selectivity for CDK9 and HDAC1, remarkably induced MV-4-11 cell apoptosis and S cell cycle arrests. Furthermore, <b>8e</b> possessed a significant antitumor potency with a <i>T</i>/<i>C</i> value of 29.98% in the MV-4-11 xenograft model. Interestingly, a potent FLT3/HDAC dual inhibitor <b>9e</b> was also identified (FLT3/HDAC1/3 IC₅₀ = 30.4/52.4/14.7 nM) and found to possess powerful apoptosis induction ability in MV-4-11 cell and potent antiproliferative capacities against FLT3 mutant-transformed BaF3 cells. Overall, our work provided valuable lead compounds for dual inhibitors with potent anticancer activity.