Design, Synthesis and Molecular Modeling of Pyrazolo[1,5-a]pyrimidine Derivatives as Dual Inhibitors of CDK2 and TRKA Kinases with Antiproliferative Activity

Compounds <b>6t</b> and <b>6s</b> exhibited potent dual inhibitory activity, showing an IC₅₀ = 0.09 µM and 0.23 µM against CDK2, and 0.45 µM against TRKA, respectively. These results were comparable to reference inhibitors ribociclib (CDK2, IC₅₀ = 0.07 µM) and larotrectinib (TRKA, IC₅₀ = 0.07 µM). Among the studied derivatives, compound <b>6n</b> displayed a notable broad-spectrum anticancer activity, achieving a mean growth inhibition (GI%) of 43.9% across 56 cell lines. Molecular docking simulations revealed that the synthesized compounds adopt modes of binding similar to those of the lead inhibitors. Conclusions<b>:</b> In this study, prepared pyrazolo[1,5-<i>a</i>]pyrimidine derivatives demonstrated significant potential as dual CDK2/TRKA inhibitors, and showed potent anticancer activity toward diverse cancer cell lines. These findings highlight their potential as key compounds for the design of novel anticancer therapeutics.