Design of Novel 3‑Pyrimidinylazaindole CDK2/9 Inhibitors with Potent In Vitro and In Vivo Antitumor Efficacy in a Triple-Negative Breast Cancer Model

In
the present study, a novel series of 3-pyrimidinylazaindoles
were designed and synthesized using a bioinformatics strategy as cyclin-dependent
kinases CDK2 and CDK9 inhibitors, which play critical roles in the
cell cycle control and regulation of cell transcription. The present
approach gives new dimensions to the existing SAR and opens a new
opportunity for the lead optimizations from comparatively inexpensive
starting materials. The study led to the identification of the alternative
lead candidate 4ab with a nanomolar potency against CDK2
and CDK9 and potent antiproliferative activities against a panel of
tested tumor cell lines along with a better safety ratio of ∼33
in comparison to reported leads. In addition, the identified lead 4ab demonstrated a good solubility and an acceptable in vivo
PK profile. The identified lead 4ab showed an in vivo
efficacy in mouse triple-negative breast cancer (TNBC) syngeneic models
with a TGI (tumor growth inhibition) of 90% without any mortality
growth inhibition in comparison to reported leads.