Discovery of <i>N</i>‑(4-(3-isopropyl-2-methyl‑2<i>H</i>‑indazol-5-yl)pyrimidin-2-yl)-4-(4-methylpiperazin-1-yl)quinazolin-7-amine as a Novel, Potent, and Oral Cyclin-Dependent Kinase Inhibitor against Haematological Malignancies

Hematologic
malignancies (HM) start in blood forming tissue or
in the cells of the immune system. Cyclin-dependent kinases (CDKs)
regulate cell cycle progression, and some of them control cellular
transcription. CDK inhibition can trigger apoptosis and could be particularly
useful in hematological malignancies. Herein, we describe our efforts
toward the discovery of a novel series of quinazoline derivatives
as CDK inhibitors. Intensive structural modifications lead to the
identification of compound 37d as the most active inhibitors
of CDKs 1, 2, 4, 8 and 9 with balancing potency and selectivity against
CDKs. Further biological studies revealed that compound 37d can arrest the cell cycle and induce apoptosis via activating PARP
and caspase 3. More importantly, compound 37d showed
good antitumor efficacy in multiple HM mice xenograft models with
no obvious toxicity. These results indicated that CDK 1, 2, 4, 8,
and 9 inhibitors could be potentially used to treat certain hematologic
malignancies.