Novel CDK2 Inhibitors as Anti-Tumor Agents

Conventional anti-cancer drugs have mainly focused on targeting DNA synthesis and cell division. Though, these drugs show experimental and clinical efficacy against a variety of cancers, they simultaneously cause severe adverse effects due to the lack of selectivity for tumor cells over normal cells.
In order to avoid these adverse effects, investigators begin to develop a new class of anti-cancer agents, and signal transduction or secondary message inhibitors is one of the successful research findings. The mechanism mainly depends on the regulation of signaling pathways on cell growth, apoptosis, and intracellular protein degradation, thus, inhibition should lead to anti-cancer effects.
The D-type cyclins and their kinase partners (CDKs) have an important role in cell cycle, because they can phosphorylate the tumor suppressor protein, strong>retinoblastoma protein (PRB) during the G-1 phase of the cell cycle and promote its inactivation. These CDK-cyclin complexes are regulated by small inhibitory proteins called Endogenous CDK inhibitors
Pyrimidopyrimidines and their derivatives have been confirmed to present many pharmacological activities including anti-tumour, antiviral, antioxidant [12], antifungal and hepatoprotective activities. Recently, El-moghazy and his group found that pyrazolo[3,4-d]pyrimidines and 3,6-disubstituted [1,2,4]triazolo[3,4-b][1,3,4]thiadiazole analogs are novel anti-cancer inhibitors and anti-proliferative agents. Biochemical Assay showed that most compounds with high activities towards CDK2 (IC50 < 1 μM) proved to be selective inhibitors. While some of them showed high growth inhibitions on Non-small cell lung cancer, Ovarian cancer, Leukemia, and Melanoma[1]. 
     These data show that pyrimido[4,5-d]pyrimidine CDK2 inhibitors, with potent and selective CDK inhibitory activities, may provide the potential therapy against cancer.

[1]. Sci Pharm. 2011; 79: 429–447