Cell division cycle 25 (Cdc25) protein phosphatases play important roles in the cell cycle under normal conditions and in response to DNA damage. They could activate cyclin-dependent kinases (CDKs) through the dephosphorylation of pThr14 and pTyr15. CDKs are the central regulators of the eukaryotic cell cycle. They could phosphorylate and activate down-stream players like retinoblastoma (Rb) protein to promote cell-cycle progression. Cdc25 shows association with various cancers. Therefore, Cdc25 phosphatases are promising targets for the discovery of novel small molecule antitumor drugs. There are three subtypes of Cdc25 phosphatases including Cdc25A, Cdc25B, and Cdc25C. Cdc25A is a regulator of G1/S and G2/M transition, and it could dephosphorylate and activate the CDK2/cyclin A and CDK2/cyclin E complexes. Cdc25B and Cdc25C are regulators of G2/M transition through their ability to dephosphorylate and activate Cdk1/cyclin A, Cdck2/cyclin A, and Cdk1/cyclin B. M2N12 is a potent and highly selective Cdc25C inhibitor.

M2N12 is a potent and highly selective Cdc25C inhibitor with an IC₅₀ of 0.09  μM. It also has promising activity against Cdc25A and Cdc25B with IC₅₀s of  0.53  μM and 1.39 μM, respectively. M2N12 has anti-tumor activity and has the potential for cancer research. In addition, M2N12 has cytotoxic activity against five tumor cell lines and a normal cell line including A-549, MDA-MB-231, KB, KB-VIN, MCF-7 and HBE (IC₅₀=3.92 μM, 4.63 μM, 5.05 μM, 6.81 μM, 4.71 μM and 6 μM, respectively).

In summary, M2N12 shows a potent activity and significant Cdc25C selectivity. It also exhibits remarkable suppression on KB-VIN cell growth. Therefore, it can be used as a small molecule probe to explore the specific mechanism of Cdc25C.

Reference:

Jing L, et al.  Eur J Med Chem. 2019 Sep 14;183:111696.