Lesson 6: CK2 (Casein Kinase 2) is also essential for the activation of PAK1 in cells

At least three distinct Tyr-kinases (ETK, JAK2 and FYN) are essential for the activation of PAK1 in cells. These kinases act down-stream of the oncogenic RAS. Recently another kinase was found to activate PAK1 in a RAS-dependent manner, too. It is called CK2 (Casein Kinase 2) which phosphorylates PAK1 at Ser 223 (1). The CK2-PAK1 interaction requires another protein called CKIP1, a PH domain protein. Furthermore, it is also known that PI-3 kinase acts upstream of the oncogenic CKIP1-CK2-PAK1 pathway. Thus, RAS-PI-3 kinase-CKIP1-CK2-PAK1 cascade has been established. In other words, CK2 inhibitors would block PAK1.

So I wonder what sort of CK2 inhibitors have been developed till now. Among several CK2 inhibitors, "D11 " is among the most potent, with the IC50 around 5 nM in vitro (2). It  was recently developed by a Danish group led by Barbara Guerra, and inhibits the PAK1-dependent growth of pancreatic cancer cells with the IC50 around 50 micro M in cell culture. Another potent CK2 inhibitor called "TF" (IC50=50 nM in vitro) inhibits the growth of cancer cells with IC50 around 50 micro M. Thus, their cell-permeability is extremely poor. I wonder if there is any potent CK2 inhibitor(s)  inhibiting the growth of cancer cells with IC50 at low nM levels.

So far CX-4945 (developed by Cylene Pharmaceuticals in US) is the most potent among CK2 inhibitors, with IC50=1 nM (in vitro) but 1 micro M (in cell culture), and inhibits the growth of human pancreatic cancer grafted in mice by 93 % with the daily dose of 75 mg/kg orally (3).

If I understand correctly, Senhwa Biosciences in Taiwan/US is currently conducting the phase1/2 clinical trials of CX-4945 for cancer therapy in combination with gemcitabin and cisplatin, hinting that CX-4945 alone is not sufficient for the complete cure of cancers.

References:

1. Kim YB, Shin YJ, Roy A, Kim JH.　The Role of the Pleckstrin Homology Domain-Containing Protein CKIP-1 in Activation of p21-activated Kinase 1 (PAK1). J Biol Chem. 2015 Jul 9.

2. Guerra B, Hochscherf J, Jensen NB, Issinger OG. Identification of a novel potent, selective and cell permeable inhibitor of protein kinase CK2 from the NIH/NCI Diversity Set Library. Mol Cell Biochem. 2015 May 12.

3. Siddiqui-Jain A¹, Drygin D, Streiner N, Chua P,et al. CX-4945, an orally bioavailable selective inhibitor of protein kinase CK2, inhibits prosurvival and angiogenic signaling and exhibits antitumor efficacy. Cancer Res. 2010; 70: 10288-98.