Casein kinase 2 is a serine/threonine selective protein kinase. Firstly, CK2 typically appears as a tetramer of two α subunits; α is 42 kDa, α’ is 38 kDa, and two β subunits, each weighing 28 kDa. Then the catalytic α domain is shown as an α or α’ variant and can form homodimers (α & α, or α’ & α’) or heterodimers (α & α’). The α subunit does not require the β regulatory subunit to function, allowing the dimer to form the catalytic domain independently of the β subunit transcription. CK2 is a protein kinase responsible for the phosphorylation of substrates in various pathways within the cell; ATP or GTP can be used as the phosphate source. CK2 has dual functions of participating in cell growth/proliferation and inhibiting apoptosis. The anti-apoptotic function of CK2s is cell cycle continuation; from G1 to S phase and G2 to M phase checkpoints.
Silmitasertib is a CK2 inhibitor for hematological tumor research.
Silmitasertib (CX-4945) is an orally bioavailable, highly selective, and potent CK2 inhibitor, with IC50 values of 1 nM against CK2α and CK2α’. Firstly, Silmitasertib (CX-4945) causes cell cycle arrest and selectively induces apoptosis in cancer cells relative to normal cells. So, that attenuates PI3K/Akt signaling. Meanwhile, the antiproliferative activity of Silmitasertib (CX-4945) correlates with the level of attenuation of CK2α catalytic subunit PI3K/Akt signaling. Secondly, Silmitasertib (CX-4945) with PS-341 treatment prevents leukemic cells from engaging a functional UPR in order to buffer the PS-341-mediated proteotoxic stress in ER lumen. And it decreases pro-survival ER chaperone BIP/Grp78 expression.
In addition, it induces cytotoxicity and apoptosis and exerts anti-proliferative effects in hematological tumors by downregulating CK2 expression. Moreover, it suppresses the activation of CK2-mediated PI3K/Akt/mTOR signaling pathways. Besides, Silmitasertib (25 or 75 mg/kg, p.o.) is well tolerated and demonstrated robust antitumor activity with concomitant reductions of the mechanism-based biomarker phosphor-p21 (T145) in murine xenograft models.
In conclusion, Silmitasertib (CX-4945) is a potent, orally available, and highly selective CK2 inhibitor.
References:
[1] Adam Siddiqui-Jain, et al. Cancer Res. 2010 Dec 15;70(24):10288-98.
[2] Hae J Chon, et al. Front Pharmacol. 2015 Mar 31;6:70.