Journal
CURRENT TOPICS IN MEDICINAL CHEMISTRY
Volume 11, Issue 11, Pages 1340-1351Publisher
BENTHAM SCIENCE PUBL LTD
DOI: 10.2174/156802611795589638
Keywords
CK2; quinalizarin; non-oncogene addiction; Promiscuity Score; PIM-1; HIPK2; DYRK1A; ERK-8
Categories
Funding
- European Commission [503467]
- Associazione Italiana per la Ricerca sul Cancro (AIRC)
- Italian Cystic Fibrosis Research Foundation [FFC 4/2009]
- MRC [MC_EX_G0800765] Funding Source: UKRI
- Medical Research Council [MC_EX_G0800765] Funding Source: researchfish
Ask authors/readers for more resources
CK2 denotes a pleiotropic, constitutively active protein kinase whose abnormally high level in many cancer cells is held as an example of non oncogene addiction. A wide spectrum of cell permeable, fairly specific ATP site-directed CK2 inhibitors are currently available which are proving useful to dissect its biological functions and which share the property of inducing apoptosis of cancer cells with no comparable effect on their normal counterparts. One of these, CX-4945, has recently entered clinical trials for the treatment of advanced solid tumors, Castelman's disease and multiple myeloma. The solution of a wide range of 3D structures of inhibitors bound to the catalytic subunits of CK2 reveals that their efficacy substantially relies on hydrophobic interactions within a cavity which is smaller than in other protein kinases. Accordingly the potency of tetra-halogenated benzimidazoles increases upon replacement of chlorine by bromine and, even more, by iodine, and decreases if two unique bulky side chains on CK2 (Val66 and Ile174) are mutated to alanines. Many CK2 inhibitors have been tested on a panel of more than 60 kinases providing Promiscuity Scores useful to evaluate their selectivity, the lowest value (9.47), denoting highest selectivity, being displayed by quinalizarin. The observation that CK2 inhibitors with medium/high promiscuity scores share the ability to inhibit a group of protein kinases as effectively as CK2 discloses the possibility of using their scaffolds for the rational development of selective inhibitors of these kinases, with special reference to PIMs, DYRKs, HIPK2, PKD and ERK8.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available