Therapeutic potential of CDK11 in cancer

Abstract

Human cyclin-dependent kinases (CDKs) direct the progression of the cell cycle and transcription. They are deregulated in tumours, and despite their involvement in the regulation of basic cellular processes, many CDKs are promising targets for cancer therapy. CDK11 is an essential gene for the growth of many malignancies; however, its primary cellular function has been obscure, and the mode-of-action of OTS964, the first CDK11 inhibitor and antiproliferative compound, has been unknown. A recent study has shown that OTS964 prevents spliceosome activation, revealing a key role of CDK11 in the regulation of pre-mRNA splicing. In light of these findings, we discuss the therapeutic potential of CDK11 in cancer.

Keywords: CDK11; OTS964; SF3B1; cancer; pladienolide B; spliceosome; splicing.

FIGURE 1

Spliceosome assembly is blocked at different stages by inhibitors of SF3B1 and CDK11. The figure represents a simplified scheme of spliceosome assembly on pre‐mRNA consisting of exon 1, exon 2, intron, 5´ and 3´ splice sites (5´SS and 3´SS) and branch point site (BPS) adenosine (A). Five small nuclear ribonucleoprotein particles (snRNPs) (colored U1, U2, U4, U5 and U6 circles), each consisting of several proteins and respective snRNAs, dynamically assemble into various spliceosome complexes. Only spliceosome complexes A, B and B^act are depicted, complexes E, B*, C, C* are omitted for simplicity. SF3B1, a core subunit of U2 snRNP, consists of the structured C‐terminal HEAT‐repeat domain (red oval) and the N‐terminal intrinsically disordered threonine‐rich domain (red wavy lane). The HEAT‐repeat domain recognizes branch point site adenosine in the pre‐mRNA in the A complex; this interaction is inhibited by the indicated groups of drugs resulting in blockage of the spliceosome assembly before the formation of the A complex. The threonine‐rich domain is phosphorylated (P) by CDK11 (yellow oval) during the spliceosome transition from the B to B^act complex, and the hyperphosphorylated SF3B1 associates with U5 and U6 snRNAs (not shown) within the U5 and U6 snRNPs (violet and green circle, respectively) in the B^act complex. The CDK11 inhibitor OTS964 inhibits the phosphorylation of SF3B1 and blocks spliceosome assembly at the B complex stage. CDK11 binds to SF3B1, but it is not known to which spliceosome complex CDK11 is recruited to and released from.