Therapeutic targeting of transcriptional cyclin-dependent kinases

Abstract

The fact that many cancer types display transcriptional addiction driven by dysregulation of oncogenic enhancers and transcription factors has led to increased interest in a group of protein kinases, known as transcriptional cyclin dependent kinases (tCDKs), as potential therapeutic targets. Despite early reservations about targeting a process that is essential to healthy cell types, there is now evidence that targeting tCDKs could provide enough therapeutic window to be effective in the clinic. Here, we discuss recent developments in this field, with an emphasis on highly-selective inhibitors and the challenges to be addressed before these inhibitors could be used for therapeutic purposes. Abbreviations: CAK: CDK-activating kinase;CDK: cyclin-dependent kinase;CMGC group: CDK-, MAPK-, GSK3-, and CLK-like;CTD: C-terminal repeat domain of the RPB1 subunit of RNA polymerase II;DRB: 5,6-dichloro-1-β-D-ribofuranosylbenzimidazole;mCRPC: metastatic castration-resistant prostate cancer;NSCLC: non-small cell lung cancer;P-TEFb: positive elongation factor b;RNAPII: RNA polymerase II;S2: serine-2 of CTD repeats;S5: serine-5 of CTD repeats;S7: serine-7 of CTD repeats;SEC: super elongation complex;tCDK: transcriptional cyclin-dependent kinase;TNBC: triple-negative breast cancer.

Keywords: CDK; CTD; RNA polymerase II; elongation; transcription.

Figure 1.

Summary of the major known roles of the transcriptional CDKs during the RNAPII transcription cycle. Black circles denote positive roles, grey circles denote indirect roles of CDK7 (via phosphorylation of CDK9), and the open circle denotes the kinase-independent inhibitory effect of CDK8 on Mediator-RNAPII interaction and preinitiation complex formation. Not depicted are CDK19 or the phosphorylation of transcription-related targets such as transcription factors.