Cdc-Like Kinases (CLKs): Biology, Chemical Probes, and Therapeutic Potential.

Paula Martín Moyano,Kamil Paruch,Václav Němec

doi:10.3390/ijms21207549

Abstract

Protein kinases represent a very pharmacologically attractive class of targets; however, some members of the family still remain rather unexplored. The biology and therapeutic potential of cdc-like kinases (CLKs) have been explored mainly over the last decade and the first CLK inhibitor, compound SM08502, entered clinical trials only recently. This review summarizes the biological roles and therapeutic potential of CLKs and their heretofore published small-molecule inhibitors, with a focus on the compounds’ potential to be utilized as quality chemical biology probes.

Highlights

Protein kinases play pivotal roles in nearly every aspect of cellular function [1]
CLK3 contains a small insert between stands β6 and β9 in the kinase core that interacts with a hydrophobic pocket near the hinge region that connects the N- and C-lobes [50]
nuclear localization sequence (NLS) strongly interacts with its substrate SRSF1 (SR protein), which is very likely important for the nuclear import of CLK1 via a “piggyback” mechanism, where CLK1 is transported inside the nucleus together with the TRN-SR2/SRSF1 complex (Figure 6)

Summary

Introduction

Protein kinases play pivotal roles in nearly every aspect of cellular function [1]. They transfer the γ-phosphate group from nucleoside triphosphate (typically ATP or GTP) to the hydroxyl group of serine, threonine, or tyrosine residues of the physiological substrate. Phosphorylation of proteins can lead to activation or deactivation of signal-transduction pathways that are important in various biological processes such as metabolism, transcription, cell cycle progression, cell movement, apoptosis, and differentiation. The kinase-driven cellular processes include alternative and constitutive splicing, which are pivotal for gene expression [15,16]. The splicing process is, to a large extent, regulated 2byof p31rotein kinasbeys tthheahtipghheorsdpihvoerrsyitlyatoefstphelicpirnogtefoamcteo[r1s6—,17c]e.nAtrbaelrrcaonmt sppolincienngtsisorfestphoensspiblliecefoorsothmeein, afoccrueraxtaemple, serinter/aanrsgliantiionne-orficghenpertoicteininfosr(mSaRtiponroitnetiontsh)e—starnudctulersesodf iprreoctteliynsa,lswohbicyhohtahseorftkeinnaasneesgiantivvoelivmepdaicnt ocnellular signavlainrigoupsatchelwlualayrs p[1ro9c,2e2ss]e. Discovered highly selective tool compounds (quality probes) that are summarized in this review

Classification and Structure of CLKs

Effects of Altered CLK Expression

CLKs as Therapeutic Targets

Small-Molecule CLK Inhibitors

Findings

Conclusions