CDK5 Subfamily

The CDK5 subfamily contains 'atypical' CDKs, which display differences in binding partners and signaling pathways compared to the CDK1 subfamily and the CDK4 subfamily. CDK5 binds non-cyclin proteins and is involved in neuronal development and function, while CDK14 and CDK16 are involved in the cell cycle and Wnt signaling.


CDK5 Subfamily Inhibitors

Cat. No. Product Name / Activity
7223 Dabrafenib mesylate
Potent and selective B-Raf, CDK16 and NEK9 inhibitor; anticancer; also targets human proteins in the SARS-CoV-2 interactome
7336 Dinaciclib
Potent and selective inhibitor of CDK2, CDK5, CDK1 and CDK9
7158 FMF-04-159-2
Potent covalent CDK14 and CDK16 inhibitor; also inhibits other TAIRE kinase family members
7159 FMF-04-159-R
Potent CDK14 and CDK16 inhibitor; displays reversible inhibition of CDK14

The CDK5 subfamily of cyclin-dependent kinases includes CDK5, CDK14, CDK15, CDK16, CDK17 and CDK18. CDK16, CDK17 and CDK18 have a PCTAIRE sequence in the C-terminal helix and bind cyclin Y.


CDK5, also known as neuronal CDC2-like kinase (NCLK), was first identified as a result of structural similarities to CDK1, however its activators are non-cyclin proteins CDK5R1 (p35) and CDK5R2 (p39). Due to the selective expression of p35 and p39, CDK5 activity is restricted to terminally differentiated cells, including neurons where it has a role in neuronal development, neuronal migration, neurite outgrowth and synapse formation. Once activated CDK5 can phosphorylate proteins involved in the actin-cytoskeleton, including neurofilaments, tau, MAP1B, doublecortin and other microtubule-associated proteins. Mice lacking p35 and p39, or CDK5 display altered laminar structures in the cerebral cortex, olfactory bulb, hippocampus and cerebellum. Since CDK5 plays a vital role in neurodevelopment, neuronal migration and synapse formation, it has been linked to pain, drug abuse and addiction, memory and cognition.

In addition to activation by p35 and p39, the activity of CDK5 is also regulated by p25, which is cleaved from p35 by calpain; p25 prolongs the activation of CDK5. High levels of p25 have been identified in the neurons of Alzheimer's disease patients and this accumulation correlates with increased CDK5 levels, leading to hyperphosphorylation of Tau that aggregates to form neurofibrillary tangles.

CDK5 is also involved in processes outside of neuroscience; it has been linked to angiogenesis, pancreatic function, immune system function and cellular circadian clock regulation. Regarding angiogenesis, CDK5 promotes the expression of VEGF, activates Notch signaling and is involved in remodeling of the cytoskeleton.

Structure of CDK5 bound to p25

Figure 1: Structure of CDK5 (green) bound to p25 (orange). Taken from Ahn et al (2005) Defining Cdk5 ligand chemical space with small molecule inhibitors of Tau phosphorylation. Chem. Biol. 12, 811. PMID: 16039528.

CDK14 and CDK16

CDK14 and CDK16 bind cyclin Y, which unlike other cyclins is membrane bound, and are associated with regulation of multiple signaling pathways. For example, CDK16 bound to cyclin Y phosphorylates proteins involved in control of exocytosis and is essential for spermatogenesis. CDK14 and CDK16 regulate Wnt signaling during G2/M phase of the cell cycle by phosphorylating the receptor of Wnt proteins, LRP, leading to activation of Wnt signaling. β-catenin and other Wnt pathway members localize to the centrosome and kinetochore and regulate the formation and orientation of mitotic spindle, and chromosome separation. FMF-04-159-2 (Cat. No. 7158) is a potent CDK14/16 inhibitor in vitro that displays irreversible, covalent binding and causes cell cycle arrest at G2/M phase.