CDK5R1

Summary

CDK5R1 (cyclin dependent kinase 5 regulatory subunit 1, HGNC:1775) is a protein-coding gene on chromosome 17q11.2, encoding Cyclin-dependent kinase 5 activator 1 (Q15078). p35 is a neuron specific activator of CDK5.

The protein encoded by this gene (p35) is a neuron-specific activator of cyclin-dependent kinase 5 (CDK5); the activation of CDK5 is required for proper development of the central nervous system. The p35 form of this protein is proteolytically cleaved by calpain, generating a p25 form. The cleavage of p35 into p25 results in relocalization of the protein from the cell periphery to nuclear and perinuclear regions. P25 deregulates CDK5 activity by prolonging its activation and changing its cellular location. The p25 form accumulates in the brain neurons of patients with Alzheimer’s disease. This accumulation correlates with an increase in CDK5 kinase activity, and may lead to aberrantly phosphorylated forms of the microtubule-associated protein tau, which contributes to Alzheimer’s disease.

Source: NCBI Gene 8851 — RefSeq curated summary.

At a glance

• Clinical variants (ClinVar): 25 total
• Druggable target: yes — 31 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_003885

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:1775
Approved symbol	CDK5R1
Name	cyclin dependent kinase 5 regulatory subunit 1
Location	17q11.2
Locus type	gene with protein product
Status	Approved
Aliases	p35nck5a, Nck5a, p35
Ensembl gene	ENSG00000176749
Ensembl biotype	protein_coding
OMIM	603460
Entrez	8851

Gene structure

Transcript identifiers

Ensembl transcripts: 7 — 6 protein_coding, 1 nonsense_mediated_decay

ENST00000313401, ENST00000584716, ENST00000584792, ENST00000877300, ENST00000877301, ENST00000877302, ENST00000956210

RefSeq mRNA: 1 — MANE Select: NM_003885 NM_003885

CCDS: CCDS11273

Canonical transcript exons

ENST00000313401 — 2 exons

Exon	Start	End
ENSE00001271005	32486993	32487162
ENSE00001271015	32487476	32491253

Expression profiles

Bgee: expression breadth ubiquitous, 239 present calls, max score 99.30.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 10.4051 / max 568.3894, expressed in 1143 samples.

FANTOM5 promoters (17 alternative TSS)

Promoter ID	TPM avg	Samples expressed
160240	2.8250	770
160248	2.3367	426
160245	1.3889	266
160243	1.2612	412
160247	0.7186	208
160252	0.3327	109
160242	0.2545	92
160251	0.2531	71
160253	0.2115	69
160241	0.1955	69

Top tissues by expression

291 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
cortical plate	UBERON:0005343	99.30	gold quality
ganglionic eminence	UBERON:0004023	98.43	gold quality
CA1 field of hippocampus	UBERON:0003881	97.93	gold quality
Brodmann (1909) area 23	UBERON:0013554	97.80	gold quality
ventricular zone	UBERON:0003053	97.79	gold quality
superior frontal gyrus	UBERON:0002661	96.44	gold quality
orbitofrontal cortex	UBERON:0004167	96.08	gold quality
Brodmann (1909) area 9	UBERON:0013540	96.02	gold quality
parietal lobe	UBERON:0001872	95.87	gold quality
postcentral gyrus	UBERON:0002581	95.85	gold quality
entorhinal cortex	UBERON:0002728	95.75	gold quality
primary visual cortex	UBERON:0002436	95.31	gold quality
occipital lobe	UBERON:0002021	95.19	gold quality
prefrontal cortex	UBERON:0000451	95.14	gold quality
lateral nuclear group of thalamus	UBERON:0002736	95.03	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	94.94	gold quality
frontal cortex	UBERON:0001870	94.62	gold quality
cerebral cortex	UBERON:0000956	94.43	gold quality
neocortex	UBERON:0001950	94.23	gold quality
middle temporal gyrus	UBERON:0002771	94.20	gold quality
Brodmann (1909) area 46	UBERON:0006483	93.94	gold quality
right frontal lobe	UBERON:0002810	93.69	gold quality
Ammon’s horn	UBERON:0001954	93.53	gold quality
temporal lobe	UBERON:0001871	93.45	gold quality
cerebellar hemisphere	UBERON:0002245	93.32	gold quality
cerebellar cortex	UBERON:0002129	93.28	gold quality
right hemisphere of cerebellum	UBERON:0014890	92.77	gold quality
cerebellum	UBERON:0002037	92.73	gold quality
telencephalon	UBERON:0001893	92.67	gold quality
amygdala	UBERON:0001876	92.17	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-GEOD-93593	yes	15.40
E-ANND-3	yes	5.36

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): EGR1, HNRNPA2B1, HSF2, JUN, TTBK1

miRNA regulators (miRDB)

116 targeting CDK5R1, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-5193	100.00	67.26	1744
HSA-MIR-186-5P	99.99	70.83	3707
HSA-MIR-4789-3P	99.99	70.75	2484
HSA-LET-7F-2-3P	99.98	70.98	2588
HSA-MIR-1185-1-3P	99.98	71.04	2593
HSA-MIR-1185-2-3P	99.98	71.04	2593
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-4267	99.96	66.53	2368
HSA-MIR-548AA	99.96	70.64	3753
HSA-MIR-548AP-3P	99.96	70.64	3753
HSA-MIR-548T-3P	99.96	70.64	3753
HSA-MIR-6772-5P	99.94	67.01	577
HSA-MIR-497-5P	99.92	71.83	2674
HSA-MIR-515-5P	99.92	69.82	2343
HSA-MIR-519E-5P	99.92	69.62	2358
HSA-MIR-15A-5P	99.90	72.80	2787
HSA-MIR-15B-5P	99.90	72.78	2798
HSA-MIR-16-5P	99.90	72.80	2780
HSA-MIR-195-5P	99.90	72.81	2805
HSA-MIR-3671	99.90	73.04	3897
HSA-MIR-424-5P	99.89	71.90	2641
HSA-MIR-6838-5P	99.89	71.94	2690
HSA-MIR-548E-5P	99.89	72.73	4486
HSA-MIR-4698	99.84	71.41	4303
HSA-MIR-1323	99.83	69.89	2471
HSA-MIR-5010-3P	99.83	70.60	2357
HSA-MIR-6756-5P	99.82	67.97	2466
HSA-MIR-3133	99.81	70.92	3506
HSA-MIR-199A-3P	99.75	70.48	929
HSA-MIR-199B-3P	99.75	70.48	929

Literature-anchored findings (GeneRIF, showing 40)

• Like p25, p29 was more stable than p39 and caused redistribution of Cdk5 in cortical neurons. Our data suggest that neurotoxic insults lead to calpain-mediated conversion of p39 to p29, which might contribute to deregulation of Cdk5. (PMID:11784720)
• cleavage of p35 to p25 greatly enhances the kinase activity of CDK5 and increases the phosphorylation of Ser(202)/Thr(205) and may play a pivotal role in neuronal cell death in Alzheimer’s disease (PMID:12226093)
• a short peptide (amino acid residues 154-279; Cdk5 inhibitory peptide; CIP), derived from p35, specifically inhibits Cdk5 activity in vitro and in HEK293 cells cotransfected with the peptide and Cdk5/p25, but had no effect on endogenous cdc2 kinase (PMID:12230554)
• p25-Cdk5 is responsible for the mitotic-like phosphoepitopes present in neurofibrillary tangles (PMID:12826674)
• Neither the CDK5 activator p25 immunoreactivity nor the p25/p35 ratio was elevated in Alzheimer disease brains or in other tauopathies (n = 34) compared with controls (n = 11) (PMID:12859671)
• Expression of p35 and CDK5 in insulin-producing beta-cellsis new signaling pathway controlled by glucose, and its functional role may comprise regulation of various biological processes in beta-cells, such as expression of the insulin gene. (PMID:14976144)
• These results suggest that Cdk5/p35 and p25 are novel players in digoxin-triggered prostate cancer cell apoptosis and, therefore, become potential therapeutic targets. (PMID:15123618)
• significantly lower levels of cyclin-dependent kinase 5, regulatory subunit 1 (p35) gene transcripts were detected in gangliogliomas compared to controls (PMID:15175076)
• CK2 acts as an inhibitor of Cdk5 in the brain (PMID:15342635)
• data suggest that Cyclin-dependent kinase 5 (Cdk5)-Cdk5 activator p35 is required to elicit the maximum GTP-induced secretory response from neutrophils (PMID:15492003)
• Cdk5 activity and p35 translocation in the ventral striatum were upregulated in methamphetamine sensitized rats. (PMID:15536496)
• an early event in neuronal cell death is p25/Cdk5-mediated retinoblastoma phosphorylation (PMID:15741232)
• role of the CDK5 molecular complex in the genetic etiology of early-onset Alzheimer disease; a yet unknown functional variant in CDK5 or in a nearby gene might lead to increased susceptibility for early onset Alzheimer disease (PMID:15917097)
• molecular analysis of the CDK5/p25 and CDK2/cyclin A systems (PMID:16407256)
• novel mutations and novel polymorphisms in coding regions and 3’UTR were detected in patients with with non-syndromic mental retardation (PMID:16425041)
• Cdk5 and Erk1/2 kinases share some common substrates but impact of their cross talk on tau phosphorylation has not previously been demonstrated. (PMID:16678793)
• nestin is a survival determinant whose action is based upon a novel mode of Cdk5 regulation, affecting the targeting, activity, and turnover of the Cdk5/p35 signaling complex (PMID:17036052)
• p35 employs pathways distinct from that used by Cdk5 for transport to the nucleus (PMID:17060323)
• phosphorylation of Thr(138) predominantly defines the susceptibility of p35 to calpain-dependent cleavage and dephosphorylation of this site is a critical determinant of Cdk5-p25-induced cell death associated with neurodegeneration (PMID:17121855)
• p35 is a microtubule-associated protein that modulates microtubule dynamics (PMID:17491008)
• Increased expression of Cdk5 was seen in stroke-affected tissue, with about a third showing increased p35 and p25 cleaved fragment. Increased Cdk5-, p-Cdk5- and p35-positive neurons and microvessels occurred in stroke-affected regions. (PMID:17493033)
• This experiment demonstrate increased immunoreactivity for the activators of cyclin-dependent kinase 5 in post-mortem human hippocampi affected by the neurodegenerative condition hippocampal sclerosis. (PMID:17496813)
• the involvement of 3’-UTR in the modulation of CDK5R1 expression (PMID:18053171)
• Data demonstrate that a decrease in the level of Egr-1, one of the targets for MAPK, by Tat has a negative impact on the level of p35 expression in NGF-treated neural cells. (PMID:18247371)
• p35 co-expression targets E-cadherin to lysosomes and p35-triggered disappearance of E-cadherin precursor can be blocked specifically by lysosomal protease inhibitors, indicating p35 induces endocytosis and subsequent degradation of precursor E-cadherin (PMID:18325333)
• p25 and cyclin-dependent kinase 5 play important roles as mediators of dopamine and glutamate in the neurotoxicity associated with Huntington’s disease. (PMID:18829967)
• Subjects carrying both the CDK5R1 (3’-UTR, rs735555) AA genotype and the GSK-3beta (-50, rs334558) CC genotype had a 12.5-fold decrease in Alzheimer disease risk suggesting synergistic effects (epistasis) between both genes (PMID:19154537)
• a role for Cdk5-p35 as a survival factor in countering MPP+-induced neuronal cell death. (PMID:19638632)
• These are the first quantitative and site-specific measurements of phosphorylation of p35 (PMID:20097924)
• CDK5/p35 may represent a biomarker for prognosis in patients with non-small cell lung cancer (PMID:20354813)
• both proteasomal degradation and calpain cleavage of p35 and p39 are stimulated by membrane association, which is in turn mediated via myristoylation of their p10 regions. (PMID:20518484)
• The present study dissects the role of 3 single nucleotide polymorphisms (rs334558 and rs6438552 of GSK3B, and rs735555 of CDK5R1) in Parkinson’s disease pathogenesis among eastern Indians. (PMID:21130530)
• Study reveals a unique role of Cdk5/p35 in activation of the major noncanonical function of EPRS, namely translational control of macrophage inflammatory gene expression. (PMID:21220307)
• The decrease in membrane-associated p35 in socially isolated transgenic mice reduces associated levels of p35, alpha-CaMKII, and GluR1 and leads to endocytosis of AMPA receptors. (PMID:21544067)
• findings indicate that miR-103 and miR-107 regulate CDK5R1 expression, allowing us to hypothesize that a miRNA-mediated mechanism may influence CDK5 activity and the associated molecular pathways (PMID:21625387)
• This study suggested that reduced p35 expression in schizophrenia has an impact on synaptic protein expression and cognition and that these deficits can be rescued, at least in part, by the inhibition of histone deacetylase 1. (PMID:21772061)
• Reduced p35 basal content and down–regulation of CDK5/p35/p25 by antipsychotics are demonstrated in postmortem prefrontal cortex of schizophrenic subjects. (PMID:22964075)
• p10, the N-terminal domain of p35, protects against CDK5/p25-induced neurotoxicity. (PMID:23151508)
• Structural basis for the different stability and activity between the Cdk5 complexes with p35 and p39 activators. (PMID:24085300)
• Expression of p35 is upregulated in human pituitary adenomas. (PMID:24550687)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	cdk5r1a	ENSDARG00000037916
danio_rerio	cdk5r1b	ENSDARG00000045087
mus_musculus	Cdk5r1	ENSMUSG00000048895
rattus_norvegicus	Cdk5r1	ENSRNOG00000068243

Paralogs (1): CDK5R2 (ENSG00000171450)

Protein

Protein identifiers

Cyclin-dependent kinase 5 activator 1 — Q15078 (reviewed: Q15078)

Alternative names: Cyclin-dependent kinase 5 regulatory subunit 1, TPKII regulatory subunit

All UniProt accessions (2): Q15078, J3QRB5

UniProt curated annotations — full annotation on UniProt →

Function. p35 is a neuron specific activator of CDK5. The complex p35/CDK5 is required for neurite outgrowth and cortical lamination. Involved in dendritic spine morphogenesis by mediating the EFNA1-EPHA4 signaling. Activator of TPKII. The complex p35/CDK5 participates in the regulation of the circadian clock by modulating the function of CLOCK protein: phosphorylates CLOCK at ‘Thr-451’ and ‘Thr-461’ and regulates the transcriptional activity of the CLOCK-BMAL1 heterodimer in association with altered stability and subcellular distribution.

Subunit / interactions. Heterodimer composed of a catalytic subunit CDK5 and a regulatory subunit CDK5R1 (p25) and macromolecular complex composed of at least CDK5, CDK5R1 (p35) and CDK5RAP1 or CDK5RAP2 or CDK5RAP3. Only the heterodimer shows kinase activity. Interacts with EPHA4 and NGEF; may mediate the activation of NGEF by EPHA4. Interacts with RASGRF2. The complex p35/CDK5 interacts with CLOCK.

Subcellular location. Cell membrane. Cell projection. Neuron projection Nucleus. Cytoplasm. Perinuclear region. Perikaryon.

Tissue specificity. Brain and neuron specific.

Post-translational modifications. The p35 form is proteolytically cleaved by calpain, giving rise to the p25 form. P35 has a 5 to 10 fold shorter half-life compared to p25. The conversion results in deregulation of the CDK5 kinase: p25/CDK5 kinase displays an increased and altered tau phosphorylation in comparison to the p35/CDK5 kinase in vivo. Myristoylated. A proper myristoylation signal is essential for the proper distribution of p35. Ubiquitinated, leading to its degradation: degradation of p35 by proteasome results in down-regulation of CDK5 activity. During this process, CDK5 phosphorylates p35 and induces its ubiquitination and subsequent degradation. Ubiquitinated by the CRL2(FEM1B) complex, which recognizes the -Gly-Leu-Asp-Arg C-degron at the C-terminus, leading to its degradation. Phosphorylation at Ser-8 and Thr-138 by CDK5 prevents calpain-mediated proteolysis.

Miscellaneous. Cleavage of p35 to p25 may be involved in the pathogenesis of cytoskeletal abnormalities and neuronal death in neurodegenerative diseases. The p25 form accumulates in neurons in the brain of patients with Alzheimer disease, but not in normal brain. This accumulation correlates with an increase in CDK5 kinase activity. Application of amyloid beta peptide A-beta(1-42) induced the conversion of p35 to p25 in primary cortical neurons. Expression of the p25/Cdk5 complex in cultured primary neurons induces cytoskeletal disruption, morphological degeneration and apoptosis.

Similarity. Belongs to the cyclin-dependent kinase 5 activator family.

RefSeq proteins (1): NP_003876* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR004944	CDK5_activator	Family
IPR036915	Cyclin-like_sf	Homologous_superfamily

Pfam: PF03261

UniProt features (27 total): mutagenesis site 7, helix 7, chain 2, turn 2, compositionally biased region 2, modified residue 2, initiator methionine 1, strand 1, region of interest 1, site 1, lipid moiety-binding region 1

Structure

Experimental structures (PDB)

11 structures.

PDB	Method	Resolution (Å)
3O0G	X-RAY DIFFRACTION	1.95
7VDP	X-RAY DIFFRACTION	2.09
1UNL	X-RAY DIFFRACTION	2.2
1UNG	X-RAY DIFFRACTION	2.3
1UNH	X-RAY DIFFRACTION	2.35
6LDP	X-RAY DIFFRACTION	2.35
7VDR	X-RAY DIFFRACTION	2.55
1H4L	X-RAY DIFFRACTION	2.65
7VDQ	X-RAY DIFFRACTION	2.91
7VDS	X-RAY DIFFRACTION	3.05
7CNG	X-RAY DIFFRACTION	3.49

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q15078-F1	73.99	0.50

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Catalytic / active sites (1): 98–99 (cleavage; by calpain)

Post-translational modifications (3): 8, 138, 2

Mutagenesis-validated functional residues (7):

Position	Phenotype
2	absent from the cell periphery.
8	increased susceptibility to calpain.
8	reduced susceptibility to calpain.
138	increased susceptibility to calpain.
138	reduced susceptibility to calpain.
305	in l-3a mutant; abolished recognition and ubiquitination by the crl2(fem1b) complex.
305	in l-3r mutant; abolished recognition and ubiquitination by the crl2(fem1b) complex, while promoting recognition and ubi

Function

Pathways and Gene Ontology

Reactome pathways

26 pathways

ID	Pathway
R-HSA-399956	CRMPs in Sema3A signaling
R-HSA-6804756	Regulation of TP53 Activity through Phosphorylation
R-HSA-8862803	Deregulated CDK5 triggers multiple neurodegenerative pathways in Alzheimer’s disease models
R-HSA-9031628	NGF-stimulated transcription
R-HSA-9032845	Activated NTRK2 signals through CDK5
R-HSA-9768919	NPAS4 regulates expression of target genes
R-HSA-1266738	Developmental Biology
R-HSA-162582	Signal Transduction
R-HSA-1643685	Disease
R-HSA-166520	Signaling by NTRKs
R-HSA-187037	Signaling by NTRK1 (TRKA)
R-HSA-198725	Nuclear Events (kinase and transcription factor activation)
R-HSA-212436	Generic Transcription Pathway
R-HSA-3700989	Transcriptional Regulation by TP53
R-HSA-373755	Semaphorin interactions
R-HSA-422475	Axon guidance
R-HSA-5633007	Regulation of TP53 Activity
R-HSA-73857	RNA Polymerase II Transcription
R-HSA-74160	Gene expression (Transcription)
R-HSA-8863678	Neurodegenerative Diseases
R-HSA-9006115	Signaling by NTRK2 (TRKB)
R-HSA-9006934	Signaling by Receptor Tyrosine Kinases
R-HSA-9634815	Transcriptional Regulation by NPAS4
R-HSA-9645723	Diseases of programmed cell death
R-HSA-9675108	Nervous system development
R-HSA-9734009	Defective Intrinsic Pathway for Apoptosis

MSigDB gene sets: 478 (showing top): MORF_RAGE, GOBP_DENDRITE_DEVELOPMENT, GNF2_RTN1, GOBP_HINDBRAIN_DEVELOPMENT, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, MULLIGHAN_NPM1_SIGNATURE_3_UP, GOBP_REGULATION_OF_AUTOPHAGY, GOBP_REGULATION_OF_PROTEIN_POLYMERIZATION, GOBP_NEURON_RECOGNITION, MORF_FLT1, GOBP_METENCEPHALON_DEVELOPMENT, GOBP_REGULATION_OF_MICROTUBULE_BASED_PROCESS, GOBP_REGULATION_OF_PHOSPHORYLATION, TGCTGCT_MIR15A_MIR16_MIR15B_MIR195_MIR424_MIR497, GOBP_RESPONSE_TO_PEPTIDE

GO Biological Process (30): regulation of cyclin-dependent protein serine/threonine kinase activity (GO:0000079), microtubule cytoskeleton organization (GO:0000226), neuron migration (GO:0001764), neuron cell-cell adhesion (GO:0007158), G protein-coupled acetylcholine receptor signaling pathway (GO:0007213), axon guidance (GO:0007411), axonal fasciculation (GO:0007413), brain development (GO:0007420), regulation of macroautophagy (GO:0016241), peptidyl-serine phosphorylation (GO:0018105), peptidyl-threonine phosphorylation (GO:0018107), cerebellum development (GO:0021549), superior olivary nucleus maturation (GO:0021722), hippocampus development (GO:0021766), layer formation in cerebral cortex (GO:0021819), neuron differentiation (GO:0030182), positive regulation of microtubule polymerization (GO:0031116), neuron projection development (GO:0031175), regulation of actin cytoskeleton organization (GO:0032956), ionotropic glutamate receptor signaling pathway (GO:0035235), positive regulation of neuron apoptotic process (GO:0043525), regulation of neuron differentiation (GO:0045664), negative regulation of DNA-templated transcription (GO:0045892), ephrin receptor signaling pathway (GO:0048013), rhythmic process (GO:0048511), regulation of dendritic spine morphogenesis (GO:0061001), G1 to G0 transition involved in cell differentiation (GO:0070315), positive regulation of protein targeting to membrane (GO:0090314), cerebral cortex radially oriented cell migration (GO:0021799), regulation of microtubule cytoskeleton organization (GO:0070507)

GO Molecular Function (15): protease binding (GO:0002020), protein kinase activity (GO:0004672), calcium ion binding (GO:0005509), kinase activity (GO:0016301), protein kinase binding (GO:0019901), protein kinase activator activity (GO:0030295), ionotropic glutamate receptor binding (GO:0035255), alpha-tubulin binding (GO:0043014), protein serine/threonine kinase activator activity (GO:0043539), cadherin binding (GO:0045296), beta-tubulin binding (GO:0048487), actin filament binding (GO:0051015), cyclin-dependent protein serine/threonine kinase activator activity (GO:0061575), actin binding (GO:0003779), protein binding (GO:0005515)

GO Cellular Component (20): cyclin-dependent protein kinase holoenzyme complex (GO:0000307), nucleus (GO:0005634), nucleoplasm (GO:0005654), cytoplasm (GO:0005737), cytosol (GO:0005829), plasma membrane (GO:0005886), postsynaptic density (GO:0014069), membrane (GO:0016020), protein kinase 5 complex (GO:0016533), axon (GO:0030424), dendrite (GO:0030425), growth cone (GO:0030426), neuromuscular junction (GO:0031594), neuron projection (GO:0043005), neuronal cell body (GO:0043025), dendritic spine (GO:0043197), perikaryon (GO:0043204), contractile muscle fiber (GO:0043292), perinuclear region of cytoplasm (GO:0048471), cell projection (GO:0042995)

Reactome top-level categories

Rollup of top-16 pathways:

Category	Pathways
Semaphorin interactions	1
Regulation of TP53 Activity	1
Neurodegenerative Diseases	1
Nuclear Events (kinase and transcription factor activation)	1
Signaling by NTRK2 (TRKB)	1
Transcriptional Regulation by NPAS4	1
Signaling by Receptor Tyrosine Kinases	1
Signaling by NTRKs	1
Signaling by NTRK1 (TRKA)	1
RNA Polymerase II Transcription	1
Generic Transcription Pathway	1
Axon guidance	1
Nervous system development	1
Transcriptional Regulation by TP53	1
Gene expression (Transcription)	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	7
cytoplasm	3
cyclin-dependent protein serine/threonine kinase activity	2
generation of neurons	2
protein phosphorylation	2
anatomical structure development	2
tubulin binding	2
serine/threonine protein kinase complex	2
neuron projection	2
regulation of protein serine/threonine kinase activity	1
cytoskeleton organization	1
microtubule-based process	1
cell migration	1
cell-cell adhesion	1
G protein-coupled receptor signaling pathway	1
G protein-coupled acetylcholine receptor activity	1
acetylcholine receptor signaling pathway	1
axonogenesis	1
neuron projection guidance	1
neuron recognition	1
axon development	1
neuron projection fasciculation	1
central nervous system development	1
animal organ development	1
head development	1
regulation of autophagy	1
macroautophagy	1
peptidyl-serine modification	1
peptidyl-threonine modification	1
metencephalon development	1
pons maturation	1
superior olivary nucleus development	1
anatomical structure maturation	1
pallium development	1
limbic system development	1
cerebral cortex radial glia-guided migration	1
anatomical structure formation involved in morphogenesis	1
cell differentiation	1
positive regulation of microtubule polymerization or depolymerization	1
regulation of microtubule polymerization	1

Protein interactions and networks

STRING

1414 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CDK5R1	CDK5	Q00535	998
CDK5R1	CDK5RAP2	Q96SN8	808
CDK5R1	CDK5RAP3	Q96JB5	759
CDK5R1	CDK5RAP1	Q96SZ6	660
CDK5R1	BACE1	P56817	646
CDK5R1	COL25A1	Q9BXS0	582
CDK5R1	PAFAH1B1	P43034	577
CDK5R1	FOSB	P53539	570
CDK5R1	AATK	Q6ZMQ8	567
CDK5R1	MAPT	P10636	558
CDK5R1	PJA2	O43164	549
CDK5R1	NDEL1	Q9GZM8	543
CDK5R1	CABLES1	Q8TDN4	520
CDK5R1	SYP	P08247	508
CDK5R1	CAPN1	P07384	503

IntAct

85 interactions, top by confidence:

A	B	Type	Score
CDK5	CDK5R1	psi-mi:“MI:0407”(direct interaction)	0.940
CDK5R1	CDK5	psi-mi:“MI:0407”(direct interaction)	0.940
CDK5	CDK5R1	psi-mi:“MI:0915”(physical association)	0.940
CDK5R1	CDK5	psi-mi:“MI:0217”(phosphorylation reaction)	0.940
CDK5R1	CDK5	psi-mi:“MI:0915”(physical association)	0.940
CDK5	FIBP	psi-mi:“MI:0914”(association)	0.840
AATK	CDK5R1	psi-mi:“MI:0915”(physical association)	0.590
CDK5R1	AATK	psi-mi:“MI:0915”(physical association)	0.590
MTUS2	CDK5R1	psi-mi:“MI:0915”(physical association)	0.560
CDK5R1	MTUS2	psi-mi:“MI:0915”(physical association)	0.560
CDK5R1	DNASE1L1	psi-mi:“MI:0915”(physical association)	0.560
CDK5R1	KLRC1	psi-mi:“MI:0915”(physical association)	0.560
CDK5R1	EPCAM	psi-mi:“MI:0915”(physical association)	0.560
CDK5R1	MAGEA2	psi-mi:“MI:0915”(physical association)	0.560
CDK5R1	SLC25A11	psi-mi:“MI:0915”(physical association)	0.560
CDK5R1	NEK6	psi-mi:“MI:0915”(physical association)	0.560
CDK5R1	TPX2	psi-mi:“MI:0915”(physical association)	0.560
CDK5R1	CAMTA2	psi-mi:“MI:0915”(physical association)	0.560
CDK5R1		psi-mi:“MI:0915”(physical association)	0.560
CDK5R1	PIAS4	psi-mi:“MI:0915”(physical association)	0.560
CDK5R1	MYNN	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (116): CDK5R1 (Two-hybrid), MTUS2 (Two-hybrid), BLOC1S6 (Two-hybrid), KRT40 (Two-hybrid), KRTAP10-3 (Two-hybrid), NOTCH2NL (Two-hybrid), CDK2 (Affinity Capture-MS), UBE2T (Affinity Capture-MS), TPM2 (Affinity Capture-MS), CDK5 (Affinity Capture-MS), DENR (Affinity Capture-MS), PROSC (Affinity Capture-MS), HMGCS1 (Affinity Capture-MS), TSC22D4 (Two-hybrid), CDK5R1 (Two-hybrid)

ESM2 similar proteins: A2A699, A2WY46, A2XE76, A2YW03, A6NKL6, A8MVW0, B6SM63, O14492, O35615, O35926, O65001, O70143, P29353, P61809, P61810, Q0JGS5, Q13319, Q14003, Q15078, Q28199, Q2QXZ2, Q2RAQ5, Q3U0S6, Q40691, Q4ACU6, Q4KMP7, Q4KYY2, Q53LP3, Q5DU25, Q5JU85, Q5R7W7, Q5T442, Q5TJF3, Q5U651, Q61127, Q62925, Q63959, Q67UX6, Q6MWG9, Q6YPD0

Diamond homologs: O35926, P61809, P61810, Q13319, Q15078, Q22695, Q28199, Q4KYY2

SIGNOR signaling

12 interactions.

A	Effect	B	Mechanism
AATK	up-regulates	CDK5R1	binding
CDK5R1	up-regulates	CDK5	binding
CHN1	up-regulates	CDK5R1	binding
CDK5	down-regulates	CDK5R1	phosphorylation
SIK2	down-regulates	CDK5R1	phosphorylation
HNRNPA2B1	“down-regulates quantity by repression”	CDK5R1	“transcriptional regulation”
CDK5R1	“form complex”	CDK5/CDK5R1	binding
CAPN1	“up-regulates activity”	CDK5R1	cleavage
CAPN3	“up-regulates activity”	CDK5R1	cleavage
CAPN2	“up-regulates activity”	CDK5R1	cleavage
CDK5R1	“up-regulates activity”	CDK5	binding

Disease & clinical

Clinical variants and AI predictions

ClinVar

25 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	17
Likely benign	0
Benign	4

Top pathogenic / likely-pathogenic (0)

SpliceAI

447 predictions. Top by Δscore:

Variant	Effect	Δscore
17:32487470:TTCCA:T	acceptor_loss	0.9900
17:32487472:CCA:C	acceptor_loss	0.9900
17:32487474:A:AG	acceptor_gain	0.9900
17:32487474:AGGC:A	acceptor_loss	0.9900
17:32487475:G:GC	acceptor_loss	0.9900
17:32487475:G:GG	acceptor_gain	0.9900
17:32487475:GGCA:G	acceptor_gain	0.9900
17:32487475:GGC:G	acceptor_gain	0.9800
17:32489783:ATT:A	acceptor_gain	0.9800
17:32487474:AG:A	acceptor_gain	0.9700
17:32487475:GG:G	acceptor_gain	0.9700
17:32489560:GTTGA:G	acceptor_gain	0.9700
17:32487159:CCGGG:C	donor_loss	0.9500
17:32487160:CGGG:C	donor_loss	0.9500
17:32487161:GG:G	donor_gain	0.9500
17:32487161:GGGT:G	donor_loss	0.9500
17:32487162:GG:G	donor_gain	0.9500
17:32487162:GGTA:G	donor_loss	0.9500
17:32487163:GT:G	donor_loss	0.9500
17:32487164:T:A	donor_loss	0.9500
17:32487158:GCCGG:G	donor_gain	0.9400
17:32488383:G:GT	donor_gain	0.9400
17:32487341:GC:G	donor_gain	0.9200
17:32489577:G:C	acceptor_gain	0.9200
17:32487163:G:GG	donor_gain	0.9100
17:32489772:A:AG	acceptor_gain	0.8900
17:32487321:GCTGC:G	donor_gain	0.8800
17:32489221:G:GA	donor_gain	0.8700
17:32489559:A:AG	acceptor_gain	0.8200
17:32489560:G:GG	acceptor_gain	0.8200

AlphaMissense

1990 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
17:32488051:T:A	V144D	1.000
17:32488060:C:T	S147F	1.000
17:32488072:T:A	L151Q	1.000
17:32488072:T:C	L151P	1.000
17:32488075:T:C	L152P	1.000
17:32488084:T:C	L155P	1.000
17:32488086:G:C	G156R	1.000
17:32488092:T:C	F158L	1.000
17:32488093:T:C	F158S	1.000
17:32488094:T:A	F158L	1.000
17:32488094:T:G	F158L	1.000
17:32488109:C:G	C163W	1.000
17:32488149:T:A	W177R	1.000
17:32488149:T:C	W177R	1.000
17:32488153:T:C	L178P	1.000
17:32488155:C:A	R179S	1.000
17:32488156:G:C	R179P	1.000
17:32488164:G:C	D182H	1.000
17:32488164:G:T	D182Y	1.000
17:32488165:A:C	D182A	1.000
17:32488165:A:T	D182V	1.000
17:32488168:G:C	R183P	1.000
17:32488174:T:A	L185Q	1.000
17:32488174:T:C	L185P	1.000
17:32488177:T:C	L186P	1.000
17:32488185:G:C	G189R	1.000
17:32488185:G:T	G189C	1.000
17:32488186:G:A	G189D	1.000
17:32488186:G:T	G189V	1.000
17:32488188:T:A	W190R	1.000

dbSNP variants (sampled 300 via entrez): RS1000018686 (17:32487002 C>T), RS1000115964 (17:32489966 A>T), RS1001557776 (17:32485990 C>G), RS1001899426 (17:32491718 A>G), RS1001945565 (17:32490963 C>T), RS1002119894 (17:32490695 T>A,C), RS1002556737 (17:32488912 G>C), RS1003217499 (17:32489836 C>G,T), RS1003597210 (17:32490125 C>G), RS1003668304 (17:32490516 G>A), RS1004022459 (17:32490368 C>T), RS1004355057 (17:32489893 G>C), RS1004359189 (17:32485195 G>T), RS1004466305 (17:32490187 C>A,T), RS1004584571 (17:32490568 C>G)

Disease associations

OMIM: gene MIM:603460 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

0 associations (top):

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (2): CHEMBL1907600 (PROTEIN COMPLEX), CHEMBL2783 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

31 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 216,090 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

Molecule	Name	Phase	Patents
CHEMBL189963	PALBOCICLIB	4	13,102
CHEMBL3301610	ABEMACICLIB	4	7,045
CHEMBL2103840	DINACICLIB	3	2,257
CHEMBL297453	EPIGALOCATECHIN GALLATE	3	22,804
CHEMBL428690	ALVOCIDIB	3	27,781
CHEMBL50	QUERCETIN	3	74,559
CHEMBL1276127	INDIRUBIN	2	181
CHEMBL14762	SELICICLIB	2	3,787
CHEMBL151	LUTEOLIN	2	23,523
CHEMBL1944698	ZOTIRACICLIB	2	2,915
CHEMBL3115681	NARAZACICLIB	2	287
CHEMBL31574	FISETIN	2	7,745
CHEMBL3655762	CYC-065	2	388
CHEMBL445813	AT-7519	2	2,614
CHEMBL5095094	CULMERCICLIB	2	12
CHEMBL5095102	INIXACICLIB	2	9
CHEMBL5199065	ISTISOCICLIB	2	21
CHEMBL564829	MILCICLIB	2	821
CHEMBL1230607	PHA-793887	1	299
CHEMBL150	KAEMPFEROL	1	25,940
CHEMBL258805	SU-9516	1
CHEMBL269538	HARMINE	1
CHEMBL296468	BMS-387032	1
CHEMBL3545083	RGB-286638	1
CHEMBL4225966	SEL-120 FREE BASE	1
CHEMBL4439321	ATUVECICLIB	1
CHEMBL4482864	TIZATERKIB	1
CHEMBL4650328	AVOTACICLIB	1
CHEMBL4784318	CIRTUVIVINT	1
CHEMBL488436	AZD-5438	1

PharmGKB: 1 entry (VIP=true, CPIC=false)

Binding affinities (BindingDB)

99 measured of 140 human assays (351 total across all organisms); most potent 50 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value
3-{2-[(thiophene-2-sulfonyl)methyl]-1,3-thiazol-4-yl}-1,2-dihydroquinolin-2-one	IC50	2.1 nM
7-(piperidin-1-ylcarbonyl)-3-[2-(pyridin-4-yl)-1,3-thiazol-4-yl]-1,2-dihydroquinolin-2-one	IC50	2.7 nM
4-amino-6-chloro-3-[2-(pyridin-4-yl)-1,3-thiazol-4-yl]-1,2-dihydroquinolin-2-one	IC50	3.8 nM
7-[(4-methylpiperazin-1-yl)carbonyl]-3-[2-(pyridin-4-yl)-1,3-thiazol-4-yl]-1,2-dihydroquinolin-2-one	IC50	4.4 nM
3-[2-(pyridin-4-yl)-1,3-thiazol-4-yl]-7-(trifluoromethyl)-1,2-dihydroquinolin-2-one	IC50	6.3 nM
N-[2-(dimethylamino)ethyl]-N-ethyl-2-oxo-3-[2-(pyridin-4-yl)-1,3-thiazol-4-yl]-1,2-dihydroquinoline-7-carboxamide	IC50	8.3 nM
3-{2-[(pyridine-2-sulfonyl)methyl]-1,3-thiazol-4-yl}-1,2-dihydroquinolin-2-one	IC50	10 nM
6-chloro-3-[2-(pyridin-4-yl)-1,3-thiazol-4-yl]-1,2-dihydroquinolin-2-one	IC50	11 nM
4-amino-3-[2-(pyridin-4-yl)-1,3-thiazol-4-yl]-1,2-dihydroquinolin-2-one	IC50	11 nM
Hymenialdisine, 28w	IC50	12 nM
3-[2-(4-hydroxyphenyl)-1,3-thiazol-4-yl]-1,2-dihydroquinolin-2-one	IC50	24 nM
3-{2-[(benzenesulfonyl)methyl]-1,3-thiazol-4-yl}-1,2-dihydroquinolin-2-one	IC50	29 nM
Hymenialdisine, 28p	IC50	32 nM
methyl 2-oxo-3-[2-(pyridin-4-yl)-1,3-thiazol-4-yl]-1,2-dihydroquinoline-5-carboxylate	IC50	33 nM
NSC 705701	IC50	35 nM
N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-(naphthalen-2-yl)acetamide	IC50	37 nM
7-bromo-3-[2-(pyridin-4-yl)-1,3-thiazol-4-yl]-1,2,3,4-tetrahydroquinazolin-2-one	IC50	38 nM
GP0210	IC50	40 nM
3-[2-(pyridin-3-yl)-1,3-thiazol-4-yl]-1,2-dihydroquinolin-2-one	IC50	50 nM
Hymenialdisine, 28aa	IC50	50 nM
Hymenialdisine, 28ai	IC50	50 nM
7-fluoro-3-[2-(pyridin-4-yl)-1,3-thiazol-4-yl]-1,2,3,4-tetrahydroquinazolin-2-one	IC50	52 nM
3-[2-(pyridin-4-yl)-1,3-thiazol-4-yl]-1,2-dihydroquinolin-2-one	IC50	54 nM
(2R)-2-({4-[(3-chlorophenyl)amino]-8-(propan-2-yl)pyrazolo[1,5-a][1,3,5]triazin-2-yl}amino)-3-methylbutan-1-ol	IC50	60 nM
(2R)-2-({6-[(3-chlorophenyl)amino]-9-(propan-2-yl)-9H-purin-2-yl}amino)-3-methylbutan-1-ol	IC50	70 nM
4-[2-Amino-5-oxo-1,5-dihydro-imidazol-(4Z)-ylidene]-2-bromo-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]azepin-8-one	IC50	70 nM
6-fluoro-3-[2-(pyridin-4-yl)-1,3-thiazol-4-yl]-1,2,3,4-tetrahydroquinazolin-2-one	IC50	72 nM
Hymenialdisine, 28ac	IC50	75 nM
3-[4-(pyridin-4-yl)-1,3-thiazol-2-yl]-1,2,3,4-tetrahydroquinazolin-2-one	IC50	77 nM
Hymenialdisine, 28ad	IC50	81 nM
6-fluoro-3-[2-(pyridin-4-yl)-1,3-thiazol-4-yl]-1,2-dihydroquinolin-2-one	IC50	110 nM
7-phenyl-3-[2-(pyridin-4-yl)-1,3-thiazol-4-yl]-1,2,3,4-tetrahydroquinazolin-2-one	IC50	113 nM
Hymenialdisine, 28ah	IC50	118 nM
4-amino-6-(4-methylpiperazin-1-yl)-3-[2-(pyridin-4-yl)-1,3-thiazol-4-yl]-1,2-dihydroquinolin-2-one	IC50	120 nM
3-{2-[(benzenesulfinyl)methyl]-1,3-thiazol-4-yl}-1,2-dihydroquinolin-2-one	IC50	120 nM
(2S)-2-{[4-(benzylamino)-8-(propan-2-yl)pyrazolo[1,5-a][1,3,5]triazin-2-yl]amino}butan-1-ol	IC50	130 nM
3-[2-(pyridin-4-yl)-1,3-thiazol-4-yl]-1,2,3,4-tetrahydroquinazolin-2-one	IC50	142 nM
4-hydroxy-3-[2-(pyridin-4-yl)-1,3-thiazol-4-yl]-1,2-dihydroquinolin-2-one	IC50	160 nM
6-methyl-3-[2-(pyridin-4-yl)-1,3-thiazol-4-yl]-1,2,3,4-tetrahydroquinazolin-2-one	IC50	165 nM
3-[2-(4-aminophenyl)-1,3-thiazol-4-yl]-1,2-dihydroquinolin-2-one	IC50	170 nM
Hymenialdisine, 28ab	IC50	179 nM
(2R)-2-{[4-(benzylamino)-7-(propan-2-yl)imidazo[1,2-a][1,2,4]triazin-2-yl]amino}butan-1-ol	IC50	220 nM
Hymenialdisine, 15	IC50	220 nM
5-bromo-3-[2-(pyridin-4-yl)-1,3-thiazol-4-yl]-1,2,3,4-tetrahydroquinazolin-2-one	IC50	228 nM
5-fluoro-3-[2-(pyridin-4-yl)-1,3-thiazol-4-yl]-1,2,3,4-tetrahydroquinazolin-2-one	IC50	240 nM
3-(2-{[(4-chlorobenzene)sulfonyl]methyl}-1,3-thiazol-4-yl)-1,2-dihydroquinolin-2-one	IC50	240 nM
4-amino-6-(piperidin-1-yl)-3-[2-(pyridin-4-yl)-1,3-thiazol-4-yl]-1,2-dihydroquinolin-2-one	IC50	250 nM
(2R)-2-[[6-(benzylamino)-9-isopropyl-purin-2-yl]amino]butan-1-ol	KD	260 nM
5-(morpholin-4-ylmethyl)-3-[2-(pyridin-4-yl)-1,3-thiazol-4-yl]-1,2,3,4-tetrahydroquinazolin-2-one	IC50	284 nM
3-[2-(methanesulfonylmethyl)-1,3-thiazol-4-yl]-1,2-dihydroquinolin-2-one	IC50	300 nM

ChEMBL bioactivities

1487 potent at pChembl≥5 of 1671 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
9.70	IC50	0.2	nM	CHEMBL261720
9.70	IC50	0.2	nM	CHEMBL5075328
9.70	IC50	0.2	nM	CHEMBL5080866
9.22	IC50	0.6	nM	CHEMBL5081712
9.22	IC50	0.6	nM	CHEMBL5077138
9.22	IC50	0.6	nM	CHEMBL5074832
9.22	IC50	0.6	nM	CHEMBL5080351
9.17	IC50	0.68	nM	CHEMBL5808524
9.10	IC50	0.8	nM	CHEMBL5078762
9.10	IC50	0.8	nM	CHEMBL5086375
9.10	IC50	0.8	nM	CHEMBL5090019
9.10	IC50	0.8	nM	CHEMBL5077028
9.10	IC50	0.8	nM	CHEMBL5808524
9.05	IC50	0.9	nM	CHEMBL5091792
9.05	IC50	0.9	nM	CHEMBL5088595
9.05	Ki	0.9	nM	CHEMBL5570901
9.00	IC50	1	nM	DINACICLIB
9.00	IC50	1	nM	CHEMBL5092400
9.00	IC50	1	nM	CHEMBL5080361
9.00	IC50	1	nM	CHEMBL5080566
9.00	Ki	1	nM	CHEMBL5571565
9.00	IC50	1	nM	CHEMBL5955040
9.00	IC50	1	nM	CHEMBL5739950
8.96	IC50	1.1	nM	CHEMBL5077125
8.92	IC50	1.2	nM	STAUROSPORINE
8.92	IC50	1.2	nM	CHEMBL5094270
8.92	IC50	1.2	nM	CHEMBL5083778
8.92	IC50	1.2	nM	CHEMBL5088315
8.92	IC50	1.2	nM	CHEMBL5078192
8.89	IC50	1.28	nM	STAUROSPORINE
8.89	IC50	1.3	nM	CHEMBL5837976
8.87	IC50	1.338	nM	SEL-120 FREE BASE
8.85	IC50	1.4	nM	CHEMBL5078596
8.85	IC50	1.4	nM	CHEMBL5837976
8.85	IC50	1.4	nM	CHEMBL567005
8.82	IC50	1.5	nM	CHEMBL2377825
8.80	IC50	1.6	nM	DINACICLIB
8.78	IC50	1.66	nM	SEL-120 FREE BASE
8.74	IC50	1.8	nM	CHEMBL5080866
8.72	IC50	1.9	nM	STAUROSPORINE
8.70	IC50	2	nM	RGB-286638
8.70	IC50	2	nM	CHEMBL5080566
8.70	Ki	2	nM	CHEMBL5277565
8.70	IC50	2	nM	CHEMBL5760232
8.70	IC50	2	nM	CHEMBL5938366
8.69	IC50	2.05	nM	STAUROSPORINE
8.68	IC50	2.1	nM	CHEMBL391906
8.67	IC50	2.16	nM	STAUROSPORINE
8.66	IC50	2.2	nM	CHEMBL5070707
8.66	IC50	2.2	nM	CHEMBL5087911

PubChem BioAssay actives

1625 with measured affinity, of 4306 total; 50 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
3-[3-fluoro-4-[[2-[(1R)-1-hydroxy-1-(1-methylpiperidin-4-yl)ethyl]-1,6-naphthyridin-7-yl]amino]phenyl]benzonitrile	1825848: Inhibition of full length N-terminal GST fused human CDK5(1 to 292 residues)/ p25 (99 to 307 residues) expressed in baculovirus expression system using FL peptide as substrate preincubated for 30 mins followed by substrate addition further incubated for 60 mins by EZ reader method	ic50	0.0002	uM
(1R)-1-[7-(2-fluoro-5-morpholin-4-ylanilino)-1,6-naphthyridin-2-yl]-1-(1-methylpiperidin-4-yl)ethanol	1825857: Inhibition of Nano-Luc fused human full length CDK5/P35 transfected in HEK293 cells incubated for 1 hr by NanoBRET assay	ic50	0.0002	uM
5-amino-N-(2,6-difluorophenyl)-3-(4-sulfamoylanilino)-1,2,4-triazole-1-carbothioamide	1513682: Inhibition of GST-tagged CDK5/p25 (unknown origin) expressed in Baculovirus infected Sf9 cells using histone H1 as substrate as substrate in presence of [gamma-33P]-ATP by radiometric filter binding assay	ic50	0.0002	uM
(1R)-1-(7-anilino-1,6-naphthyridin-2-yl)-1-(1-methylpiperidin-4-yl)ethanol	1825848: Inhibition of full length N-terminal GST fused human CDK5(1 to 292 residues)/ p25 (99 to 307 residues) expressed in baculovirus expression system using FL peptide as substrate preincubated for 30 mins followed by substrate addition further incubated for 60 mins by EZ reader method	ic50	0.0006	uM
(1R)-1-[7-(2-fluoro-4-methylsulfonylanilino)-1,6-naphthyridin-2-yl]-1-(1-methylpiperidin-4-yl)ethanol	1825848: Inhibition of full length N-terminal GST fused human CDK5(1 to 292 residues)/ p25 (99 to 307 residues) expressed in baculovirus expression system using FL peptide as substrate preincubated for 30 mins followed by substrate addition further incubated for 60 mins by EZ reader method	ic50	0.0006	uM
(1R)-1-[7-(2-fluoro-5-propan-2-yloxyanilino)-1,6-naphthyridin-2-yl]-1-(1-methylpiperidin-4-yl)ethanol	1825848: Inhibition of full length N-terminal GST fused human CDK5(1 to 292 residues)/ p25 (99 to 307 residues) expressed in baculovirus expression system using FL peptide as substrate preincubated for 30 mins followed by substrate addition further incubated for 60 mins by EZ reader method	ic50	0.0006	uM
(1R)-1-[7-(5-ethyl-2-fluoroanilino)-1,6-naphthyridin-2-yl]-1-(1-methylpiperidin-4-yl)ethanol	1825848: Inhibition of full length N-terminal GST fused human CDK5(1 to 292 residues)/ p25 (99 to 307 residues) expressed in baculovirus expression system using FL peptide as substrate preincubated for 30 mins followed by substrate addition further incubated for 60 mins by EZ reader method	ic50	0.0006	uM
(1R)-1-[7-(2-fluoro-4-pyrazol-1-ylanilino)-1,6-naphthyridin-2-yl]-1-(1-methylpiperidin-4-yl)ethanol	1825848: Inhibition of full length N-terminal GST fused human CDK5(1 to 292 residues)/ p25 (99 to 307 residues) expressed in baculovirus expression system using FL peptide as substrate preincubated for 30 mins followed by substrate addition further incubated for 60 mins by EZ reader method	ic50	0.0008	uM
5-fluoro-4-[[2-[(1R)-1-hydroxy-1-(1-methylpiperidin-4-yl)ethyl]-1,6-naphthyridin-7-yl]amino]-2-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)benzonitrile	1825848: Inhibition of full length N-terminal GST fused human CDK5(1 to 292 residues)/ p25 (99 to 307 residues) expressed in baculovirus expression system using FL peptide as substrate preincubated for 30 mins followed by substrate addition further incubated for 60 mins by EZ reader method	ic50	0.0008	uM
(1R)-1-[7-[(5-fluoro-2-propan-2-yl-4-pyridinyl)amino]-1,6-naphthyridin-2-yl]-1-(1-methylpiperidin-4-yl)ethanol	1825848: Inhibition of full length N-terminal GST fused human CDK5(1 to 292 residues)/ p25 (99 to 307 residues) expressed in baculovirus expression system using FL peptide as substrate preincubated for 30 mins followed by substrate addition further incubated for 60 mins by EZ reader method	ic50	0.0008	uM
3-fluoro-4-[[2-[(1R)-1-hydroxy-1-(1-methylpiperidin-4-yl)ethyl]-1,6-naphthyridin-7-yl]amino]benzonitrile	1825848: Inhibition of full length N-terminal GST fused human CDK5(1 to 292 residues)/ p25 (99 to 307 residues) expressed in baculovirus expression system using FL peptide as substrate preincubated for 30 mins followed by substrate addition further incubated for 60 mins by EZ reader method	ic50	0.0008	uM
(1R)-1-[7-[(5-fluoro-2-pyrrolidin-1-yl-4-pyridinyl)amino]-1,6-naphthyridin-2-yl]-1-(1-methylpiperidin-4-yl)ethanol	1825848: Inhibition of full length N-terminal GST fused human CDK5(1 to 292 residues)/ p25 (99 to 307 residues) expressed in baculovirus expression system using FL peptide as substrate preincubated for 30 mins followed by substrate addition further incubated for 60 mins by EZ reader method	ic50	0.0009	uM
(1R)-1-[7-[(2-ethyl-5-fluoro-4-pyridinyl)amino]-1,6-naphthyridin-2-yl]-1-(1-methylpiperidin-4-yl)ethanol	1825848: Inhibition of full length N-terminal GST fused human CDK5(1 to 292 residues)/ p25 (99 to 307 residues) expressed in baculovirus expression system using FL peptide as substrate preincubated for 30 mins followed by substrate addition further incubated for 60 mins by EZ reader method	ic50	0.0009	uM
(3S,4S)-4-[(20-propan-2-yl-10-oxa-2,16,18,22,23,24-hexazatetracyclo[15.6.1.04,9.019,23]tetracosa-1(24),4,6,8,17,19,21-heptaen-16-yl)methyl]pyrrolidin-3-ol	2107678: Inhibition of human CDK5/p25NCK using histone H1 as substrate preincubated for 10 mins followed by substrate and ATP addition and measured after 60 mins by ADP-Glo reagent based microplate reader assay	ki	0.0009	uM
5-fluoro-4-[[2-[(1R)-1-hydroxy-1-(1-methylpiperidin-4-yl)ethyl]-1,6-naphthyridin-7-yl]amino]-2-morpholin-4-ylbenzonitrile	1825857: Inhibition of Nano-Luc fused human full length CDK5/P35 transfected in HEK293 cells incubated for 1 hr by NanoBRET assay	ic50	0.0010	uM
5-fluoro-4-[[2-[(1R)-1-hydroxy-1-(1-methylpiperidin-4-yl)ethyl]-1,6-naphthyridin-7-yl]amino]-2-propan-2-ylbenzonitrile	1825848: Inhibition of full length N-terminal GST fused human CDK5(1 to 292 residues)/ p25 (99 to 307 residues) expressed in baculovirus expression system using FL peptide as substrate preincubated for 30 mins followed by substrate addition further incubated for 60 mins by EZ reader method	ic50	0.0010	uM
(1R)-1-[7-[2-fluoro-4-[3-(hydroxymethyl)pyrazol-1-yl]anilino]-1,6-naphthyridin-2-yl]-1-(1-methylpiperidin-4-yl)ethanol	1825848: Inhibition of full length N-terminal GST fused human CDK5(1 to 292 residues)/ p25 (99 to 307 residues) expressed in baculovirus expression system using FL peptide as substrate preincubated for 30 mins followed by substrate addition further incubated for 60 mins by EZ reader method	ic50	0.0010	uM
16-[(1-methylpiperidin-4-yl)methyl]-20-propan-2-yl-10-oxa-2,16,18,22,23,24-hexazatetracyclo[15.6.1.04,9.019,23]tetracosa-1(24),4,6,8,17,19,21-heptaene	2107678: Inhibition of human CDK5/p25NCK using histone H1 as substrate preincubated for 10 mins followed by substrate and ATP addition and measured after 60 mins by ADP-Glo reagent based microplate reader assay	ki	0.0010	uM
2-[(2S)-1-[3-ethyl-7-[(1-oxidopyridin-1-ium-3-yl)methylamino]pyrazolo[1,5-a]pyrimidin-5-yl]piperidin-2-yl]ethanol	1317327: Inhibition of recombinant CDK5/p25 (unknown origin) expressed in baculovirus infected Sf9 insect cells using biotinylated histone H1 as substrate after 1 hr by gamma32P-ATP based liquid scintillation counting analysis	ic50	0.0010	uM
(1R)-1-[7-(2-fluoroanilino)-1,6-naphthyridin-2-yl]-1-(1-methylpiperidin-4-yl)ethanol	1825848: Inhibition of full length N-terminal GST fused human CDK5(1 to 292 residues)/ p25 (99 to 307 residues) expressed in baculovirus expression system using FL peptide as substrate preincubated for 30 mins followed by substrate addition further incubated for 60 mins by EZ reader method	ic50	0.0011	uM
(1R)-1-[7-[(5-fluoro-2-morpholin-4-yl-4-pyridinyl)amino]-1,6-naphthyridin-2-yl]-1-(1-methylpiperidin-4-yl)ethanol	1825857: Inhibition of Nano-Luc fused human full length CDK5/P35 transfected in HEK293 cells incubated for 1 hr by NanoBRET assay	ic50	0.0012	uM
(1R)-1-[7-[(5-fluoro-2-propan-2-yloxy-4-pyridinyl)amino]-1,6-naphthyridin-2-yl]-1-(1-methylpiperidin-4-yl)ethanol	1825848: Inhibition of full length N-terminal GST fused human CDK5(1 to 292 residues)/ p25 (99 to 307 residues) expressed in baculovirus expression system using FL peptide as substrate preincubated for 30 mins followed by substrate addition further incubated for 60 mins by EZ reader method	ic50	0.0012	uM
3-[3-fluoro-4-[[2-[(1R)-1-hydroxy-1-(1-methylpiperidin-4-yl)ethyl]-1,6-naphthyridin-7-yl]amino]phenyl]-1-methylpyridin-2-one	1825857: Inhibition of Nano-Luc fused human full length CDK5/P35 transfected in HEK293 cells incubated for 1 hr by NanoBRET assay	ic50	0.0012	uM
(1R)-1-[7-[2-fluoro-5-(trifluoromethyl)anilino]-1,6-naphthyridin-2-yl]-1-(1-methylpiperidin-4-yl)ethanol	1825848: Inhibition of full length N-terminal GST fused human CDK5(1 to 292 residues)/ p25 (99 to 307 residues) expressed in baculovirus expression system using FL peptide as substrate preincubated for 30 mins followed by substrate addition further incubated for 60 mins by EZ reader method	ic50	0.0012	uM
(2S,3R,4R,6R)-3-methoxy-2-methyl-4-(methylamino)-29-oxa-1,7,17-triazaoctacyclo[12.12.2.12,6.07,28.08,13.015,19.020,27.021,26]nonacosa-8,10,12,14,19,21,23,25,27-nonaen-16-one	745524: Inhibition of CDK5/P25 (unknown origin)-mediated phosphorylation of peptide substrate incubated for 15 mins prior to substrate addition measured after 90 mins by P33-radiolabeled assay	ic50	0.0012	uM
6,7-dibromo-5-methyl-2-piperazin-1-yl-1,3-diazatricyclo[6.3.1.04,12]dodeca-2,4,6,8(12)-tetraene	2070968: Inhibition of CDK5/p35NCK (unknown origin) by ADP-Glo chemiluminescence assay	ic50	0.0013	uM
ethyl 5-[2-(benzenesulfonylmethyl)-1,3-thiazol-4-yl]-6-oxo-2-propyl-1H-pyridine-3-carboxylate	439136: Inhibition of human CDK5/p25 assessed as histone h1 phosphorylation in presence of ATP	ic50	0.0014	uM
(1R)-1-(1-methylpiperidin-4-yl)-1-[7-(3-morpholin-4-ylanilino)-1,6-naphthyridin-2-yl]ethanol	1825848: Inhibition of full length N-terminal GST fused human CDK5(1 to 292 residues)/ p25 (99 to 307 residues) expressed in baculovirus expression system using FL peptide as substrate preincubated for 30 mins followed by substrate addition further incubated for 60 mins by EZ reader method	ic50	0.0014	uM
4-[[4-amino-5-(2-nitrobenzoyl)-1,3-thiazol-2-yl]amino]benzenesulfonamide	745524: Inhibition of CDK5/P25 (unknown origin)-mediated phosphorylation of peptide substrate incubated for 15 mins prior to substrate addition measured after 90 mins by P33-radiolabeled assay	ic50	0.0015	uM
1-[3-[4-[[4-(2-methoxyethyl)piperazin-1-yl]methyl]phenyl]-4-oxo-1H-indeno[2,1-d]pyrazol-5-yl]-3-morpholin-4-ylurea	1317363: Inhibition of CDK5/p35 (unknown origin)	ic50	0.0020	uM
5-chloro-4-(1,3-dimethylpyrazol-4-yl)-N-(1-methylsulfonylpiperidin-4-yl)pyrimidin-2-amine	1940572: Inhibition of CDK5/p25 (unknown origin) assessed as inhibition constant incubated for 30 to 60 mins presence of dithiothreitol by Cheng-Prusoff equation analysis	ki	0.0020	uM
3-[2-(thiophen-2-ylsulfonylmethyl)-1,3-thiazol-4-yl]-1H-quinolin-2-one	1798015: CDK Inhibition Assay from Article 10.1016/j.bmcl.2007.07.045: “Design and synthesis of quinolin-2(1H)-one derivatives as potent CDK5 inhibitors.”	ic50	0.0021	uM
5-fluoro-4-[[2-[(1R)-1-hydroxy-1-(1-methylpiperidin-4-yl)ethyl]-1,6-naphthyridin-7-yl]amino]-2-propan-2-yloxybenzonitrile	1825848: Inhibition of full length N-terminal GST fused human CDK5(1 to 292 residues)/ p25 (99 to 307 residues) expressed in baculovirus expression system using FL peptide as substrate preincubated for 30 mins followed by substrate addition further incubated for 60 mins by EZ reader method	ic50	0.0022	uM
5-fluoro-4-[[2-[(1R)-1-hydroxy-1-(1-methylpiperidin-4-yl)ethyl]-1,6-naphthyridin-7-yl]amino]-2-(trifluoromethyl)benzonitrile	1825848: Inhibition of full length N-terminal GST fused human CDK5(1 to 292 residues)/ p25 (99 to 307 residues) expressed in baculovirus expression system using FL peptide as substrate preincubated for 30 mins followed by substrate addition further incubated for 60 mins by EZ reader method	ic50	0.0022	uM
N-[3-[6-[(3-chlorophenyl)methylamino]purin-9-yl]cyclobutyl]-6-methylpyridine-2-carboxamide	1463773: Inhibition of CDK5/p35 (unknown origin) using ULingt-4E-BP as substrate after 1 hr in presence of ATP by fluorescence assay	ic50	0.0023	uM
(1R)-1-[7-[[5-fluoro-2-(trifluoromethyl)-4-pyridinyl]amino]-1,6-naphthyridin-2-yl]-1-(1-methylpiperidin-4-yl)ethanol	1825848: Inhibition of full length N-terminal GST fused human CDK5(1 to 292 residues)/ p25 (99 to 307 residues) expressed in baculovirus expression system using FL peptide as substrate preincubated for 30 mins followed by substrate addition further incubated for 60 mins by EZ reader method	ic50	0.0023	uM
2,6-bis(2-aminopyrimidin-4-yl)pyridin-3-ol	1868084: Inhibition of CDK5/p35 (unknown origin)	ic50	0.0024	uM
7-methylsulfonyl-16-(piperidin-4-ylmethyl)-20-propan-2-yl-10-oxa-2,16,18,22,23,24-hexazatetracyclo[15.6.1.04,9.019,23]tetracosa-1(24),4(9),5,7,17,19,21-heptaene	2107678: Inhibition of human CDK5/p25NCK using histone H1 as substrate preincubated for 10 mins followed by substrate and ATP addition and measured after 60 mins by ADP-Glo reagent based microplate reader assay	ki	0.0024	uM
6-fluoro-16-(piperidin-4-ylmethyl)-20-propan-2-yl-10-oxa-2,16,18,22,23,24-hexazatetracyclo[15.6.1.04,9.019,23]tetracosa-1(24),4(9),5,7,17,19,21-heptaene	2107678: Inhibition of human CDK5/p25NCK using histone H1 as substrate preincubated for 10 mins followed by substrate and ATP addition and measured after 60 mins by ADP-Glo reagent based microplate reader assay	ki	0.0025	uM
1-[4-[4-fluoro-3-[[2-[(1R)-1-hydroxy-1-(1-methylpiperidin-4-yl)ethyl]-1,6-naphthyridin-7-yl]amino]phenyl]piperazin-1-yl]ethanone	1825848: Inhibition of full length N-terminal GST fused human CDK5(1 to 292 residues)/ p25 (99 to 307 residues) expressed in baculovirus expression system using FL peptide as substrate preincubated for 30 mins followed by substrate addition further incubated for 60 mins by EZ reader method	ic50	0.0027	uM
7-(piperidine-1-carbonyl)-3-(2-pyridin-4-yl-1,3-thiazol-4-yl)-1H-quinolin-2-one	1798015: CDK Inhibition Assay from Article 10.1016/j.bmcl.2007.07.045: “Design and synthesis of quinolin-2(1H)-one derivatives as potent CDK5 inhibitors.”	ic50	0.0027	uM
(1R)-1-[7-[(2-cyclobutyloxy-5-fluoro-4-pyridinyl)amino]-1,6-naphthyridin-2-yl]-1-(1-methylpiperidin-4-yl)ethanol	1825848: Inhibition of full length N-terminal GST fused human CDK5(1 to 292 residues)/ p25 (99 to 307 residues) expressed in baculovirus expression system using FL peptide as substrate preincubated for 30 mins followed by substrate addition further incubated for 60 mins by EZ reader method	ic50	0.0030	uM
4-(4-propoxy-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-2-amine	1317344: Inhibition of human recombinant CDK5/p25 expressed in baculovirus infected Sf9 insect cells after 30 mins by [gamma-33P]ATP based scintillation counting analysis	ic50	0.0030	uM
4-(4-propan-2-yloxy-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-2-amine	315301: Inhibition of recombinant GST-CDK5/p25 expressed in Escherichia coli	ic50	0.0030	uM
3-[[4-[4-(3-chloroanilino)-1,3,5-triazin-2-yl]-2-pyridinyl]amino]propan-1-ol	2141061: Inhibition of CDK5/p25 (unknown origin)	ic50	0.0030	uM
ethyl 5-[2-(benzenesulfonylmethyl)-1,3-thiazol-4-yl]-2-methyl-6-oxo-1H-pyridine-3-carboxylate	439136: Inhibition of human CDK5/p25 assessed as histone h1 phosphorylation in presence of ATP	ic50	0.0033	uM
(1R)-1-[7-[2-fluoro-4-[3-(hydroxymethyl)pyrazol-1-yl]anilino]-1,6-naphthyridin-2-yl]-1-piperidin-4-ylethanol	1825848: Inhibition of full length N-terminal GST fused human CDK5(1 to 292 residues)/ p25 (99 to 307 residues) expressed in baculovirus expression system using FL peptide as substrate preincubated for 30 mins followed by substrate addition further incubated for 60 mins by EZ reader method	ic50	0.0036	uM
20-propan-2-yl-16-(pyrrolidin-3-ylmethyl)-10-oxa-2,16,18,22,23,24-hexazatetracyclo[15.6.1.04,9.019,23]tetracosa-1(24),4,6,8,17,19,21-heptaene	2107678: Inhibition of human CDK5/p25NCK using histone H1 as substrate preincubated for 10 mins followed by substrate and ATP addition and measured after 60 mins by ADP-Glo reagent based microplate reader assay	ki	0.0036	uM
4-amino-6-chloro-3-(2-pyridin-4-yl-1,3-thiazol-4-yl)-1H-quinolin-2-one	1798015: CDK Inhibition Assay from Article 10.1016/j.bmcl.2007.07.045: “Design and synthesis of quinolin-2(1H)-one derivatives as potent CDK5 inhibitors.”	ic50	0.0038	uM
[1-[3-fluoro-4-[[2-(1-methylpiperidin-4-yl)oxy-1,6-naphthyridin-7-yl]amino]phenyl]pyrazol-3-yl]methanol	1825848: Inhibition of full length N-terminal GST fused human CDK5(1 to 292 residues)/ p25 (99 to 307 residues) expressed in baculovirus expression system using FL peptide as substrate preincubated for 30 mins followed by substrate addition further incubated for 60 mins by EZ reader method	ic50	0.0039	uM

CTD chemical–gene interactions

80 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
trichostatin A	affects cotreatment, increases expression, decreases expression	4
methylmercuric chloride	increases expression, affects cotreatment	3
Benzo(a)pyrene	increases methylation, decreases expression, increases expression	3
Estradiol	affects expression, decreases reaction, affects cotreatment, increases expression	3
Tobacco Smoke Pollution	decreases expression, increases expression	3
Vorinostat	affects cotreatment, increases expression	2
Cisplatin	increases expression	2
Formaldehyde	decreases expression	2
Tretinoin	increases expression	2
aristolochic acid I	increases expression	1
3-((6-(2-methoxyphenyl)pyrimidin-4-yl)amino)phenyl)methane sulfonamide	decreases expression	1
FR900359	decreases phosphorylation	1
bis(tri-n-butyltin)oxide	decreases expression	1
potassium perchlorate	decreases expression	1
2,5,2’,5’-tetrachlorobiphenyl	decreases expression	1
tributyltin	decreases expression	1
arsenite	increases cleavage, increases expression, decreases reaction	1
sodium arsenite	decreases expression	1
cobaltous chloride	decreases expression	1
ochratoxin A	decreases expression	1
potassium chromate(VI)	affects cotreatment, increases expression	1
methylmercury II	decreases expression	1
epigallocatechin gallate	affects cotreatment, increases expression	1
diethyl malate	increases expression	1
polyhexamethyleneguanidine	increases expression	1
di-n-butylphosphoric acid	affects expression	1
calpeptin	decreases reaction, increases cleavage	1
azoxystrobin	decreases expression	1
CGP 52608	affects binding, increases reaction	1
apicidin	decreases expression	1

ChEMBL screening assays

649 unique, capped per target: 644 binding, 3 admet, 2 functional

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1022216	Binding	Inhibition of recombinant CDK5/p25 expressed in Escherichia coli	Synthesis and cytotoxic activity of new azepino[3’,4’:4,5]pyrrolo[2,1-a]isoquinolin-12-ones. — Bioorg Med Chem
CHEMBL1963958	Functional	PUBCHEM_BIOASSAY: Development of CDK5 inhibitors Measured in Biochemical System Using Plate Reader - 2083-01_Inhibitor_Dose_DryPowder_Activity. (Class of assay: confirmatory)	PubChem BioAssay data set
CHEMBL4605131	ADMET	Inhibition of recombinant human full-length N-terminal GST-tagged CDK5/p35 expressed in baculovirus infected Sf9 insect cells at 1 uM using histone H1 as substrate measured after 10 to 60 mins by ADP-glo assay relative to control	Discovery and SARs of 5-Chloro-N4-phenyl-N2-(pyridin-2-yl)pyrimidine-2,4-diamine Derivatives as Oral Available and Dual CDK 6 and 9 Inhibitors with Potent Antitumor Activity. — J Med Chem

Clinical trials (associated diseases)

0 trials via MONDO — disease-level, not drug-specific.