CDK5

Summary

CDK5 (cyclin dependent kinase 5, HGNC:1774) is a protein-coding gene on chromosome 7q36.1, encoding Cyclin-dependent kinase 5 (Q00535). Proline-directed serine/threonine-protein kinase essential for neuronal cell cycle arrest and differentiation and may be involved in apoptotic cell death in neuronal diseases by triggering abortive cell cycle re-entry.

This gene encodes a proline-directed serine/threonine kinase that is a member of the cyclin-dependent kinase family of proteins. Unlike other members of the family, the protein encoded by this gene does not directly control cell cycle regulation. Instead the protein, which is predominantly expressed at high levels in mammalian postmitotic central nervous system neurons, functions in diverse processes such as synaptic plasticity and neuronal migration through phosphorylation of proteins required for cytoskeletal organization, endocytosis and exocytosis, and apoptosis. In humans, an allelic variant of the gene that results in undetectable levels of the protein has been associated with lethal autosomal recessive lissencephaly-7. Alternative splicing results in multiple transcript variants.

Source: NCBI Gene 1020 — RefSeq curated summary.

At a glance

• Gene–disease (curated): lissencephaly 7 with cerebellar hypoplasia (Strong, GenCC) — +1 more curated relationship
• GWAS associations: 8
• Clinical variants (ClinVar): 86 total — 1 pathogenic, 1 likely-pathogenic
• Phenotypes (HPO): 26
• Druggable target: yes — 58 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_004935

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:1774
Approved symbol	CDK5
Name	cyclin dependent kinase 5
Location	7q36.1
Locus type	gene with protein product
Status	Approved
Aliases	PSSALRE
Ensembl gene	ENSG00000164885
Ensembl biotype	protein_coding
OMIM	123831
Entrez	1020

Gene structure

Transcript identifiers

Ensembl transcripts: 13 — 10 protein_coding, 3 retained_intron

ENST00000297518, ENST00000469108, ENST00000476691, ENST00000485972, ENST00000487703, ENST00000891063, ENST00000891064, ENST00000891065, ENST00000920874, ENST00000920875, ENST00000920876, ENST00000920877, ENST00000967084

RefSeq mRNA: 2 — MANE Select: NM_004935 NM_001164410, NM_004935

CCDS: CCDS47748, CCDS55184

Canonical transcript exons

ENST00000485972 — 12 exons

Exon	Start	End
ENSE00001088271	151054212	151054292
ENSE00001088281	151055277	151055373
ENSE00001247179	151053815	151054095
ENSE00001598399	151055027	151055096
ENSE00001621502	151054405	151054465
ENSE00001895936	151057812	151057897
ENSE00003459627	151055532	151055606
ENSE00003486655	151056580	151056636
ENSE00003508423	151056908	151056975
ENSE00003532330	151056736	151056796
ENSE00003626826	151057072	151057160
ENSE00003665172	151055753	151055848

Expression profiles

Bgee: expression breadth ubiquitous, 235 present calls, max score 95.47.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 16.4268 / max 200.9506, expressed in 1808 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
86855	15.3839	1806
86854	0.7761	366
86856	0.2668	102

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right frontal lobe	UBERON:0002810	95.47	gold quality
prefrontal cortex	UBERON:0000451	95.39	gold quality
nucleus accumbens	UBERON:0001882	95.19	gold quality
lateral nuclear group of thalamus	UBERON:0002736	95.17	gold quality
Brodmann (1909) area 9	UBERON:0013540	95.02	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	94.90	gold quality
frontal cortex	UBERON:0001870	94.43	gold quality
cingulate cortex	UBERON:0003027	94.40	gold quality
anterior cingulate cortex	UBERON:0009835	94.30	gold quality
caudate nucleus	UBERON:0001873	94.22	gold quality
neocortex	UBERON:0001950	94.03	gold quality
cortical plate	UBERON:0005343	93.90	gold quality
amygdala	UBERON:0001876	93.72	gold quality
cerebral cortex	UBERON:0000956	93.60	gold quality
putamen	UBERON:0001874	93.49	gold quality
telencephalon	UBERON:0001893	93.24	gold quality
Brodmann (1909) area 46	UBERON:0006483	93.01	gold quality
Ammon’s horn	UBERON:0001954	92.81	gold quality
temporal lobe	UBERON:0001871	92.79	gold quality
pons	UBERON:0000988	92.67	gold quality
forebrain	UBERON:0001890	92.44	gold quality
superior frontal gyrus	UBERON:0002661	92.42	gold quality
postcentral gyrus	UBERON:0002581	92.21	gold quality
entorhinal cortex	UBERON:0002728	92.04	gold quality
hypothalamus	UBERON:0001898	91.87	gold quality
parietal lobe	UBERON:0001872	91.67	gold quality
brain	UBERON:0000955	91.59	gold quality
central nervous system	UBERON:0001017	91.45	gold quality
right hemisphere of cerebellum	UBERON:0014890	91.30	gold quality
middle temporal gyrus	UBERON:0002771	91.26	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	3.34

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): AR, EGR1, FOS, FOSB, MEF2A, MYC, NPAS4, PDX1, RNF112, SP1, SP3, TP53

miRNA regulators (miRDB)

16 targeting CDK5, 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-4648	99.91	67.00	710
HSA-MIR-6739-5P	99.80	67.87	2806
HSA-MIR-4668-5P	99.79	70.58	3782
HSA-MIR-6733-5P	99.74	67.94	2759
HSA-MIR-3153	99.55	67.59	2337
HSA-MIR-142-5P	99.48	70.92	2416
HSA-MIR-5590-3P	99.48	70.91	2429
HSA-MIR-6507-3P	99.35	67.32	1059
HSA-MIR-6846-5P	98.81	65.86	1121
HSA-MIR-6848-5P	98.81	65.49	1126
HSA-MIR-1233-5P	98.19	66.71	1201
HSA-MIR-6778-5P	98.19	66.59	1239
HSA-MIR-505-5P	97.01	65.54	778
HSA-MIR-134-3P	96.83	66.22	1001
HSA-MIR-4654	95.86	65.72	751
HSA-MIR-4769-5P	95.37	66.09	570

Literature-anchored findings (GeneRIF, showing 40)

• Our data suggest that neurotoxic insults lead to calpain-mediated conversion of p39 to p29, which might contribute to deregulation of Cdk5 (PMID:11784720)
• Total cdk5 protein levels are significantly increased in progressive supranuclear palsy brain tissue. (PMID:11865137)
• This suggests a close, stable intermolecular association between cdk5 and phosphorylated tau, consistent with phosphorylation of tau by cdk5 in AD brain. (PMID:12071639)
• CDK5 binds to roscovitine in the ATP-binding pocket (PMID:12372407)
• role in phosphorylation of tau protein (PMID:12387894)
• cdk5 can initiate a major impact on tau pathology progression that probably involves several kinases. (PMID:12765608)
• p25-Cdk5 is responsible for the mitotic-like phosphoepitopes present in neurofibrillary tangles and Cdk5 has a critical role in neurodegenerative mechanisms (PMID:12826674)
• we show that alpha-chimaerin is a Cdk5p35-binding protein; in transfected HeLa cells, Cdk5p35 and alpha-chimaerin displayed an overlapping distribution pattern (PMID:15013773)
• 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)
• 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)
• an early event in neuronal cell death is p25/Cdk5-mediated retinoblastoma phosphorylation (PMID:15741232)
• These data predict that the ability of cdk5 phosphorylation to protect against htt cleavage, aggregation, and toxicity is compromised in cells expressing toxic fragments of htt. (PMID:15911879)
• 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)
• This is the first report of cdk5/p35 expression and kinase activity in colon cancer cells, which is associated with ciglitazone-induced antiproliferation in HT-29 cells (PMID:16327995)
• molecular analysis of the CDK5/p25 and CDK2/cyclin A systems (PMID:16407256)
• Mediates exocytosis and decreases beta-amyloid peptide formation in Alzheimer disease. (PMID:16413130)
• 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)
• phosphorylation of tau at Thr231 and Ser262 by cdk5 plus GSK-3, which inhibits its normal biological activity, is regulated both by its amino terminal inserts and its physical state (PMID:17045592)
• 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 that dephosphorylation of this site is a critical determinant of Cdk5-p25-induced cell death associated with neurodegeneration (PMID:17121855)
• Cdk5 kinase supports the proliferation of the medullary thyroid carcinoma cells. (PMID:17145757)
• microtubules play an important role in the control of Cdk5 activation (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)
• Results show that Cdk5, a critical signalling effector of various neurotoxic insults in the brain, is activated by EV71 infection of neuronal cells. (PMID:17581253)
• The Cdk5/DNA damage pathway is dysregulated in Huntington’s disease. (PMID:17611284)
• Phosphorylation on a conserved Thr14 can inhibit activities of both the kinases, but phosphorylating another conserved Tyr15, however, can lead to totally opposite inhibition and stimulation consequences in CDK2 and CDK5. (PMID:17713927)
• Thr-138 phosphorylation plays a critical role in the control of the p35 functions in microtubule assembly and neurite outgrowth (PMID:18326489)
• In our analysis, the haplotype tagged by the G allele of SNP rs2069442 was significantly associated with AD (p = 0.05). In conclusion, our study suggests that CDK5 may be associated with AD. (PMID:18350355)
• Cdk5 activation in cells that overexpress cyclin G1 leads to c-Myc phosphorylation on Ser-62, which is responsible for cyclin G1-mediated transcriptional activation of cyclin B1. (PMID:18408012)
• relative resistance to phosphatases might be a common feature of Cdk5 substrates and could contribute to the hyperphosphorylation of CRMP2 and Tau observed in Alzheimer disease (PMID:18460467)
• Cdk5 may cause Golgi fragmentation upon deregulation in Alzheimer’s disease (PMID:18480410)
• Cdk5 phosphorylates PIKE-A and stimulates its GTPase activity, which activates nuclear Akt and promotes glioblastoma cell migration and invasion. (PMID:18487454)
• c-Abl and Cdk5 cooperatively regulate maximal activation of p53, resulting in neuronal death in response to oxidative stress by hydrogen peroxide. (PMID:18490454)
• REVIEW. crucial role of Cdk5 as a cell cycle suppressor in normal post-mitotic neurons; Cdk5 exits the nucleus in neurons risk to death in an AD patient’s brain. The shift in sub-cellular location is accompanied by cell cycle re-entry and neuronal death. (PMID:19001851)
• Phosphorylation of parkin by casein kinase I and cdk5 decreases parkin solubility, leading to its aggregation and inactivation. (PMID:19050041)
• CDK5 promoter polymorphisms contribute to the genetic susceptibility to lung cancer in the Korean population. (PMID:19343042)
• regulates insulin secretion of pancreatic beta cells. (review) (PMID:19514266)
• plays a role in dopamine signaling and substance addiction. (review) (PMID:19514267)
• Its deregulation causes neuronal death and neurodegenerative diseases. (review) (PMID:19514268)
• Our negative findings in the Spanish population argue against the hypothesis that CDK5 genetic variations are causally related to Alzheimer’s disease risk (PMID:19615060)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	cdk5	ENSDARG00000056683
mus_musculus	Cdk5	ENSMUSG00000028969
rattus_norvegicus	Cdk5	ENSRNOG00000008017
drosophila_melanogaster	Cdk5	FBGN0013762
caenorhabditis_elegans	cdk-2	WBGENE00019362

Paralogs (26): CDKL3 (ENSG00000006837), CDKL5 (ENSG00000008086), CDK11A (ENSG00000008128), CDK14 (ENSG00000058091), CDK17 (ENSG00000059758), CDK13 (ENSG00000065883), CDKL1 (ENSG00000100490), CDK16 (ENSG00000102225), CDK6 (ENSG00000105810), PRP4K (ENSG00000112739), CDK18 (ENSG00000117266), CDK2 (ENSG00000123374), CDK8 (ENSG00000132964), CDK7 (ENSG00000134058), CDK4 (ENSG00000135446), CDK9 (ENSG00000136807), CDK15 (ENSG00000138395), CDKL2 (ENSG00000138769), CDK19 (ENSG00000155111), CDK20 (ENSG00000156345), CDK12 (ENSG00000167258), CDK1 (ENSG00000170312), CDK10 (ENSG00000185324), CDKL4 (ENSG00000205111), CDK11B (ENSG00000248333), CDK3 (ENSG00000250506)

Protein

Protein identifiers

Cyclin-dependent kinase 5 — Q00535 (reviewed: Q00535)

Alternative names: Cell division protein kinase 5, Cyclin-dependent-like kinase 5, Serine/threonine-protein kinase PSSALRE, Tau protein kinase II catalytic subunit

All UniProt accessions (3): A0A090N7W4, A0A0S2Z355, Q00535

UniProt curated annotations — full annotation on UniProt →

Function. Proline-directed serine/threonine-protein kinase essential for neuronal cell cycle arrest and differentiation and may be involved in apoptotic cell death in neuronal diseases by triggering abortive cell cycle re-entry. Interacts with D1 and D3-type G1 cyclins. Phosphorylates SRC, NOS3, VIM/vimentin, p35/CDK5R1, MEF2A, SIPA1L1, SH3GLB1, PXN, PAK1, MCAM/MUC18, SEPT5, SYN1, DNM1, AMPH, SYNJ1, CDK16, RAC1, RHOA, CDC42, TONEBP/NFAT5, MAPT/TAU, MAP1B, histone H1, p53/TP53, HDAC1, APEX1, PTK2/FAK1, huntingtin/HTT, ATM, MAP2, NEFH and NEFM. Regulates several neuronal development and physiological processes including neuronal survival, migration and differentiation, axonal and neurite growth, synaptogenesis, oligodendrocyte differentiation, synaptic plasticity and neurotransmission, by phosphorylating key proteins. Negatively regulates the CACNA1B/CAV2.2 -mediated Ca(2+) release probability at hippocampal neuronal soma and synaptic terminals. Activated by interaction with CDK5R1 (p35) and CDK5R2 (p39), especially in postmitotic neurons, and promotes CDK5R1 (p35) expression in an autostimulation loop. Phosphorylates many downstream substrates such as Rho and Ras family small GTPases (e.g. PAK1, RAC1, RHOA, CDC42) or microtubule-binding proteins (e.g. MAPT/TAU, MAP2, MAP1B), and modulates actin dynamics to regulate neurite growth and/or spine morphogenesis. Also phosphorylates exocytosis associated proteins such as MCAM/MUC18, SEPT5, SYN1, and CDK16/PCTAIRE1 as well as endocytosis associated proteins such as DNM1, AMPH and SYNJ1 at synaptic terminals. In the mature central nervous system (CNS), regulates neurotransmitter movements by phosphorylating substrates associated with neurotransmitter release and synapse plasticity; synaptic vesicle exocytosis, vesicles fusion with the presynaptic membrane, and endocytosis. Promotes cell survival by activating anti-apoptotic proteins BCL2 and STAT3, and negatively regulating of JNK3/MAPK10 activity. Phosphorylation of p53/TP53 in response to genotoxic and oxidative stresses enhances its stabilization by preventing ubiquitin ligase-mediated proteasomal degradation, and induces transactivation of p53/TP53 target genes, thus regulating apoptosis. Phosphorylation of p35/CDK5R1 enhances its stabilization by preventing calpain-mediated proteolysis producing p25/CDK5R1 and avoiding ubiquitin ligase-mediated proteasomal degradation. During aberrant cell-cycle activity and DNA damage, p25/CDK5 activity elicits cell-cycle activity and double-strand DNA breaks that precedes neuronal death by deregulating HDAC1. DNA damage triggered phosphorylation of huntingtin/HTT in nuclei of neurons protects neurons against polyglutamine expansion as well as DNA damage mediated toxicity. Phosphorylation of PXN reduces its interaction with PTK2/FAK1 in matrix-cell focal adhesions (MCFA) during oligodendrocytes (OLs) differentiation. Negative regulator of Wnt/beta-catenin signaling pathway. Activator of the GAIT (IFN-gamma-activated inhibitor of translation) pathway, which suppresses expression of a post-transcriptional regulon of proinflammatory genes in myeloid cells; phosphorylates the linker domain of glutamyl-prolyl tRNA synthetase (EPRS) in a IFN-gamma-dependent manner, the initial event in assembly of the GAIT complex. Phosphorylation of SH3GLB1 is required for autophagy induction in starved neurons. Phosphorylation of TONEBP/NFAT5 in response to osmotic stress mediates its rapid nuclear localization. MEF2 is inactivated by phosphorylation in nucleus in response to neurotoxin, thus leading to neuronal apoptosis. APEX1 AP-endodeoxyribonuclease is repressed by phosphorylation, resulting in accumulation of DNA damage and contributing to neuronal death. NOS3 phosphorylation down regulates NOS3-derived nitrite (NO) levels. SRC phosphorylation mediates its ubiquitin-dependent degradation and thus leads to cytoskeletal reorganization. May regulate endothelial cell migration and angiogenesis via the modulation of lamellipodia formation. Involved in dendritic spine morphogenesis by mediating the EFNA1-EPHA4 signaling. 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. Under neurotoxic stress and neuronal injury conditions, p35 is cleaved by calpain to generate p25 that hyperactivates CDK5, that becomes functionally disabled and often toxic. Found in a trimolecular complex with CABLES1 and ABL1. Interacts with CABLES1 and CABLES2. Interacts with AATK and GSTP1. Binds to HDAC1 when in complex with p25. Interaction with myristoylation p35 promotes CDK5 association with membranes. Both isoforms 1 and 2 interacts with beta-catenin/CTNNB1. Interacts with delta-catenin/CTNND2 and APEX1. Interacts with P53/TP53 in neurons. Interacts with EPHA4; may mediate the activation of NGEF by EPHA4. Interacts with PTK2/FAK1. The complex p35/CDK5 interacts with CLOCK. Interacts with HTR6.

Subcellular location. Cytoplasm. Nucleus. Cell membrane. Perikaryon. Cell projection. Lamellipodium. Growth cone. Postsynaptic density. Synapse Nucleus.

Tissue specificity. Ubiquitously expressed. Accumulates in cortical neurons (at protein level). Expressed in the testis, skeletal muscle, colon, bone marrow and ovary.

Post-translational modifications. Phosphorylation on Tyr-15 by ABL1 and FYN, and on Ser-159 by casein kinase 1 promotes kinase activity. By contrast, phosphorylation at Thr-14 inhibits activity. Phosphorylation at Ser-159 is essential for maximal catalytic activity.

Disease relevance. Lissencephaly 7, with cerebellar hypoplasia (LIS7) [MIM:616342] A form of lissencephaly, a disorder of cortical development characterized by agyria or pachygyria and disorganization of the clear neuronal lamination of normal six-layered cortex. LIS7 patients manifest lack of psychomotor development, facial dysmorphism, arthrogryposis, and early-onset intractable seizures resulting in death in infancy. The disease is caused by variants affecting the gene represented in this entry.

Activity regulation. Inhibited by 2-(1-ethyl-2-hydroxyethylamino)-6-benzylamino-9-isopropylpurine (roscovitine), 1-isopropyl-4-aminobenzyl-6-ether-linked benzimidazoles, resveratrol, AT-7519 and olomoucine. Activated by CDK5R1 (p35) and CDK5R2 (p39) during the development of the nervous system; degradation of CDK5R1 (p35) and CDK5R2 (p39) by proteasome result in down regulation of kinase activity, during this process, CDK5 phosphorylates p35 and induces its ubiquitination and subsequent degradation. Kinase activity is mainly determined by the amount of p35 available and subcellular location; reversible association to plasma membrane inhibits activity. Long-term inactivation as well as CDK5R1 (p25)-mediated hyperactivation of CDK5 triggers cell death. The pro-death activity of hyperactivated CDK5 is suppressed by membrane association of CDK5, via myristoylation of p35. Brain-derived neurotrophic factor, glial-derived neurotrophic factor, nerve growth factor (NGF), retinoic acid, laminin and neuregulin promote activity. Neurotoxicity enhances nuclear activity, thus leading to MEF2 phosphorylation and inhibition prior to apoptosis of cortical neurons. Repression by GSTP1 via p25/p35 translocation prevents neurodegeneration.

Miscellaneous. Dysregulation of CDK5 is associated with neurodegenerative disorders such as Alzheimer, Parkinson, and Niemann-Pick type C diseases, ischemia, and amyotrophic lateral sclerosis.

Similarity. Belongs to the protein kinase superfamily. CMGC Ser/Thr protein kinase family. CDC2/CDKX subfamily.

Isoforms (2)

UniProt ID	Names	Canonical?
Q00535-1	1	yes
Q00535-2	2, CDK5-SV

RefSeq proteins (2): NP_001157882, NP_004926* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000719	Prot_kinase_dom	Domain
IPR008271	Ser/Thr_kinase_AS	Active_site
IPR011009	Kinase-like_dom_sf	Homologous_superfamily
IPR017441	Protein_kinase_ATP_BS	Binding_site
IPR050108	CDK	Family

Pfam: PF00069

Enzyme classification (BRENDA):

• EC 2.7.11.1 — non-specific serine/threonine protein kinase (BRENDA: 71 organisms, 682 substrates, 228 inhibitors, 23 Km, 6 kcat entries)
• EC 2.7.11.22 — cyclin-dependent kinase (BRENDA: 49 organisms, 441 substrates, 555 inhibitors, 8 Km, 4 kcat entries)

Substrate kinetics (BRENDA)

12 substrates with measured Km, best-characterized 12. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
ATP	0.0007–0.64	11
KKRAARATSNVFA	0.013–0.045	3
PAH1 PHOSPHATIDATE PHOSPHATASE	0.0002	2
RRRLSSLRA	0.0036–0.0037	2
ADAQHATPPKKKRKVEDPKDF	0.046–0.521	2
ATP	0.0052–0.017	2
GTP	0.46	1
KKRAARASSNVFA	0.02	1
LYS-LYS-PHE-ASN-ARG-THR-LEU-SER-VAL-ALA	0.0093	1
MYELIN BASIC PROTEIN	0.145	1
FIN1	0.003	1
PKTPKKAKKL	0.0029	1

Catalyzed reactions (Rhea), 2 shown:

• L-seryl-[protein] + ATP = O-phospho-L-seryl-[protein] + ADP + H(+) (RHEA:17989)
• L-threonyl-[protein] + ATP = O-phospho-L-threonyl-[protein] + ADP + H(+) (RHEA:46608)

UniProt features (42 total): helix 15, strand 10, modified residue 5, turn 3, mutagenesis site 2, binding site 2, chain 1, domain 1, splice variant 1, sequence variant 1, active site 1

Structure

Experimental structures (PDB)

10 structures.

PDB	Method	Resolution (Å)
4AU8	X-RAY DIFFRACTION	1.9
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
7VDR	X-RAY DIFFRACTION	2.55
1H4L	X-RAY DIFFRACTION	2.65
7VDQ	X-RAY DIFFRACTION	2.91
7VDS	X-RAY DIFFRACTION	3.05

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q00535-F1	91.83	0.78

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): 126 (proton acceptor)

Ligand- & substrate-binding residues (2): 10–18; 33

Post-translational modifications (5): 15, 17, 56, 72, 159

Mutagenesis-validated functional residues (2):

Position	Phenotype
159	no phenotype.
159	impaired p35/p25 (cdk5r1) binding.

Function

Pathways and Gene Ontology

Reactome pathways

40 pathways

ID	Pathway
R-HSA-180024	DARPP-32 events
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-983231	Factors involved in megakaryocyte development and platelet production
R-HSA-9841922	MLL4 and MLL3 complexes regulate expression of PPARG target genes in adipogenesis and hepatic steatosis
R-HSA-9931529	Phosphorylation and nuclear translocation of BMAL1 (ARNTL) and CLOCK
R-HSA-9931530	Phosphorylation and nuclear translocation of the CRY:PER:kinase complex
R-HSA-109582	Hemostasis
R-HSA-111885	Opioid Signalling
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-212165	Epigenetic regulation of gene expression
R-HSA-212436	Generic Transcription Pathway
R-HSA-3700989	Transcriptional Regulation by TP53
R-HSA-372790	Signaling by GPCR
R-HSA-373755	Semaphorin interactions
R-HSA-388396	GPCR downstream signalling
R-HSA-418594	G alpha (i) signalling events
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)

MSigDB gene sets: 608 (showing top): GOBP_NEUROMUSCULAR_JUNCTION_DEVELOPMENT, GOBP_DENDRITE_DEVELOPMENT, GOBP_SYNAPTIC_VESICLE_LOCALIZATION, GOBP_HINDBRAIN_DEVELOPMENT, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, GOBP_REGULATION_OF_AUTOPHAGY, GOBP_NEGATIVE_REGULATION_OF_CELL_DEVELOPMENT, GOBP_NEGATIVE_REGULATION_OF_PROTEOLYSIS, GOBP_METENCEPHALON_DEVELOPMENT, BUYTAERT_PHOTODYNAMIC_THERAPY_STRESS_DN, GOBP_MUSCLE_TISSUE_DEVELOPMENT, GOBP_COGNITION, GOBP_POSITIVE_REGULATION_OF_CALCIUM_ION_DEPENDENT_EXOCYTOSIS, GOBP_BEHAVIOR, GOBP_NEURON_PROJECTION_EXTENSION

GO Biological Process (73): microtubule cytoskeleton organization (GO:0000226), neuron migration (GO:0001764), synaptic transmission, dopaminergic (GO:0001963), intracellular protein transport (GO:0006886), cell-matrix adhesion (GO:0007160), chemical synaptic transmission (GO:0007268), axonogenesis (GO:0007409), synapse assembly (GO:0007416), skeletal muscle tissue development (GO:0007519), motor neuron axon guidance (GO:0008045), visual learning (GO:0008542), Schwann cell development (GO:0014044), synaptic vesicle exocytosis (GO:0016079), regulation of macroautophagy (GO:0016241), sensory perception of pain (GO:0019233), cerebellar cortex formation (GO:0021697), hippocampus development (GO:0021766), layer formation in cerebral cortex (GO:0021819), central nervous system neuron development (GO:0021954), corpus callosum development (GO:0022038), actin cytoskeleton organization (GO:0030036), neuron differentiation (GO:0030182), regulation of cell migration (GO:0030334), negative regulation of axon extension (GO:0030517), neuron projection development (GO:0031175), negative regulation of protein ubiquitination (GO:0031397), negative regulation of synaptic plasticity (GO:0031914), receptor catabolic process (GO:0032801), synaptic transmission, glutamatergic (GO:0035249), protein localization to synapse (GO:0035418), regulation of apoptotic process (GO:0042981), receptor clustering (GO:0043113), positive regulation of neuron apoptotic process (GO:0043525), negative regulation of cell cycle (GO:0045786), negative regulation of proteolysis (GO:0045861), negative regulation of DNA-templated transcription (GO:0045892), positive regulation of calcium ion-dependent exocytosis (GO:0045956), negative regulation of protein export from nucleus (GO:0046826), behavioral response to cocaine (GO:0048148), regulation of synaptic plasticity (GO:0048167)

GO Molecular Function (18): p53 binding (GO:0002039), protein kinase activity (GO:0004672), protein serine/threonine kinase activity (GO:0004674), cyclin-dependent protein serine/threonine kinase activity (GO:0004693), ErbB-2 class receptor binding (GO:0005176), ATP binding (GO:0005524), kinase activity (GO:0016301), signaling receptor inhibitor activity (GO:0030547), acetylcholine receptor activator activity (GO:0030549), ionotropic glutamate receptor binding (GO:0035255), ErbB-3 class receptor binding (GO:0043125), tau protein binding (GO:0048156), tau-protein kinase activity (GO:0050321), Hsp90 protein binding (GO:0051879), protein serine kinase activity (GO:0106310), nucleotide binding (GO:0000166), protein binding (GO:0005515), transferase activity (GO:0016740)

GO Cellular Component (24): 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), lamellipodium (GO:0030027), cell junction (GO:0030054), filopodium (GO:0030175), axon (GO:0030424), dendrite (GO:0030425), growth cone (GO:0030426), neuromuscular junction (GO:0031594), neuron projection (GO:0043005), neuronal cell body (GO:0043025), perikaryon (GO:0043204), presynapse (GO:0098793), microtubule (GO:0005874), cell projection (GO:0042995), synapse (GO:0045202), postsynapse (GO:0098794)

Reactome top-level categories

Rollup of top-15 pathways:

Category	Pathways
Circadian clock	2
Opioid Signalling	1
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
Hemostasis	1
Epigenetic regulation of adipogenesis genes by MLL3 and MLL4 complexes	1
G alpha (i) signalling events	1
Signaling by Receptor Tyrosine Kinases	1
Signaling by NTRKs	1
Signaling by NTRK1 (TRKA)	1
Gene expression (Transcription)	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	7
anatomical structure formation involved in morphogenesis	2
anatomical structure development	2
protein kinase activity	2
protein serine/threonine kinase activity	2
signaling receptor binding	2
serine/threonine protein kinase complex	2
plasma membrane bounded cell projection	2
neuron projection	2
synapse	2
cytoskeleton organization	1
microtubule-based process	1
cell migration	1
generation of neurons	1
chemical synaptic transmission	1
intracellular protein localization	1
protein transport	1
intracellular transport	1
cell-substrate adhesion	1
anterograde trans-synaptic signaling	1
cell morphogenesis involved in neuron differentiation	1
neuron projection morphogenesis	1
axon development	1
nervous system development	1
cell junction assembly	1
synapse organization	1
striated muscle tissue development	1
skeletal muscle organ development	1
axon guidance	1
visual behavior	1
associative learning	1
Schwann cell differentiation	1
glial cell development	1
neurotransmitter secretion	1
regulated exocytosis	1
establishment of localization in cell	1
presynapse	1
vesicle-mediated transport in synapse	1
synaptic vesicle cycle	1
signal release from synapse	1

Protein interactions and networks

STRING

3246 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CDK5	CDK5R1	Q15078	998
CDK5	CDK5R2	Q13319	966
CDK5	MAPT	P10636	948
CDK5	CCNL2	Q96S94	933
CDK5	CDK5RAP1	Q96SZ6	910
CDK5	BACE1	P56817	875
CDK5	CDK2	P24941	873
CDK5	APP	P05067	860
CDK5	PSEN1	P49768	853
CDK5	CDK5RAP3	Q96JB5	840
CDK5	TP53	P04637	831
CDK5	NEFH	P12036	819
CDK5	CCNG1	P51959	813
CDK5	DPYSL2	Q16555	809
CDK5	GRIN2B	Q13224	800

IntAct

201 interactions, top by confidence:

A	B	Type	Score
CCND1	CDK4	psi-mi:“MI:0914”(association)	0.990
CCND3	CDK4	psi-mi:“MI:0914”(association)	0.980
CDK5	CCND2	psi-mi:“MI:0915”(physical association)	0.960
CCND2	CDK5	psi-mi:“MI:0915”(physical association)	0.960
CCND2	CDK4	psi-mi:“MI:0914”(association)	0.960
CDK5	CDK5R1	psi-mi:“MI:0407”(direct interaction)	0.940
CDK5R1	CDK5	psi-mi:“MI:0407”(direct interaction)	0.940
CDKN1B	CDK5	psi-mi:“MI:0407”(direct interaction)	0.940
CDKN1B	CDK5	psi-mi:“MI:0915”(physical association)	0.940
CDK5	CDKN1B	psi-mi:“MI:0407”(direct interaction)	0.940
CDK5	CDKN1B	psi-mi:“MI:0915”(physical association)	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

BioGRID (403): CDK5 (Affinity Capture-MS), CDK5 (Two-hybrid), PPARG (Biochemical Activity), MAPT (Biochemical Activity), CDK5 (Affinity Capture-Western), MAPT (Biochemical Activity), CABLES1 (Affinity Capture-MS), CABLES2 (Affinity Capture-MS), CCNB1 (Affinity Capture-MS), CCNI (Affinity Capture-MS), CCT2 (Affinity Capture-MS), CCT3 (Affinity Capture-MS), CCT4 (Affinity Capture-MS), CCT5 (Affinity Capture-MS), CCT6A (Affinity Capture-MS)

ESM2 similar proteins: A8WIP6, A8XA58, G5EFV5, O96821, P00546, P04551, P06242, P06493, P11440, P13863, P17157, P23573, P24033, P34556, P35567, P38973, P39951, P43063, P48734, P49615, P51166, P51958, P54119, P54664, Q00535, Q00646, Q02399, Q03114, Q06309, Q26671, Q27032, Q2V419, Q38775, Q4Y4B1, Q4Z6R1, Q5RCH1, Q64261, Q6FKD4, Q6ZAG3, Q7RM49

Diamond homologs: A2X6X1, A2XUW1, A2Y4B6, A8WIP6, A8XA58, G5ECH7, G5EFV5, O55076, O74456, O96821, P00546, P04551, P06242, P06493, P11440, P13863, P20911, P23111, P23437, P23572, P23573, P24033, P24100, P24923, P24941, P29618, P29619, P29620, P34112, P34117, P35567, P38973, P39951, P43063, P43450, P48609, P48734, P48963, P49615, P50613

SIGNOR signaling

183 interactions.

A	Effect	B	Mechanism
CDK5	“down-regulates activity”	MEF2A	phosphorylation
CDK5	down-regulates	LMTK2	phosphorylation
CDK5R1	up-regulates	CDK5	binding
CDK5	up-regulates	STAT3	phosphorylation
CDK5	down-regulates	PIP5K1C	phosphorylation
CDK5	down-regulates	RB1	phosphorylation
CDK5	up-regulates	CRMP1	phosphorylation
CDK5	“up-regulates activity”	DPYSL3	phosphorylation
CDK5	“down-regulates activity”	PPP1CA	phosphorylation
CDK5	down-regulates	PRKN	phosphorylation
CDK5	“down-regulates activity”	NR3C1	phosphorylation
CDK5	up-regulates	TP53	phosphorylation
CDK5	up-regulates	HTT	phosphorylation
CDK5	down-regulates	STXBP2	phosphorylation
CDK5	down-regulates	NOS3	phosphorylation
CDK5	down-regulates	PIK3C3	phosphorylation
CDK5	down-regulates	STMN1	phosphorylation
CDK5	down-regulates	PMAIP1	phosphorylation
CDK5	up-regulates	NFAT5	phosphorylation
CDK5	down-regulates	MAPT	phosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 130 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Defective binding of RB1 mutants to E2F1,(E2F2, E2F3)	10	74.6×	3e-15
TP53 Regulates Transcription of Cell Cycle Genes	9	57.6×	1e-12
TP53 Regulates Transcription of Genes Involved in G1 Cell Cycle Arrest	6	50.4×	4e-08
p53-Dependent G1 DNA Damage Response	6	50.4×	4e-08
p53-Dependent G1/S DNA damage checkpoint	6	50.4×	4e-08
Aberrant regulation of mitotic cell cycle due to RB1 defects	10	48.0×	7e-13
G1/S DNA Damage Checkpoints	6	47.4×	5e-08
G1 Phase	10	46.3×	7e-13

GO biological processes:

GO term	Partners	Fold	FDR
G1/S transition of mitotic cell cycle	18	30.6×	3e-19
positive regulation of microtubule polymerization	5	28.6×	2e-04
regulation of canonical Wnt signaling pathway	5	23.0×	4e-04
positive regulation of G1/S transition of mitotic cell cycle	5	17.0×	1e-03
G2/M transition of mitotic cell cycle	6	15.9×	4e-04
positive regulation of fibroblast proliferation	6	15.0×	5e-04
cellular senescence	5	12.5×	3e-03
mitotic spindle organization	5	11.5×	4e-03

Disease & clinical

Cancer significance

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	1
Uncertain significance	13
Likely benign	48
Benign	11

Top pathogenic / likely-pathogenic (2)

Variant ID	HGVS	Classification
190117	NM_004935.4(CDK5):c.580+1G>A	Pathogenic
2683824	NM_004935.4(CDK5):c.149G>A (p.Arg50Gln)	Likely pathogenic

SpliceAI

2344 predictions. Top by Δscore:

Variant	Effect	Δscore
7:151051808:A:AG	acceptor_gain	1.0000
7:151051809:G:GG	acceptor_gain	1.0000
7:151051873:G:GT	donor_gain	1.0000
7:151051885:G:GT	donor_gain	1.0000
7:151051885:GAT:G	donor_gain	1.0000
7:151051897:GCTTG:G	donor_gain	1.0000
7:151051899:TTGGT:T	donor_loss	1.0000
7:151051900:TG:T	donor_loss	1.0000
7:151051901:GG:G	donor_loss	1.0000
7:151051902:G:GG	donor_gain	1.0000
7:151051904:G:GG	donor_gain	1.0000
7:151051978:CACAG:C	acceptor_loss	1.0000
7:151051980:CAGGT:C	acceptor_loss	1.0000
7:151051981:A:AG	acceptor_gain	1.0000
7:151051981:A:T	acceptor_loss	1.0000
7:151051982:G:GG	acceptor_gain	1.0000
7:151051982:G:GT	acceptor_loss	1.0000
7:151051982:GGT:G	acceptor_gain	1.0000
7:151052058:G:GG	donor_gain	1.0000
7:151052058:GTGAG:G	donor_loss	1.0000
7:151052059:TGAGG:T	donor_loss	1.0000
7:151052060:GAGGT:G	donor_loss	1.0000
7:151052061:AGGT:A	donor_loss	1.0000
7:151052062:GGTG:G	donor_loss	1.0000
7:151054096:C:CC	acceptor_gain	1.0000
7:151054102:A:C	acceptor_gain	1.0000
7:151054208:CTA:C	donor_loss	1.0000
7:151054210:A:AC	donor_gain	1.0000
7:151054211:C:CC	donor_gain	1.0000
7:151054211:CCTG:C	donor_gain	1.0000

AlphaMissense

1906 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
7:151055063:C:T	G205D	1.000
7:151055064:C:G	G205R	1.000
7:151055287:G:C	C190W	1.000
7:151055288:C:T	C190Y	1.000
7:151055291:C:T	G189D	1.000
7:151055292:C:G	G189R	1.000
7:151055299:C:A	W186C	1.000
7:151055299:C:G	W186C	1.000
7:151055301:A:G	W186R	1.000
7:151055301:A:T	W186R	1.000
7:151055306:T:A	D184V	1.000
7:151055307:C:A	D184Y	1.000
7:151055307:C:G	D184H	1.000
7:151055354:C:G	R168P	1.000
7:151055355:G:T	R168S	1.000
7:151055358:A:G	Y167H	1.000
7:151055361:A:G	W166R	1.000
7:151055361:A:T	W166R	1.000
7:151055366:G:A	T164I	1.000
7:151055572:G:T	A148D	1.000
7:151055575:A:G	L147P	1.000
7:151055575:A:T	L147Q	1.000
7:151055578:C:T	G146D	1.000
7:151055579:C:G	G146R	1.000
7:151055583:A:C	D144E	1.000
7:151055583:A:T	D144E	1.000
7:151055584:T:A	D144V	1.000
7:151055584:T:C	D144G	1.000
7:151055584:T:G	D144A	1.000
7:151055585:C:G	D144H	1.000

dbSNP variants (sampled 300 via entrez): RS1000324881 (7:151054558 C>G), RS1000675589 (7:151054779 G>C), RS1001064694 (7:151057383 G>A), RS1001323510 (7:151057711 G>A,C,T), RS1002467832 (7:151055819 C>T), RS1002901213 (7:151054596 T>G), RS1003109582 (7:151056777 T>A), RS1005170701 (7:151058316 A>T), RS1005454280 (7:151056063 A>C,G,T), RS1007145014 (7:151055223 A>G), RS1007759996 (7:151059385 C>G), RS1008135373 (7:151053468 G>A,T), RS1008563319 (7:151053810 C>T), RS1008612787 (7:151058521 G>A), RS1008684958 (7:151058781 C>T)

Disease associations

OMIM: gene MIM:123831 | disease phenotypes: MIM:616342

GenCC curated gene-disease

Disease	Classification	Inheritance
lissencephaly 7 with cerebellar hypoplasia	Strong	Autosomal recessive

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
lissencephaly with cerebellar hypoplasia	Moderate	AR

Mondo (1): lissencephaly 7 with cerebellar hypoplasia (MONDO:0014596)

Orphanet (0):

HPO phenotypes

26 total (26 of 26 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000252	Microcephaly
HP:0000293	Full cheeks
HP:0000294	Low anterior hairline
HP:0000347	Micrognathia
HP:0000350	Small forehead
HP:0000470	Short neck
HP:0001004	Lymphedema
HP:0001007	Hirsutism
HP:0001188	Hand clenching
HP:0001250	Seizure
HP:0001263	Global developmental delay
HP:0001274	Agenesis of corpus callosum
HP:0001284	Areflexia
HP:0001321	Cerebellar hypoplasia
HP:0001339	Lissencephaly
HP:0001522	Death in infancy
HP:0002151	Increased circulating lactate concentration
HP:0002714	Downturned corners of mouth
HP:0002804	Arthrogryposis multiplex congenita
HP:0003577	Congenital onset
HP:0003811	Neonatal death
HP:0010851	EEG with burst suppression
HP:0011922	Abnormal activity of mitochondrial respiratory chain
HP:0031882	Agyria
HP:0032988	Persistent head lag

GWAS associations

8 associations (top):

Study	Trait	p-value
GCST003476_9	Eyebrow thickness	7.000000e-06
GCST90000047_240	Age at first sexual intercourse	3.000000e-09
GCST90002383_441	Hematocrit	3.000000e-10
GCST90002384_166	Hemoglobin	4.000000e-13
GCST90002392_342	Mean corpuscular volume	8.000000e-12
GCST90002396_360	Mean reticulocyte volume	5.000000e-13
GCST90002397_316	Mean spheric corpuscular volume	5.000000e-14
GCST90002403_594	Red blood cell count	3.000000e-23

EFO canonical traits (5, from GWAS)

EFO ID	Trait name
EFO:0009749	age at first sexual intercourse measurement
EFO:0004348	hematocrit
EFO:0004509	hemoglobin measurement
EFO:0010701	mean reticulocyte volume
EFO:0004305	erythrocyte count

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (7): CHEMBL1907600 (PROTEIN COMPLEX), CHEMBL3559691 (PROTEIN FAMILY), CHEMBL3885549 (PROTEIN COMPLEX), CHEMBL4036 (SINGLE PROTEIN), CHEMBL4523701 (PROTEIN-PROTEIN INTERACTION), CHEMBL5483185 (PROTEIN COMPLEX), CHEMBL6066140 (PROTEIN-PROTEIN INTERACTION)

Molecules with ChEMBL bioactivity

58 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 379,233 (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
CHEMBL1336	SORAFENIB	4	86,060
CHEMBL2028663	DABRAFENIB	4	12,430
CHEMBL535	SUNITINIB	4	79,020
CHEMBL2103840	DINACICLIB	3	2,257
CHEMBL297453	EPIGALOCATECHIN GALLATE	3	22,804
CHEMBL428690	ALVOCIDIB	3	27,781
CHEMBL50	QUERCETIN	3	74,559
CHEMBL2105728	CRENOLANIB	3	2,167
CHEMBL3137331	DEFACTINIB	3	1,229
CHEMBL38380	FASUDIL	3	11,953
CHEMBL603469	LESTAURTINIB	3
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
CHEMBL5095094	CULMERCICLIB	2
CHEMBL5095102	INIXACICLIB	2
CHEMBL5199065	ISTISOCICLIB	2
CHEMBL564829	MILCICLIB	2
CHEMBL103667	DORAMAPIMOD	2
CHEMBL1230165	SILMITASERTIB	2
CHEMBL1738757	REBASTINIB	2
CHEMBL1967878	CENISERTIB	2
CHEMBL1976040	ADAVOSERTIB	2

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

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: enzyme — CDK5 subfamily

Most potent curated ligand interactions (24 total), top 24:

Ligand	Action	Affinity	Parameter
tanuxiciclib	Inhibition	9.15	pIC50
dinaciclib	Inhibition	9.0	pIC50
zotiraciclib	Inhibition	8.4	pIC50
RGB-286638	Inhibition	8.3	pIC50
purvalanol B	Inhibition	8.22	pIC50
AT-7519	Inhibition	7.89	pIC50
CDK inhibitor 4.35	Inhibition	7.82	pIC50
aminopurvalanol A	Inhibition	7.7	pIC50
SU9516	Inhibition	7.66	pIC50
CGP74514A	Inhibition	7.59	pIC50
BS-194	Inhibition	7.52	pIC50
kinase inhibitor 2 [PMID: 30199702]	Inhibition	7.3	pIC50
purvalanol A	Inhibition	7.12	pIC50
GSK-3 inhibitor IX	Inhibition	7.08	pIC50
(R)-CR8	Inhibition	6.96	pIC50
(S)-CR8	Inhibition	6.92	pIC50
aloisine A	Inhibition	6.8	pIC50
voruciclib	Inhibition	6.68	pIC50
milciclib	Inhibition	6.42	pIC50
Cdk1/5 inhibitor	Inhibition	6.4	pIC50
kenpaullone	Inhibition	6.07	pIC50
RO3306	Inhibition	5.61	pIC50
1-azakenpaullone	Inhibition	5.38	pIC50
Cdk2 inhibitor IV	Inhibition	4.82	pIC50

Binding affinities (BindingDB)

92 measured of 124 human assays (335 total across all organisms); most potent 50 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
BDBM50375663	IC50	0.23 nM
1-[2-(4-methylphenyl)-5-tert-butyl-pyrazol-3-yl]-3-[4-(2-morpholin-4-ylethoxy)naphthalen-1-yl]urea	KD	0.37 nM
Staurosporine	KD	1.7 nM
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
3-[2-(4-hydroxyphenyl)-1,3-thiazol-4-yl]-1,2-dihydroquinolin-2-one	IC50	24 nM
Alsterpaullone derivative, 5	IC50	25 nM
Alsterpaullone derivative, 4	IC50	27 nM
3-{2-[(benzenesulfonyl)methyl]-1,3-thiazol-4-yl}-1,2-dihydroquinolin-2-one	IC50	29 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
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
3-[2-(cyclopropanecarbonylamino)-[1,3]thiazolo[5,4-b]pyridin-5-yl]-N-[4-[(4-ethylpiperazin-1-yl)methyl]-3-(trifluoromethyl)phenyl]benzamide	KD	57 nM	US-8765747: Fused 2-aminothiazole compounds
(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
Pyrazolopyrimidone analog, RGB-286147	IC50	71 nM
6-fluoro-3-[2-(pyridin-4-yl)-1,3-thiazol-4-yl]-1,2,3,4-tetrahydroquinazolin-2-one	IC50	72 nM
3-[4-(pyridin-4-yl)-1,3-thiazol-2-yl]-1,2,3,4-tetrahydroquinazolin-2-one	IC50	77 nM
Alsterpaullone derivative, 3	IC50	80 nM
cis-(1S,3R)-3-acetamido-N-[4-(4-fluoro-2-methoxyphenyl)-2-pyridinyl]cyclohexane-1-carboxamide	IC50	94 nM	US-9067888: Inhibitors of protein kinases
Alsterpaullone derivative, 6	IC50	100 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
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
(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
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

ChEMBL bioactivities

2267 potent at pChembl≥5 of 2493 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
10.00	IC50	0.1	nM	RG-547
9.70	IC50	0.2	nM	CHEMBL261720
9.70	IC50	0.2	nM	CHEMBL5075328
9.70	IC50	0.2	nM	CHEMBL5080866
9.50	Ki	0.3162	nM	CHEMBL2006674
9.30	Ki	0.5012	nM	JNJ-7706621
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
9.20	Ki	0.631	nM	CHEMBL1980407
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	CHEMBL3775792
9.00	IC50	1	nM	DINACICLIB
9.00	IC50	1	nM	CHEMBL4292930
9.00	IC50	1	nM	CHEMBL5092400
9.00	IC50	1	nM	CHEMBL5080361
9.00	IC50	1	nM	CHEMBL5080566
9.00	IC50	1	nM	CHEMBL5171657
9.00	IC50	1	nM	CHEMBL5266005
9.00	Ki	1	nM	CHEMBL5571565
9.00	IC50	1	nM	CHEMBL5955040
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
8.90	Ki	1.259	nM	CHEMBL1968930
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	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

PubChem BioAssay actives

1775 with measured affinity, of 6100 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
[4-amino-2-[(1-methylsulfonylpiperidin-4-yl)amino]pyrimidin-5-yl]-(2,3-difluoro-6-methoxyphenyl)methanone	1890134: Inhibition of CDK5 (unknown origin) by kinase selectivity assay	ic50	0.0001	uM
(2R)-2-[[6-(benzylamino)-9-propan-2-ylpurin-2-yl]amino]butan-1-ol	1876287: Inhibition of CDK5 (unknown origin)	ic50	0.0002	uM
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
2-methyl-1-[[3-propan-2-yl-7-[(4-pyridin-2-ylphenyl)methylamino]-2H-pyrazolo[4,3-d]pyrimidin-5-yl]amino]propan-2-ol	1283433: Inhibition of CDK5 (unknown origin) using histone H1 as substrate in presence of [gamma33P]-ATP	ic50	0.0010	uM
2-[(2R)-1-[3-methyl-7-[(1-oxidopyridin-1-ium-3-yl)methylamino]pyrazolo[1,5-a]pyrimidin-5-yl]piperidin-2-yl]ethanol	1424516: Inhibition of recombinant CDK5 (unknown origin) expressed in Sf9 cells using histone H1 derived biotinylated peptide and 33P-ATP incubated for 1 hr by liquid scintillation counting method	ic50	0.0010	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
2-[(1S)-2-[3-ethyl-7-[(1-oxidopyridin-1-ium-3-yl)methylamino]pyrazolo[1,5-a]pyrimidin-5-yl]cyclohexyl]ethanol	1890155: Inhibition of recombinant CDK5 (unknown origin) expressed in baculovirus infected Sf9 insect cells using biotinylated-histone H1 as substrate incubated for 1 hr in presence of 33P-ATP by liquid scintillation counter 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
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
(16E)-14-methyl-20-oxa-5,7,14,27-tetrazatetracyclo[19.3.1.12,6.18,12]heptacosa-1(25),2(27),3,5,8,10,12(26),16,21,23-decaene	1317391: Inhibition of human GST-tagged CDK5	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
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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	decreases expression, increases abundance, increases expression, affects methylation, affects binding (+1 more)	5
Valproic Acid	affects expression, increases expression	5
Arsenic	affects methylation, increases expression, decreases expression, increases abundance	3
Cannabidiol	decreases expression	2
Hydrogen Peroxide	affects expression, increases expression	2
Cyclosporine	decreases expression	2
Genistein	decreases expression, increases expression	2
urushiol	decreases expression	1
methylselenic acid	increases expression	1
beta-lapachone	decreases expression	1
arsenite	affects binding, increases reaction	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
cobaltous chloride	decreases expression	1
azoxystrobin	decreases expression	1
deguelin	decreases expression	1
thifluzamide	decreases expression	1
AG-012986	decreases activity	1
pyrachlostrobin	decreases expression	1
olaparib	increases expression	1
jinfukang	affects cotreatment, increases expression	1
7-benzylamino-5-(2-(hydroxymethyl)propyl)amino-3-isopropyl-1(2)H-pyrazolo(4,3-d)pyrimidine	decreases activity	1
Sunitinib	decreases expression	1
Lycopene	decreases expression	1
Roscovitine	decreases activity	1
Acetaminophen	decreases expression	1
Air Pollutants	decreases expression, increases abundance	1
Antimycin A	decreases expression	1
Atrazine	decreases expression	1
Carbamazepine	affects expression	1
Chlorpromazine	decreases expression	1

ChEMBL screening assays

1044 unique, capped per target: 1036 binding, 4 admet, 3 functional, 1 toxicity

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

Cellosaurus cell lines

6 cell lines: 5 cancer cell line, 1 transformed cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_B2U1	Abcam HEK293T CDK5 KO	Transformed cell line	Female
CVCL_B8DE	Abcam HCT 116 CDK5 KO	Cancer cell line	Male
CVCL_B8TW	Abcam MCF-7 CDK5 KO	Cancer cell line	Female
CVCL_B9FL	Abcam A-549 CDK5 KO	Cancer cell line	Male
CVCL_SI38	HAP1 CDK5 (-) 1	Cancer cell line	Male
CVCL_SI39	HAP1 CDK5 (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

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