CCND3

Summary

CCND3 (cyclin D3, HGNC:1585) is a protein-coding gene on chromosome 6p21.1, encoding G1/S-specific cyclin-D3 (P30281). Regulatory component of the cyclin D3-CDK4 (DC) complex that phosphorylates and inhibits members of the retinoblastoma (RB) protein family including RB1 and regulates the cell-cycle during G(1)/S transition. In precision oncology, CCND1 Amplification OR CCND2 Amplification OR CCND3 Amplification confers sensitivity to Palbociclib in Cancer (CIViC Level B); 1 further curated variant–drug associations are listed below. It is a selective cancer dependency (DepMap: 17.0% of cell lines).

The protein encoded by this gene belongs to the highly conserved cyclin family, whose members are characterized by a dramatic periodicity in protein abundance through the cell cycle. Cyclins function as regulators of CDK kinases. Different cyclins exhibit distinct expression and degradation patterns which contribute to the temporal coordination of each mitotic event. This cyclin forms a complex with and functions as a regulatory subunit of CDK4 or CDK6, whose activtiy is required for cell cycle G1/S transition. This protein has been shown to interact with and be involved in the phosphorylation of tumor suppressor protein Rb. The CDK4 activity associated with this cyclin was reported to be necessary for cell cycle progression through G2 phase into mitosis after UV radiation. Several transcript variants encoding different isoforms have been found for this gene.

Source: NCBI Gene 896 — RefSeq curated summary.

At a glance

• GWAS associations: 127
• Clinical variants (ClinVar): 41 total
• Druggable target: yes — 17 molecules with ChEMBL bioactivity
• Precision-oncology evidence (CIViC): 2 curated variant–drug associations
• Cancer driver (intOGen): activating (oncogene-like) across 4 cancer types
• Cancer dependency (DepMap): dependent in 17.0% of screened cell lines
• MANE Select transcript: NM_001760

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:1585
Approved symbol	CCND3
Name	cyclin D3
Location	6p21.1
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000112576
Ensembl biotype	protein_coding
OMIM	123834
Entrez	896

Gene structure

Transcript identifiers

Ensembl transcripts: 23 — 13 protein_coding, 6 protein_coding_CDS_not_defined, 4 retained_intron

ENST00000372987, ENST00000372988, ENST00000372991, ENST00000414200, ENST00000415497, ENST00000502771, ENST00000505064, ENST00000505672, ENST00000505884, ENST00000506555, ENST00000508143, ENST00000510058, ENST00000510503, ENST00000511161, ENST00000511642, ENST00000511686, ENST00000512381, ENST00000512426, ENST00000513956, ENST00000514382, ENST00000514588, ENST00000612455, ENST00000616010

RefSeq mRNA: 15 — MANE Select: NM_001760 NM_001136017, NM_001136125, NM_001136126, NM_001287427, NM_001287434, NM_001424052, NM_001424053, NM_001424055, NM_001424056, NM_001424057, NM_001424058, NM_001424059, NM_001424060, NM_001424061, NM_001760

CCDS: CCDS47425, CCDS47426, CCDS47427, CCDS4863, CCDS75452

Canonical transcript exons

ENST00000372991 — 5 exons

Exon	Start	End
ENSE00001459243	41941452	41941808
ENSE00001901613	41934952	41936107
ENSE00003544014	41936559	41936695
ENSE00003577008	41940370	41940585
ENSE00003662175	41937235	41937394

Expression profiles

Bgee: expression breadth ubiquitous, 287 present calls, max score 99.13.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 70.7413 / max 1294.1085, expressed in 1819 samples.

FANTOM5 promoters (11 alternative TSS)

Promoter ID	TPM avg	Samples expressed
73583	29.3377	1793
73593	22.7835	1558
73584	8.4371	1710
73585	7.8773	1660
73582	0.8379	550
73579	0.5105	267
73591	0.4734	176
73592	0.3087	140
73590	0.0797	40
73581	0.0614	24

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
granulocyte	CL:0000094	99.13	gold quality
thymus	UBERON:0002370	99.01	gold quality
blood	UBERON:0000178	98.57	gold quality
spleen	UBERON:0002106	98.47	gold quality
lymph node	UBERON:0000029	98.37	gold quality
leukocyte	CL:0000738	98.36	gold quality
mononuclear cell	CL:0000842	98.31	gold quality
monocyte	CL:0000576	98.30	gold quality
right adrenal gland cortex	UBERON:0035827	98.09	gold quality
right lung	UBERON:0002167	98.00	gold quality
right adrenal gland	UBERON:0001233	97.92	gold quality
bone marrow	UBERON:0002371	97.75	gold quality
upper lobe of left lung	UBERON:0008952	97.72	gold quality
left adrenal gland	UBERON:0001234	97.63	gold quality
adrenal cortex	UBERON:0001235	97.62	gold quality
left adrenal gland cortex	UBERON:0035825	97.45	gold quality
upper lobe of lung	UBERON:0008948	97.44	gold quality
adrenal gland	UBERON:0002369	97.41	gold quality
trabecular bone tissue	UBERON:0002483	97.10	gold quality
bone marrow cell	CL:0002092	96.93	gold quality
apex of heart	UBERON:0002098	96.75	gold quality
dorsal root ganglion	UBERON:0000044	96.64	gold quality
trigeminal ganglion	UBERON:0001675	96.29	gold quality
tibial nerve	UBERON:0001323	96.19	gold quality
omental fat pad	UBERON:0010414	96.15	gold quality
mucosa of stomach	UBERON:0001199	96.12	gold quality
peritoneum	UBERON:0002358	96.11	gold quality
right lobe of thyroid gland	UBERON:0001119	95.96	gold quality
vermiform appendix	UBERON:0001154	95.92	gold quality
body of stomach	UBERON:0001161	95.86	gold quality

Single-cell (SCXA)

Detected in 20 experiment(s), a significant marker in 17.

Experiment	Marker?	Max mean expression
E-MTAB-9388	yes	1098.05
E-MTAB-8205	yes	142.25
E-HCAD-1	yes	97.14
E-CURD-122	yes	43.82
E-CURD-112	yes	38.32
E-MTAB-6701	yes	32.31
E-HCAD-4	yes	31.77
E-HCAD-10	yes	17.39
E-MTAB-9067	yes	15.74
E-CURD-88	yes	15.23
E-MTAB-8410	yes	14.49
E-MTAB-8271	yes	11.45
E-MTAB-10042	yes	9.75
E-MTAB-6678	yes	9.42
E-CURD-119	yes	5.77

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): AR, ATF2, ATF3, ATF5, CEBPB, CREB1, CTNNB1, DIDO1, E2F1, E2F2, E2F3, EGR1, ELF3, ETS1, ETV4, GTF2I, HBP1, HR, ID1, LYL1, MYC, MYF5, MYOD1, MYOG, NANOG, NR3C1, NRG1, PAX7, RBPJ, RUNX1, SMAD3, SP1, STAT1, STAT3, STAT5A, STAT5B, TCF3, TFAP2A, TP53, TP63

miRNA regulators (miRDB)

56 targeting CCND3, 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-3662	99.99	73.82	5684
HSA-MIR-497-5P	99.92	71.83	2674
HSA-MIR-652-5P	99.91	67.49	505
HSA-MIR-10527-5P	99.91	72.28	3754
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-6838-5P	99.89	71.94	2690
HSA-MIR-424-5P	99.89	71.90	2641
HSA-MIR-7845-5P	99.88	64.88	771
HSA-MIR-4671-3P	99.88	72.46	1045
HSA-MIR-765	99.84	68.24	2442
HSA-MIR-1321	99.84	65.30	1811
HSA-MIR-4756-5P	99.84	64.98	1809
HSA-MIR-4739	99.84	65.25	1832
HSA-MIR-11181-3P	99.75	66.38	2205
HSA-MIR-646	99.68	67.84	1645
HSA-MIR-6892-3P	99.68	66.40	1178
HSA-MIR-6887-3P	99.66	67.83	1778
HSA-MIR-4663	99.62	65.33	957
HSA-MIR-7106-5P	99.53	67.47	3574
HSA-MIR-486-3P	99.51	66.82	1901
HSA-MIR-642A-5P	99.51	65.10	1152
HSA-MIR-4441	99.49	66.56	3216
HSA-MIR-1207-5P	99.49	69.11	2983
HSA-MIR-8064	99.45	66.92	875
HSA-MIR-330-3P	99.41	69.95	2521
HSA-MIR-6808-5P	99.31	66.23	2150
HSA-MIR-6893-5P	99.31	66.25	2119

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 17.0% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 40)

• Ubiquitin/proteasome-dependent degradation of D-type cyclins is linked to tumor necrosis factor-induced cell cycle arrest. (PMID:11864973)
• High cyclin D3 expression had a significantly lower response to antineoplastic agents in diffuse large B-cell lymphomas (PMID:11895902)
• interaction with p58(PITSLRE) (PMID:12082095)
• A cofactor of retinoic acid receptors, modulating their activity in the presence of cellular retinoic acid-binding protein II. (PMID:12482873)
• cyclin D3 is activated by E2F1;the essential E2F regulatory element of the cyclin D3 promoter is between nucleotides -143 and -135 relative to the initiating methionine codon (PMID:12611887)
• overexpression of cyclin D3 was mutually exclusive with Rb/p16 aberrant expression status supporting an oncogenic role for cyclin D3 (PMID:12647795)
• High levels of this protein are gound in malignant glioma. (PMID:12778072)
• cyclin D3 protein is expressed in a fraction of human goiters but it is strongly overexpressed in most follicular adenomas (PMID:14576819)
• stabilized by HSV-1 ICP0 through degradation of cdc34 (PMID:14645576)
• In cervical cancers cyclin D3 may compensate for low levels of cyclin D1, whereas in corpus cancers both isoforms may contribute to the neoplastic phenotype. (PMID:14666699)
• cyclin d3 does not have a role in regulating AML1/RUNX1 increase during G1 to S cell cycle progression (PMID:14747476)
• GSK-3beta has a role in cAMP-induced degradation of cyclin D3 (PMID:15252116)
• Increased expression of Cyclin D3 is associated with follicular lymphoma (PMID:15305377)
• cyclin D3 is degraded via proteasome and that Thr-283 is essential for its degradation (PMID:15326477)
• cyclin D3 specifically interacted with eIF3k through its C-terminal domain; eIF3k distributed both in nucleus and cytoplasm and colocalized with cyclin D3 (PMID:15327989)
• activating transcription factor 5 (ATF5) is a new interacting partner of cyclin D3 (PMID:15358120)
• silencing cyclin D3 by RNA interference inhibits S phase entry and sensitizes breast cancer cells to TRAIL, indicating a key role for cyclin D3 repression in these events (PMID:15569667)
• cyclin D3 may have a role in progression of laryngeal squamous cell carcinoma (PMID:15671552)
• Cyclin D1, D2, or D3 expression appears to be increased and/or dysregulated in virtually all MM tumors despite their low proliferative capacity (PMID:15755896)
• Cyclin D3 up-regulated transcriptional activity of VDR and this effect was counteracted by overexpression of CDK4 and CDK6 (PMID:16105657)
• direct association of cyclin D3 with runt-related transcription factor 1 functions as a putative feedback mechanism to regulate cell cycle progression and differentiation (PMID:16287839)
• activating transcription factor 5 increases cisplatin-induced apoptosis through up-regulation of Cyclin D3 transcription, which elicits survival signals in HeLa cells (PMID:16300731)
• Sars virus 7a protein expression was correlated with a significant reduction of cyclin D3 level of mRNA transcription and expression and prevention of cell cycle progression at the G0/G1 phase. (PMID:16303160)
• Overexpression of CCND3 through genomic amplification is associated with diffuse large B-cell lymphoma (PMID:16322284)
• These findings further expand distinct roles of cyclin D3 and suggest the potential activity of ERK3 in cell proliferation. (PMID:16360641)
• Galangin, abioflavonoid, may be useful as a chemotherapeutic agent in breast cancer by downregulation of cyclin D3. (PMID:16569260)
• cyclin D3 is an important regulator of melanoma G1-S cell cycle progression and D-type cyclins are differentially regulated in melanoma cells (PMID:16815849)
• cyclin D3 overexpression with the loss of PTEN expression is associated with endometrial carcinoma (PMID:16884382)
• Cyclin D1 or cyclin D3 are differentially used in the distinct mitogenic stimulations by growth factors or TSH. (PMID:16916940)
• all-trans retinoic acid(RA), via RA receptor, stimulates IL-2-induced signaling in a JAK-dependent manner to enhance cyclin D3 expression and thereby promote T cell proliferation (PMID:16920920)
• Cyclin D3 expression was expressed in human precursor T-lymphoblastic leukemia/lymphomas (T-LBLL), a neoplastic counterpart of T cells at the early developmental stages of differentiation. (PMID:17300668)
• SARS-CoV 3a protein, through limiting the expression of cyclin D3, may inhibit Rb phosphorylation, which in turn leads to a block in the G1 phase of the cell cycle and an inhibition of cell proliferation (PMID:17413032)
• E1AF increases cell cycle progression via upregulation of Cyclin D3 transcription, which elicits a new mechanism of breast cancer growth and a new mechanism of Cyclin D3 transcription (PMID:17467662)
• These data suggest that cyclin D3/CDK11p58 signaling is involved in the negative regulation of AR function. (PMID:17698582)
• role for D-type cyclins in the excessive basal-cell proliferation and perturbed keratinocyte differentiation in the psoriatic epidermis (PMID:17882269)
• absent or decreased cyclin D3 expression is adversely related to several clinicopathologic indicators of aggressiveness in ovarian adenocarcinomas (PMID:17885491)
• high cyclin expression may contribute to deregulation of the cell cycle in bone and soft tissue tumors (PMID:18019405)
• Cyclin D3 is a critical modulator of the androgen response, whose deregulation may foster unchecked AR activity in prostate cancer. (PMID:18084330)
• Report overexpression of cyclin D1, D3, and p21 in renal carcinomas with Xp11.2 TFE3-gene fusion. (PMID:18358634)
• cyclin E expression in 2 t(11;14)-negative mantle cell lymphomas characterized by a cryptic t(2;14)(p24;q32) and identification of MYCN as a new lymphoma oncogene associated with a blastoid mantle cell lymphoma (PMID:18391076)

Cross-species orthologs

15 orthologs

Organism	Symbol	Gene ID
danio_rerio	ccndx	ENSDARG00000019741
mus_musculus	Ccnd3	ENSMUSG00000034165
rattus_norvegicus	Ccnd3	ENSRNOG00000050258
drosophila_melanogaster	CycA	FBGN0000404
drosophila_melanogaster	CycB	FBGN0000405
drosophila_melanogaster	CycD	FBGN0010315
drosophila_melanogaster	CycE	FBGN0010382
caenorhabditis_elegans		WBGENE00000863
caenorhabditis_elegans		WBGENE00000864
caenorhabditis_elegans		WBGENE00000865
caenorhabditis_elegans		WBGENE00000866
caenorhabditis_elegans	cyb-2.2	WBGENE00000867
caenorhabditis_elegans		WBGENE00000870
caenorhabditis_elegans	cye-1	WBGENE00000871
caenorhabditis_elegans		WBGENE00017259

Paralogs (18): CCNE1 (ENSG00000105173), CCNP (ENSG00000105219), CCNJ (ENSG00000107443), CCND1 (ENSG00000110092), CCNG1 (ENSG00000113328), CCNI (ENSG00000118816), CCND2 (ENSG00000118971), CCNA1 (ENSG00000133101), CCNB1 (ENSG00000134057), CCNJL (ENSG00000135083), CCNG2 (ENSG00000138764), CCNA2 (ENSG00000145386), CCNB3 (ENSG00000147082), CCNO (ENSG00000152669), CCNB2 (ENSG00000157456), CCNF (ENSG00000162063), CCNE2 (ENSG00000175305), CCNI2 (ENSG00000205089)

Protein

Protein identifiers

G1/S-specific cyclin-D3 — P30281 (reviewed: P30281)

All UniProt accessions (8): A0A1D5RMS0, D6RDF8, D6RDL3, D6RI00, D6RIX2, P30281, H0Y8M4, Q5T8J1

UniProt curated annotations — full annotation on UniProt →

Function. Regulatory component of the cyclin D3-CDK4 (DC) complex that phosphorylates and inhibits members of the retinoblastoma (RB) protein family including RB1 and regulates the cell-cycle during G(1)/S transition. Phosphorylation of RB1 allows dissociation of the transcription factor E2F from the RB/E2F complex and the subsequent transcription of E2F target genes which are responsible for the progression through the G(1) phase. Hypophosphorylates RB1 in early G(1) phase. Cyclin D-CDK4 complexes are major integrators of various mitogenenic and antimitogenic signals. Component of the ternary complex, cyclin D3/CDK4/CDKN1B, required for nuclear translocation and activity of the cyclin D-CDK4 complex. Shows transcriptional coactivator activity with ATF5 independently of CDK4.

Subunit / interactions. Interacts with the CDK4 and CDK6 protein kinases to form a serine/threonine kinase holoenzyme complex. Interacts with isoform p58 of CDK11 (CDK11A or CDK11B) to form a serine/threonine kinase holoenzyme complex. The cyclin subunit imparts substrate specificity to the complex. Interacts with ATF5. Interacts with EIF3K. Component of the ternary complex cyclin D/CDK4/CDKN1B required for nuclear translocation and modulation of CDK4-mediated kinase activity. Can form similar complexes with either CDKN1A or CDKN2A.

Subcellular location. Nucleus. Cytoplasm.

Post-translational modifications. Phosphorylation at Thr-283 by MAP kinases is required for ubiquitination and degradation by the DCX(AMBRA1) complex. Ubiquitinated by the DCX(AMBRA1) complex during the transition from G1 to S cell phase, leading to its degradation: ubiquitination is dependent on Thr-283 phosphorylation. The DCX(AMBRA1) complex represents the major regulator of CCND3 stability during the G1/S transition. Polyubiquitinated by the SCF(FBXL2) complex, leading to proteasomal degradation.

Similarity. Belongs to the cyclin family. Cyclin D subfamily.

Isoforms (4)

UniProt ID	Names	Canonical?
P30281-1	1	yes
P30281-2	2
P30281-3	3
P30281-4	4

RefSeq proteins (15): NP_001129489, NP_001129597, NP_001129598, NP_001274356, NP_001274363, NP_001410981, NP_001410982, NP_001410984, NP_001410985, NP_001410986, NP_001410987, NP_001410988, NP_001410989, NP_001410990, NP_001751* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR004367	Cyclin_C-dom	Domain
IPR006671	Cyclin_N	Domain
IPR013763	Cyclin-like_dom	Domain
IPR036915	Cyclin-like_sf	Homologous_superfamily
IPR039361	Cyclin	Family
IPR048258	Cyclins_cyclin-box	Conserved_site

Pfam: PF00134, PF02984

UniProt features (33 total): helix 16, turn 4, sequence variant 3, modified residue 3, splice variant 3, chain 1, domain 1, region of interest 1, compositionally biased region 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
7SJ3	X-RAY DIFFRACTION	2.51
3G33	X-RAY DIFFRACTION	3

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P30281-F1	87.70	0.75

Functional residue map

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

Post-translational modifications (3): 264, 279, 283

Function

Pathways and Gene Ontology

Reactome pathways

22 pathways

ID	Pathway
R-HSA-381340	Transcriptional regulation of white adipocyte differentiation
R-HSA-5687128	MAPK6/MAPK4 signaling
R-HSA-69231	Cyclin D associated events in G1
R-HSA-8934593	Regulation of RUNX1 Expression and Activity
R-HSA-9661069	Defective binding of RB1 mutants to E2F1,(E2F2, E2F3)
R-HSA-9754119	Drug-mediated inhibition of CDK4/CDK6 activity
R-HSA-1266738	Developmental Biology
R-HSA-162582	Signal Transduction
R-HSA-1640170	Cell Cycle
R-HSA-1643685	Disease
R-HSA-212436	Generic Transcription Pathway
R-HSA-453279	Mitotic G1 phase and G1/S transition
R-HSA-5683057	MAPK family signaling cascades
R-HSA-69236	G1 Phase
R-HSA-69278	Cell Cycle, Mitotic
R-HSA-73857	RNA Polymerase II Transcription
R-HSA-74160	Gene expression (Transcription)
R-HSA-8878171	Transcriptional regulation by RUNX1
R-HSA-9659787	Aberrant regulation of mitotic G1/S transition in cancer due to RB1 defects
R-HSA-9675126	Diseases of mitotic cell cycle
R-HSA-9687139	Aberrant regulation of mitotic cell cycle due to RB1 defects
R-HSA-9843745	Adipogenesis

MSigDB gene sets: 399 (showing top): REACTOME_TRANSCRIPTIONAL_REGULATION_OF_WHITE_ADIPOCYTE_DIFFERENTIATION, ELVIDGE_HYPOXIA_DN, BUYTAERT_PHOTODYNAMIC_THERAPY_STRESS_DN, FISCHER_G1_S_CELL_CYCLE, GOBP_CELL_CYCLE_PHASE_TRANSITION, GOBP_POSITIVE_REGULATION_OF_MITOTIC_CELL_CYCLE, DACOSTA_UV_RESPONSE_VIA_ERCC3_UP, IVANOVA_HEMATOPOIESIS_MATURE_CELL, GHO_ATF5_TARGETS_DN, MODULE_16, BAKER_HEMATOPOIESIS_STAT3_TARGETS, BAKER_HEMATOPOESIS_STAT5_TARGETS, GOCC_MICROTUBULE_ORGANIZING_CENTER, GOBP_POSITIVE_REGULATION_OF_G1_S_TRANSITION_OF_MITOTIC_CELL_CYCLE, GOMF_KINASE_ACTIVATOR_ACTIVITY

GO Biological Process (8): G1/S transition of mitotic cell cycle (GO:0000082), negative regulation of transcription by RNA polymerase II (GO:0000122), signal transduction (GO:0007165), T cell proliferation (GO:0042098), regulation of cell population proliferation (GO:0042127), cell division (GO:0051301), positive regulation of G1/S transition of mitotic cell cycle (GO:1900087), regulation of cell cycle (GO:0051726)

GO Molecular Function (6): cyclin-dependent protein serine/threonine kinase activity (GO:0004693), cyclin-dependent protein serine/threonine kinase regulator activity (GO:0016538), protein kinase binding (GO:0019901), protein serine/threonine kinase activator activity (GO:0043539), cyclin-dependent protein serine/threonine kinase activator activity (GO:0061575), protein binding (GO:0005515)

GO Cellular Component (8): cyclin-dependent protein kinase holoenzyme complex (GO:0000307), nucleus (GO:0005634), nucleoplasm (GO:0005654), cytoplasm (GO:0005737), microtubule organizing center (GO:0005815), cytosol (GO:0005829), cyclin D3-CDK4 complex (GO:0097130), cyclin D3-CDK6 complex (GO:0097133)

Reactome top-level categories

Rollup of top-15 pathways:

Category	Pathways
Adipogenesis	1
MAPK family signaling cascades	1
G1 Phase	1
Transcriptional regulation by RUNX1	1
Aberrant regulation of mitotic G1/S transition in cancer due to RB1 defects	1
Cyclin D associated events in G1	1
RNA Polymerase II Transcription	1
Cell Cycle, Mitotic	1
Signal Transduction	1
Mitotic G1 phase and G1/S transition	1
Cell Cycle	1
Gene expression (Transcription)	1
Generic Transcription Pathway	1
Aberrant regulation of mitotic cell cycle due to RB1 defects	1
Disease	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
regulation of cellular process	3
cellular process	2
protein serine/threonine kinase activity	2
cyclin-dependent protein serine/threonine kinase activity	2
cyclin-dependent protein kinase holoenzyme complex	2
mitotic cell cycle	1
mitotic cell cycle phase transition	1
cell cycle G1/S phase transition	1
regulation of transcription by RNA polymerase II	1
transcription by RNA polymerase II	1
negative regulation of DNA-templated transcription	1
cell communication	1
signaling	1
cellular response to stimulus	1
T cell activation	1
lymphocyte proliferation	1
cell population proliferation	1
G1/S transition of mitotic cell cycle	1
positive regulation of mitotic cell cycle phase transition	1
positive regulation of cell cycle G1/S phase transition	1
regulation of G1/S transition of mitotic cell cycle	1
cell cycle	1
cyclin-dependent protein kinase activity	1
cyclin-dependent protein kinase regulator activity	1
kinase binding	1
protein kinase activator activity	1
cyclin-dependent protein serine/threonine kinase regulator activity	1
protein serine/threonine kinase activator activity	1
binding	1
serine/threonine protein kinase complex	1
intracellular membrane-bounded organelle	1
nuclear lumen	1
intracellular anatomical structure	1
microtubule cytoskeleton	1
cytoplasm	1

Protein interactions and networks

STRING

2216 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CCND3	CDK4	P11802	997
CCND3	CDK6	Q00534	997
CCND3	CDK2	P24941	943
CCND3	CCNL2	Q96S94	909
CCND3	CDKN1B	P46527	902
CCND3	CDKN1A	P38936	884
CCND3	EIF3K	Q9UBQ5	817
CCND3	CDKN2D	P55273	771
CCND3	CDKN2A	P42771	768
CCND3	CDK14	O94921	756
CCND3	MAFB	Q9Y5Q3	747
CCND3	AKT1	P31749	746
CCND3	IGHV4-38-2	P0DP08	741
CCND3	CDKN2C	P42773	726
CCND3	RB1	P06400	712

IntAct

229 interactions, top by confidence:

A	B	Type	Score
CCND3	CDK4	psi-mi:“MI:0915”(physical association)	0.980
CDK4	CCND3	psi-mi:“MI:0915”(physical association)	0.980
CDK4	CCND3	psi-mi:“MI:0914”(association)	0.980
CDK4	CCND3	psi-mi:“MI:0407”(direct interaction)	0.980
CCND3	CDK4	psi-mi:“MI:0914”(association)	0.980
CDK6	CCND3	psi-mi:“MI:0915”(physical association)	0.970

BioGRID (247): CDK4 (Affinity Capture-Western), CDKN1A (Affinity Capture-Western), CDK4 (Two-hybrid), CDK6 (Two-hybrid), CDKN1A (Two-hybrid), TFIP11 (Two-hybrid), POLR3GL (Two-hybrid), CDK2 (Affinity Capture-MS), CDK1 (Affinity Capture-MS), ZNF2 (Affinity Capture-MS), CDK4 (Affinity Capture-MS), RBL2 (Affinity Capture-MS), CDK6 (Affinity Capture-MS), CLU (Affinity Capture-MS), CDKN1B (Affinity Capture-MS)

ESM2 similar proteins: O08918, O15995, O42575, O96020, P24385, P24864, P25322, P30279, P30280, P30281, P30282, P39948, P39949, P39950, P47794, P48961, P49706, P49707, P50755, P50756, P51945, P51959, P53782, P55169, Q01043, Q01J96, Q04827, Q0P5D3, Q16589, Q2KI22, Q32NM1, Q3MHH5, Q503D6, Q52QT8, Q5E9I1, Q5E9K7, Q5R5D0, Q5R6J5, Q5XGG5, Q61457

Diamond homologs: A0MEB5, A2YH60, O77689, O93229, O95067, P04962, P07818, P0C242, P13350, P13351, P13952, P14635, P14785, P15206, P18063, P18606, P20439, P22674, P24385, P24860, P24868, P24869, P25010, P25011, P25012, P25322, P29332, P30183, P30274, P30276, P30277, P30278, P30281, P30283, P34800, P34801, P36630, P37881, P37882, P37883

SIGNOR signaling

13 interactions.

A	Effect	B	Mechanism
ROBO	down-regulates	CCND3	phosphorylation
GSK3B	down-regulates	CCND3	phosphorylation
PPP1CA	up-regulates	CCND3	dephosphorylation
4-(2,6-dichlorobenzamido)-N-(piperidin-4-yl)-pyrazole-3-carboxamide	down-regulates	CCND3	“chemical inhibition”
PP1	up-regulates	CCND3	dephosphorylation
FBXL2	“down-regulates quantity by destabilization”	CCND3	binding
“Cullin 1-RBX1-Skp1”	“down-regulates quantity by destabilization”	CCND3	polyubiquitination
MAPK11	“down-regulates quantity by destabilization”	CCND3	phosphorylation
MYOD1	“up-regulates quantity by expression”	CCND3	“transcriptional regulation”
CCND3	up-regulates	Cell_cycle_exit
CCND3	“form complex”	CyclinD3/CDK6	binding
CCND3	“form complex”	CyclinD3/CDK11A	binding
CCND3	“form complex”	CyclinD3/CDK11B	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 65 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)	9	114.2×	4e-15
G1 Phase	10	78.8×	4e-15
TP53 Regulates Transcription of Genes Involved in G1 Cell Cycle Arrest	5	71.4×	1e-07
p53-Dependent G1 DNA Damage Response	5	71.4×	1e-07
p53-Dependent G1/S DNA damage checkpoint	5	71.4×	1e-07
G1/S DNA Damage Checkpoints	5	67.2×	2e-07
Aberrant regulation of mitotic cell cycle due to RB1 defects	8	65.3×	2e-11
TP53 Regulates Transcription of Cell Cycle Genes	6	65.3×	8e-09

GO biological processes:

GO term	Partners	Fold	FDR
positive regulation of DNA replication	5	47.6×	9e-06
G1/S transition of mitotic cell cycle	13	42.8×	2e-15
regulation of G1/S transition of mitotic cell cycle	5	25.1×	2e-04
negative regulation of cell growth	6	14.2×	3e-04
cell division	14	10.6×	1e-08
protein phosphorylation	9	10.0×	3e-05
regulation of cell cycle	7	8.6×	9e-04
cell population proliferation	5	8.4×	9e-03

Disease & clinical

Cancer significance

From CIViC — curated cancer-variant interpretation:

Cyclin D has been shown in many cancer types to be misregulated. Well established for their oncogenic properties, the cyclins and the cyclin-dependent kinases (CDK’s) they activate have been the focus of major research and development efforts over the past decade. The methods by which the cyclins are misregulated are widely variable, ranging from genomic amplification to changes in promoter methylation. Cyclin D3 loss has been reported in T-ALL, a seemingly unique trend when compared to the amplifcations and overexpressions of the other cyclin D’s. In a mouse study, the targeted therapeutic palbociclib significantly increased the median survival of the cyclin D3 knockouts.

From intOGen — cancer-driver classification: activating (oncogene-like) across 4 cancer types — BL, DLBCLNOS, MLYM, NHL.

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	28
Likely benign	1
Benign	3

Top pathogenic / likely-pathogenic (0)

SpliceAI

1017 predictions. Top by Δscore:

Variant	Effect	Δscore
6:41936697:T:C	acceptor_gain	1.0000
6:41936697:T:TC	acceptor_gain	1.0000
6:41937230:CTTA:C	donor_loss	1.0000
6:41937231:TTACC:T	donor_loss	1.0000
6:41937232:TAC:T	donor_loss	1.0000
6:41937233:A:AC	donor_gain	1.0000
6:41937233:ACC:A	donor_loss	1.0000
6:41937234:C:CC	donor_gain	1.0000
6:41937390:CAGTC:C	acceptor_gain	1.0000
6:41937391:AGTC:A	acceptor_gain	1.0000
6:41937392:GTC:G	acceptor_gain	1.0000
6:41937393:TC:T	acceptor_gain	1.0000
6:41937394:CC:C	acceptor_gain	1.0000
6:41937395:C:A	acceptor_loss	1.0000
6:41937395:C:CC	acceptor_gain	1.0000
6:41937396:T:A	acceptor_loss	1.0000
6:41937404:C:CT	acceptor_gain	1.0000
6:41940365:CGCA:C	donor_gain	1.0000
6:41940367:CACC:C	donor_loss	1.0000
6:41940368:A:AC	donor_gain	1.0000
6:41940368:A:AG	donor_loss	1.0000
6:41940368:AC:A	donor_gain	1.0000
6:41940369:C:CC	donor_gain	1.0000
6:41940369:C:CT	donor_loss	1.0000
6:41940369:CC:C	donor_gain	1.0000
6:41940369:CCCG:C	donor_gain	1.0000
6:41941453:T:TA	donor_gain	1.0000
6:41936558:CCA:C	donor_gain	0.9900
6:41936696:C:CC	acceptor_gain	0.9900
6:41937271:TTTTG:T	donor_gain	0.9900

AlphaMissense

1872 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
6:41936649:G:C	S207R	0.999
6:41936649:G:T	S207R	0.999
6:41936651:T:G	S207R	0.999
6:41936653:C:T	G206D	0.999
6:41936659:G:T	A204D	0.999
6:41937361:A:G	W150R	0.999
6:41937361:A:T	W150R	0.999
6:41937378:A:T	V144D	0.999
6:41940466:G:C	C106W	0.999
6:41940467:C:T	C106Y	0.999
6:41940468:A:G	C106R	0.999
6:41940476:C:T	G103D	0.999
6:41940477:C:G	G103R	0.999
6:41940518:A:G	L89P	0.999
6:41940524:C:G	R87P	0.999
6:41940527:T:A	D86V	0.999
6:41941459:A:C	M64R	0.999
6:41941461:C:A	W63C	0.999
6:41941461:C:G	W63C	0.999
6:41941463:A:G	W63R	0.999
6:41941463:A:T	W63R	0.999
6:41936638:G:T	A211E	0.998
6:41936654:C:G	G206R	0.998
6:41937242:A:C	C189W	0.998
6:41937243:C:T	C189Y	0.998
6:41937264:G:T	A182D	0.998
6:41937265:C:G	A182P	0.998
6:41937329:G:C	F160L	0.998
6:41937329:G:T	F160L	0.998
6:41937331:A:G	F160L	0.998

dbSNP variants (sampled 300 via entrez): RS1000010041 (6:42006249 G>T), RS1000012201 (6:41960520 C>A), RS1000052894 (6:42013706 C>A), RS1000125155 (6:41967790 G>A), RS1000173579 (6:41999334 C>T), RS1000189664 (6:41965940 A>C), RS1000216837 (6:42041129 C>T), RS1000220372 (6:41954679 C>G), RS1000261950 (6:42046596 A>G), RS1000309432 (6:41999098 C>A,T), RS1000311356 (6:42034357 A>G), RS1000327029 (6:41964530 G>C), RS1000357713 (6:41992711 T>A), RS1000370707 (6:42019306 G>A), RS1000394227 (6:41971771 G>A,C)

Disease associations

OMIM: gene MIM:123834 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

127 associations (top):

Study	Trait	p-value
GCST000498_6	Hematological parameters	7.000000e-19
GCST000503_2	Mean corpuscular volume	1.000000e-31
GCST000504_1	Mean corpuscular hemoglobin	8.000000e-20
GCST000585_11	Mean corpuscular volume	4.000000e-27
GCST000587_12	Mean corpuscular hemoglobin	2.000000e-20
GCST000588_5	Red blood cell count	1.000000e-10
GCST001059_5	Neutrophil count	8.000000e-06
GCST001765_45	Red blood cell traits	2.000000e-40
GCST001781_8	Mean corpuscular volume	9.000000e-08
GCST001821_7	Metabolite levels (5-HIAA/ MHPG Ratio)	5.000000e-06
GCST004004_36	Mean corpuscular volume	9.000000e-62
GCST004006_32	Mean corpuscular hemoglobin	1.000000e-08
GCST004007_17	Mean corpuscular hemoglobin concentration	1.000000e-08
GCST004008_15	Red blood cell count	2.000000e-09
GCST004008_5	Red blood cell count	1.000000e-08
GCST004131_8	Inflammatory bowel disease	3.000000e-08
GCST004132_45	Crohn’s disease	2.000000e-07
GCST004232_87	HDL cholesterol levels	2.000000e-07
GCST004334_8	Mean corpuscular hemoglobin	1.000000e-08
GCST004335_4	Mean corpuscular volume	1.000000e-09
GCST004601_78	Red blood cell count	1.000000e-58
GCST004601_79	Red blood cell count	7.000000e-40
GCST004601_80	Red blood cell count	3.000000e-85
GCST004602_109	Mean corpuscular volume	4.000000e-35
GCST004602_110	Mean corpuscular volume	2.000000e-121
GCST004602_111	Mean corpuscular volume	3.000000e-260
GCST004602_112	Mean corpuscular volume	3.000000e-211
GCST004608_27	Granulocyte percentage of myeloid white cells	2.000000e-27
GCST004609_68	Monocyte percentage of white cells	8.000000e-28
GCST004611_100	High light scatter reticulocyte count	1.000000e-17

EFO canonical traits (20, from GWAS)

EFO ID	Trait name
EFO:0004527	mean corpuscular hemoglobin
EFO:0004509	hemoglobin measurement
EFO:0004305	erythrocyte count
EFO:0004833	neutrophil count
EFO:0005132	5-HIAA measurement
EFO:0005133	MHPG measurement
EFO:0004528	mean corpuscular hemoglobin concentration
EFO:0004612	high density lipoprotein cholesterol measurement
EFO:0007997	granulocyte percentage of myeloid white cells
EFO:0007989	monocyte percentage of leukocytes
EFO:0007986	reticulocyte count
EFO:0009188	Red cell distribution width
EFO:0005091	monocyte count
EFO:0004329	alcohol drinking
EFO:0004614	apolipoprotein A 1 measurement
EFO:0008039	BMI-adjusted hip circumference
EFO:0004980	appendicular lean mass
EFO:0010701	mean reticulocyte volume
EFO:0007985	platelet crit
EFO:0007984	platelet component distribution width

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (8): CHEMBL2095942 (PROTEIN COMPLEX GROUP), CHEMBL2111448 (PROTEIN COMPLEX), CHEMBL2422 (SINGLE PROTEIN), CHEMBL3038472 (PROTEIN COMPLEX), CHEMBL4296065 (PROTEIN COMPLEX), CHEMBL4523716 (PROTEIN-PROTEIN INTERACTION), CHEMBL5483183 (PROTEIN COMPLEX GROUP), CHEMBL5483185 (PROTEIN COMPLEX)

Molecules with ChEMBL bioactivity

17 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 67,358 (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
CHEMBL3545110	RIBOCICLIB	4	8,018
CHEMBL3894860	TRILACICLIB	4	2,086
CHEMBL428690	ALVOCIDIB	3	27,781
CHEMBL3904602	LEROCICLIB	3	1,012
CHEMBL3545283	RIVICICLIB	2	968
CHEMBL4067549	ULECACICLIB	2	41
CHEMBL4277900	CROZBACICLIB	2	18
CHEMBL4446357	EBVACICLIB	2	599
CHEMBL445813	AT-7519	2	2,614
CHEMBL5187755	ATIRMOCICLIB	2	50
CHEMBL296468	BMS-387032	1	2,075
CHEMBL3545083	RGB-286638	1	551
CHEMBL488436	AZD-5438	1	1,333
CHEMBL5095191	PF-06842874	1	58
CHEMBL5834528	INX-315	1	7

Clinical evidence (CIViC)

Drug × variant × indication: 2 predictive associations from 2 curated evidence items.

Variant	Therapy	Indication	Effect	Level	CIViC
CCND1 Amplification OR CCND2 Amplification OR CCND3 Amplification	Palbociclib	Cancer	Sensitivity/Response	CIViC B	EID11673
CCND3 Loss	Palbociclib	T-cell Lymphoblastic Leukemia/lymphoma	Sensitivity/Response	CIViC D	EID263

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

Binding affinities (BindingDB)

23 measured of 81 human assays (182 total across all organisms); most potent 23 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
4-[[6-(2,2-difluoroethyl)-8-[(1R,2R)-2-hydroxy-2-methylcyclopentyl]-7-oxopyrido[2,3-d]pyrimidin-2-yl]amino]-N-methylpiperidine-1-sulfonamide	KI	0.09 nM	US-10233188: CDK2/4/6 inhibitors
6-(2-hydroxyethyl)-8-[(1R,2R)-2-hydroxy-2-methylcyclopentyl]-2-[(1-methylsulfonylpiperidin-4-yl)amino]pyrido[2,3-d]pyrimidin-7-one	KI	0.11 nM	US-10233188: CDK2/4/6 inhibitors
6-chloro-8-[(1R,2R)-2-hydroxy-2-methylcyclopentyl]-2-{[1-(methylsulfonyl)-piperidin-4-yl]amino}pyrido[2,3-d]pyrimidin-7(8H)-one	KI	0.16 nM	US-10233188: CDK2/4/6 inhibitors
2-[8-[(1R,2R)-2-hydroxy-2-methylcyclopentyl]-2-[(1-methylsulfonylpiperidin-4-yl)amino]-7-oxopyrido[2,3-d]pyrimidin-6-yl]acetonitrile	KI	0.16 nM	US-10233188: CDK2/4/6 inhibitors
8-[(1R,2R)-2-hydroxy-2-methylcyclopentyl]-2-{[1-(methylsulfonyl)piperidin-4-yl]amino}pyrido[2,3-d]pyrimidin-7(8H)-one	KI	0.2 nM	US-10233188: CDK2/4/6 inhibitors
8-[(1R,3R)-3-hydroxycyclohexyl]-2-{[1-(methylsulfonyl)piperidin-4-yl]-amino}pyrido[2,3-d]pyrimidin-7(8H)-one	KI	0.26 nM	US-10233188: CDK2/4/6 inhibitors
4-[[6-fluoro-8-[(1R,2R)-2-hydroxy-2-methylcyclopentyl]-7-oxopyrido[2,3-d]pyrimidin-2-yl]amino]-N-methylpiperidine-1-sulfonamide	KI	0.48 nM	US-10233188: CDK2/4/6 inhibitors
6-chloro-8-cyclopentyl-2-[(1-methylsulfonylpiperidin-4-yl)amino]pyrido[2,3-d]pyrimidin-7-one	KI	1.4 nM	US-10233188: CDK2/4/6 inhibitors
1-Isopropyl-N-(4-methyl-5-(piperazin- 1-yl)pyridin-2-yl)-1H-[1,2,3]triazolo[4,5- h]quinazolin-8-amine hydrochloride	IC50	30 nM	US-12312355: 1H-[1, 2, 3]triazolo[4, 5-h] quinazoline compounds acting as protein kinase inhibitors
1-Isobutyl-N-(5-morpholinopyridin-2- yl)-1H-[1,2,3]triazolo[4,5-h]quinazolin- 8-amine	IC50	30 nM	US-12312355: 1H-[1, 2, 3]triazolo[4, 5-h] quinazoline compounds acting as protein kinase inhibitors
N-(3-Fluoro-4-morpholinophenyl)-1-iso- propyl-1H-[1,2,3]triazolo[4,5-h]quinazo- lin-8-amine hydrochloride	IC50	30 nM	US-12312355: 1H-[1, 2, 3]triazolo[4, 5-h] quinazoline compounds acting as protein kinase inhibitors
6-(difluoromethyl)-8-[(1R,2R)-2-hydroxy-2-methylcyclopentyl]-2-{[1-(methylsulfonyl)piperidin-4-yl]amino}pyrido[2,3-d]pyrimidin-7(8H)-one	IC50	46 nM	US-20260001887: CYCLIN-DEPENDENT KINASE INHIBITORS
(E)-3-(4-(((6-((5-fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino)pyridin-3-yl)(methyl)amino)methyl)phenyl)-N-hydroxyacrylamide	IC50	55 nM	US-12415797: Heterocyclic compound as CDK-HDAC double-channel inhibitor
salt	IC50	55 nM	US-12415797: Heterocyclic compound as CDK-HDAC double-channel inhibitor
Pyrazolopyrimidone analog, RGB-286147	IC50	71 nM
3-(1-(4-((1-isopropyl-1H-[1,2,3]triazolo [4,5-h]quinazolin-8-yl)amino)phenyl)pi- peridin-4-yl)propan-1-ol	IC50	75 nM	US-12312355: 1H-[1, 2, 3]triazolo[4, 5-h] quinazoline compounds acting as protein kinase inhibitors
N-(2-Fluoro-4-morpholinophenyl)-1-iso- propyl-1H-[1,2,3]triazolo[4,5-h]quinazo- lin-8-amine	IC50	75 nM	US-12312355: 1H-[1, 2, 3]triazolo[4, 5-h] quinazoline compounds acting as protein kinase inhibitors
1-Isopropyl-N-(2-methoxy-4-(4-methyl- piperazin-1-yl)phenyl)-1H-[1,2,3]triazo- lo[4,5-h]quinazolin-8-amine	IC50	75 nM	US-12312355: 1H-[1, 2, 3]triazolo[4, 5-h] quinazoline compounds acting as protein kinase inhibitors
4-[[5-(4-morpholin-4-ylpiperidin-1-yl)-2-pyridinyl]amino]spiro[1,3,5,11-tetrazatricyclo[7.4.0.02,7]trideca-2,4,6,8-tetraene-13,1’-cyclohexane]-10-one	IC50	857 nM	US-9527857: HSPC-sparing treatments for RB-positive abnormal cellular proliferation
Flavopiridol	IC50	1340 nM
4-[[5-(4-propan-2-ylpiperazin-1-yl)-2-pyridinyl]amino]spiro[1,3,5,11-tetrazatricyclo[7.4.0.02,7]trideca-2,4,6,8-tetraene-13,1’-cyclohexane]-10-one	IC50	1510 nM	US-9527857: HSPC-sparing treatments for RB-positive abnormal cellular proliferation
Trilaciclib	IC50	1670 nM	US-9527857: HSPC-sparing treatments for RB-positive abnormal cellular proliferation
4-[(5-piperazin-1-yl-2-pyridinyl)amino]spiro[1,3,5,11-tetrazatricyclo[7.4.0.02,7]trideca-2,4,6,8-tetraene-13,1’-cyclohexane]-10-one	IC50	3030 nM	US-9527857: HSPC-sparing treatments for RB-positive abnormal cellular proliferation

ChEMBL bioactivities

1347 potent at pChembl≥5 of 1415 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
9.80	Ki	0.16	nM	CHEMBL4750658
9.80	Ki	0.16	nM	CHEMBL5746772
9.80	Ki	0.16	nM	CHEMBL5281860
9.70	IC50	0.2	nM	CHEMBL5970111
9.62	IC50	0.24	nM	CHEMBL4289226
9.59	Ki	0.26	nM	PALBOCICLIB
9.47	Ki	0.34	nM	CHEMBL4745424
9.41	IC50	0.39	nM	CHEMBL4285830
9.40	IC50	0.4	nM	CHEMBL4285830
9.40	Ki	0.4	nM	CHEMBL4546255
9.40	Ki	0.4	nM	CHEMBL4560219
9.40	Ki	0.4	nM	CHEMBL5876670
9.40	IC50	0.4	nM	CHEMBL5739950
9.38	IC50	0.42	nM	CHEMBL4277525
9.37	IC50	0.43	nM	CHEMBL4279832
9.31	IC50	0.49	nM	CHEMBL4279832
9.30	IC50	0.5	nM	CHEMBL4279832
9.30	IC50	0.5	nM	CHEMBL4287693
9.18	Ki	0.66	nM	CHEMBL4796501
9.15	IC50	0.71	nM	CHEMBL4448494
9.15	IC50	0.7	nM	CHEMBL142619
9.14	IC50	0.73	nM	CROZBACICLIB
9.10	Ki	0.8	nM	CHEMBL4466797
9.10	IC50	0.8	nM	CHEMBL4778367
9.05	Ki	0.9	nM	CHEMBL5749795
9.05	IC50	0.9	nM	CHEMBL5903827
9.04	Ki	0.92	nM	CHEMBL5964436
9.02	IC50	0.96	nM	CHEMBL4550287
9.02	IC50	0.96	nM	CHEMBL4287743
9.01	IC50	0.98	nM	PALBOCICLIB
9.00	IC50	1	nM	CHEMBL4281514
9.00	IC50	1	nM	CROZBACICLIB
9.00	IC50	0.99	nM	CHEMBL4463172
9.00	Ki	1	nM	CHEMBL4578267
9.00	Ki	1	nM	CHEMBL4539133
9.00	Ki	1	nM	CHEMBL5816600
8.99	IC50	1.02	nM	CHEMBL4438059
8.98	IC50	1.04	nM	CHEMBL4446626
8.97	IC50	1.08	nM	CHEMBL4462493
8.96	IC50	1.1	nM	CHEMBL4448494
8.96	Ki	1.1	nM	CHEMBL5921680
8.96	IC50	1.09	nM	CHEMBL4294940
8.95	Ki	1.12	nM	CHEMBL5271753
8.92	Ki	1.2	nM	CHEMBL5779295
8.89	Ki	1.3	nM	CHEMBL4520067
8.89	Ki	1.3	nM	CHEMBL5757450
8.89	Ki	1.3	nM	PF-06842874
8.89	Ki	1.3	nM	CHEMBL5970583
8.87	IC50	1.34	nM	CHEMBL4463716
8.87	IC50	1.35	nM	CHEMBL4439999

PubChem BioAssay actives

671 with measured affinity, of 1693 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
6-(2,2-difluoroethyl)-8-[(1S,2S)-2-hydroxy-2-methylcyclopentyl]-2-[(1-methylsulfonylpiperidin-4-yl)amino]pyrido[2,3-d]pyrimidin-7-one	1685179: Inhibition of non-phosphorylated CDK4/Cyclin D3 (unknown origin) assessed as reduction in production of ADP using 5-FAM-RRRFRPASPLRGPPK peptide as substrate preincubated with enzyme for 12 mins and measured after 35 mins in presence of ATP by fluorescence-based microfluidic mobility shift assay	ki	0.0002	uM
2-[8-[(1R,2R)-2-hydroxy-2-methylcyclopentyl]-2-[(1-methylsulfonylpiperidin-4-yl)amino]-7-oxopyrido[2,3-d]pyrimidin-6-yl]acetonitrile	1685179: Inhibition of non-phosphorylated CDK4/Cyclin D3 (unknown origin) assessed as reduction in production of ADP using 5-FAM-RRRFRPASPLRGPPK peptide as substrate preincubated with enzyme for 12 mins and measured after 35 mins in presence of ATP by fluorescence-based microfluidic mobility shift assay	ki	0.0003	uM
N-[5-(6-ethyl-2,6-diazaspiro[3.3]heptan-2-yl)-2-pyridinyl]-5-fluoro-4-[(4R)-4-methyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a]azepin-3-yl]pyrimidin-2-amine	1588588: Inhibition of human full length GST-tagged CDK4 (1 to 303(end) amino acids)/Cyclin D3 (1 to 292(end) amino acids) expressed in baculovirus expression system assessed as inhibition constant using Ulight-4E-BP1 as substrate preincubated for 30 mins followed by substrate addition and incubated for 90 mins by TR-FRET assay	ki	0.0003	uM
5-fluoro-N-[5-(4-methylpiperazin-1-yl)-2-pyridinyl]-4-[(4R)-4-methyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a]azepin-3-yl]pyrimidin-2-amine	1588588: Inhibition of human full length GST-tagged CDK4 (1 to 303(end) amino acids)/Cyclin D3 (1 to 292(end) amino acids) expressed in baculovirus expression system assessed as inhibition constant using Ulight-4E-BP1 as substrate preincubated for 30 mins followed by substrate addition and incubated for 90 mins by TR-FRET assay	ki	0.0003	uM
5-fluoro-N-[5-[6-(3-fluoropropyl)-2,6-diazaspiro[3.3]heptan-2-yl]-2-pyridinyl]-4-[(4R)-4-methyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a]azepin-3-yl]pyrimidin-2-amine	1588588: Inhibition of human full length GST-tagged CDK4 (1 to 303(end) amino acids)/Cyclin D3 (1 to 292(end) amino acids) expressed in baculovirus expression system assessed as inhibition constant using Ulight-4E-BP1 as substrate preincubated for 30 mins followed by substrate addition and incubated for 90 mins by TR-FRET assay	ki	0.0003	uM
5-fluoro-N-[5-[6-(2-fluoroethyl)-2,6-diazaspiro[3.3]heptan-2-yl]-2-pyridinyl]-4-[(4R)-4-methyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a]azepin-3-yl]pyrimidin-2-amine	1588588: Inhibition of human full length GST-tagged CDK4 (1 to 303(end) amino acids)/Cyclin D3 (1 to 292(end) amino acids) expressed in baculovirus expression system assessed as inhibition constant using Ulight-4E-BP1 as substrate preincubated for 30 mins followed by substrate addition and incubated for 90 mins by TR-FRET assay	ki	0.0003	uM
5-fluoro-N-[5-(6-methyl-2,6-diazaspiro[3.3]heptan-2-yl)-2-pyridinyl]-4-[(4R)-4-methyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a]azepin-3-yl]pyrimidin-2-amine	1588588: Inhibition of human full length GST-tagged CDK4 (1 to 303(end) amino acids)/Cyclin D3 (1 to 292(end) amino acids) expressed in baculovirus expression system assessed as inhibition constant using Ulight-4E-BP1 as substrate preincubated for 30 mins followed by substrate addition and incubated for 90 mins by TR-FRET assay	ki	0.0003	uM
5-fluoro-4-(7’-fluoro-2’-methylspiro[cyclopentane-1,3’-indole]-5’-yl)-N-(5-piperidin-4-yl-2-pyridinyl)pyrimidin-2-amine	1402379: Inhibition of CDK6/Cyclin-D3 (unknown origin) using histoneH1 as substrate after 90 mins by ADP-Glo assay	ic50	0.0004	uM
5-fluoro-4-[(4R)-4-methyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a]azepin-3-yl]-N-(5-morpholin-4-yl-2-pyridinyl)pyrimidin-2-amine	1588588: Inhibition of human full length GST-tagged CDK4 (1 to 303(end) amino acids)/Cyclin D3 (1 to 292(end) amino acids) expressed in baculovirus expression system assessed as inhibition constant using Ulight-4E-BP1 as substrate preincubated for 30 mins followed by substrate addition and incubated for 90 mins by TR-FRET assay	ki	0.0004	uM
5-fluoro-4-[(4R)-4-methyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a]azepin-3-yl]-N-[5-[6-(oxetan-3-yl)-2,6-diazaspiro[3.3]heptan-2-yl]-2-pyridinyl]pyrimidin-2-amine	1588588: Inhibition of human full length GST-tagged CDK4 (1 to 303(end) amino acids)/Cyclin D3 (1 to 292(end) amino acids) expressed in baculovirus expression system assessed as inhibition constant using Ulight-4E-BP1 as substrate preincubated for 30 mins followed by substrate addition and incubated for 90 mins by TR-FRET assay	ki	0.0004	uM
2-[4-[6-[[5-fluoro-4-(7’-fluoro-2’-methylspiro[cyclopentane-1,3’-indole]-5’-yl)pyrimidin-2-yl]amino]-3-pyridinyl]piperidin-1-yl]ethanol	1402379: Inhibition of CDK6/Cyclin-D3 (unknown origin) using histoneH1 as substrate after 90 mins by ADP-Glo assay	ic50	0.0005	uM
6-[2-(dimethylamino)ethyl]-N-[5-fluoro-4-(7-fluoro-2-methyl-3-propan-2-ylbenzimidazol-5-yl)pyrimidin-2-yl]-7,8-dihydro-5H-1,6-naphthyridin-2-amine	1509614: Inhibition of recombinant human full length N-terminal GST-tagged CDK4 (1 to 303 residues)/cyclin D3 (1 to 292 residues) expressed in baculovirus expression system using eIF4E-binding protein 1 peptide and ATP as substrate incubated for 30 mins by LANCE ultra kinase assay	ic50	0.0007	uM
6-chloro-8-cyclopentyl-2-[(1-methylsulfonylpiperidin-4-yl)amino]pyrido[2,3-d]pyrimidin-7-one	1685179: Inhibition of non-phosphorylated CDK4/Cyclin D3 (unknown origin) assessed as reduction in production of ADP using 5-FAM-RRRFRPASPLRGPPK peptide as substrate preincubated with enzyme for 12 mins and measured after 35 mins in presence of ATP by fluorescence-based microfluidic mobility shift assay	ki	0.0007	uM
8-cyclopentyl-2-[4-[2-(diethylamino)ethoxy]anilino]pyrido[2,3-d]pyrimidin-7-one	54016: Inhibition of Cyclin-dependent kinase 4-cyclin D	ic50	0.0007	uM
5-fluoro-N-[5-(1-methylpiperidin-4-yl)-2-pyridinyl]-4-[(4R)-4-methyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a]azepin-3-yl]pyrimidin-2-amine	1588588: Inhibition of human full length GST-tagged CDK4 (1 to 303(end) amino acids)/Cyclin D3 (1 to 292(end) amino acids) expressed in baculovirus expression system assessed as inhibition constant using Ulight-4E-BP1 as substrate preincubated for 30 mins followed by substrate addition and incubated for 90 mins by TR-FRET assay	ki	0.0008	uM
1-[8-methyl-12-(4-piperazin-1-ylanilino)-4-propan-2-yl-2,5,11,13-tetrazatricyclo[7.4.0.02,6]trideca-1(13),3,5,7,9,11-hexaen-7-yl]ethanone	1737183: Inhibition of recombinant human full-length N-terminal GST-fused CDK4 (1 to 303 residues)/GST-tagged CyclinD3 (1 to 292 residues) expressed in baculovirus expression system using ULight-elF4E-binding protein 1 peptide as substrate measured after 30 mins by LANCE assay	ic50	0.0008	uM
5-fluoro-4-(7’-fluoro-2’-methylspiro[cyclopentane-1,3’-indole]-5’-yl)-N-[5-(1-methylpiperidin-4-yl)-2-pyridinyl]pyrimidin-2-amine	1402379: Inhibition of CDK6/Cyclin-D3 (unknown origin) using histoneH1 as substrate after 90 mins by ADP-Glo assay	ic50	0.0010	uM
4-(3-ethyl-7-fluoro-2,3-dimethylindol-5-yl)-5-fluoro-N-[5-(4-methylpiperazin-1-yl)-2-pyridinyl]pyrimidin-2-amine	1402379: Inhibition of CDK6/Cyclin-D3 (unknown origin) using histoneH1 as substrate after 90 mins by ADP-Glo assay	ic50	0.0010	uM
N-[4-[3-(1-cyclopropylethyl)-7-fluoro-2-methylbenzimidazol-5-yl]-5-fluoropyrimidin-2-yl]-6-[2-(dimethylamino)ethyl]-7,8-dihydro-5H-1,6-naphthyridin-2-amine	1509614: Inhibition of recombinant human full length N-terminal GST-tagged CDK4 (1 to 303 residues)/cyclin D3 (1 to 292 residues) expressed in baculovirus expression system using eIF4E-binding protein 1 peptide and ATP as substrate incubated for 30 mins by LANCE ultra kinase assay	ic50	0.0010	uM
N-[4-(3-cyclopentyl-7-fluoro-2-methylbenzimidazol-5-yl)-5-fluoropyrimidin-2-yl]-6-[2-(dimethylamino)ethyl]-7,8-dihydro-5H-1,6-naphthyridin-2-amine	1509614: Inhibition of recombinant human full length N-terminal GST-tagged CDK4 (1 to 303 residues)/cyclin D3 (1 to 292 residues) expressed in baculovirus expression system using eIF4E-binding protein 1 peptide and ATP as substrate incubated for 30 mins by LANCE ultra kinase assay	ic50	0.0010	uM
1-[2-[2-[[5-fluoro-4-(7-fluoro-2-methyl-3-propan-2-ylbenzimidazol-5-yl)pyrimidin-2-yl]amino]-7,8-dihydro-5H-1,6-naphthyridin-6-yl]ethyl]-1-methylguanidine	1509614: Inhibition of recombinant human full length N-terminal GST-tagged CDK4 (1 to 303 residues)/cyclin D3 (1 to 292 residues) expressed in baculovirus expression system using eIF4E-binding protein 1 peptide and ATP as substrate incubated for 30 mins by LANCE ultra kinase assay	ic50	0.0010	uM
N-[4-(3-cyclohexyl-7-fluoro-2-methylbenzimidazol-5-yl)-5-fluoropyrimidin-2-yl]-6-[2-(dimethylamino)ethyl]-7,8-dihydro-5H-1,6-naphthyridin-2-amine	1509614: Inhibition of recombinant human full length N-terminal GST-tagged CDK4 (1 to 303 residues)/cyclin D3 (1 to 292 residues) expressed in baculovirus expression system using eIF4E-binding protein 1 peptide and ATP as substrate incubated for 30 mins by LANCE ultra kinase assay	ic50	0.0010	uM
5-fluoro-N-[5-(4-methylpiperazin-1-yl)-2-pyridinyl]-4-[(4S)-4-methyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a]azepin-3-yl]pyrimidin-2-amine	1588588: Inhibition of human full length GST-tagged CDK4 (1 to 303(end) amino acids)/Cyclin D3 (1 to 292(end) amino acids) expressed in baculovirus expression system assessed as inhibition constant using Ulight-4E-BP1 as substrate preincubated for 30 mins followed by substrate addition and incubated for 90 mins by TR-FRET assay	ki	0.0010	uM
N-[5-[4-(dimethylamino)piperidin-1-yl]-2-pyridinyl]-5-fluoro-4-[(4R)-4-methyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a]azepin-3-yl]pyrimidin-2-amine	1588588: Inhibition of human full length GST-tagged CDK4 (1 to 303(end) amino acids)/Cyclin D3 (1 to 292(end) amino acids) expressed in baculovirus expression system assessed as inhibition constant using Ulight-4E-BP1 as substrate preincubated for 30 mins followed by substrate addition and incubated for 90 mins by TR-FRET assay	ki	0.0010	uM
6-[2-(dimethylamino)ethyl]-N-[5-fluoro-4-(7-fluoro-2-methyl-3-pentan-3-ylbenzimidazol-5-yl)pyrimidin-2-yl]-7,8-dihydro-5H-1,6-naphthyridin-2-amine	1509614: Inhibition of recombinant human full length N-terminal GST-tagged CDK4 (1 to 303 residues)/cyclin D3 (1 to 292 residues) expressed in baculovirus expression system using eIF4E-binding protein 1 peptide and ATP as substrate incubated for 30 mins by LANCE ultra kinase assay	ic50	0.0011	uM
N-[5-fluoro-4-(7-fluoro-2-methyl-3-propan-2-ylbenzimidazol-5-yl)pyrimidin-2-yl]-6-[2-[methyl(prop-2-ynyl)amino]ethyl]-7,8-dihydro-5H-1,6-naphthyridin-2-amine	1509614: Inhibition of recombinant human full length N-terminal GST-tagged CDK4 (1 to 303 residues)/cyclin D3 (1 to 292 residues) expressed in baculovirus expression system using eIF4E-binding protein 1 peptide and ATP as substrate incubated for 30 mins by LANCE ultra kinase assay	ic50	0.0013	uM
N-[5-[(4-ethylpiperazin-1-yl)methyl]-2-pyridinyl]-5-fluoro-4-[(4R)-4-methyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a]azepin-3-yl]pyrimidin-2-amine	1588588: Inhibition of human full length GST-tagged CDK4 (1 to 303(end) amino acids)/Cyclin D3 (1 to 292(end) amino acids) expressed in baculovirus expression system assessed as inhibition constant using Ulight-4E-BP1 as substrate preincubated for 30 mins followed by substrate addition and incubated for 90 mins by TR-FRET assay	ki	0.0013	uM
6-(difluoromethyl)-8-[(1R,2R)-2-hydroxy-2-methylcyclopentyl]-2-[(1-methylsulfonylpiperidin-4-yl)amino]pyrido[2,3-d]pyrimidin-7-one	1685179: Inhibition of non-phosphorylated CDK4/Cyclin D3 (unknown origin) assessed as reduction in production of ADP using 5-FAM-RRRFRPASPLRGPPK peptide as substrate preincubated with enzyme for 12 mins and measured after 35 mins in presence of ATP by fluorescence-based microfluidic mobility shift assay	ki	0.0014	uM
N-[5-fluoro-4-(7-fluoro-2-methyl-3-propan-2-ylbenzimidazol-5-yl)pyrimidin-2-yl]-6-[2-[methyl(2-trimethylsilylethyl)amino]ethyl]-7,8-dihydro-5H-1,6-naphthyridin-2-amine	1509614: Inhibition of recombinant human full length N-terminal GST-tagged CDK4 (1 to 303 residues)/cyclin D3 (1 to 292 residues) expressed in baculovirus expression system using eIF4E-binding protein 1 peptide and ATP as substrate incubated for 30 mins by LANCE ultra kinase assay	ic50	0.0014	uM
5-fluoro-N-[5-(4-methylpiperazin-1-yl)-2-pyridinyl]-4-[(4R)-4-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl]pyrimidin-2-amine	1588588: Inhibition of human full length GST-tagged CDK4 (1 to 303(end) amino acids)/Cyclin D3 (1 to 292(end) amino acids) expressed in baculovirus expression system assessed as inhibition constant using Ulight-4E-BP1 as substrate preincubated for 30 mins followed by substrate addition and incubated for 90 mins by TR-FRET assay	ki	0.0014	uM
2-[2-[2-[2-[[5-fluoro-4-(7-fluoro-2-methyl-3-propan-2-ylbenzimidazol-5-yl)pyrimidin-2-yl]amino]-7,8-dihydro-5H-1,6-naphthyridin-6-yl]ethyl-methylamino]ethyl]guanidine	1509614: Inhibition of recombinant human full length N-terminal GST-tagged CDK4 (1 to 303 residues)/cyclin D3 (1 to 292 residues) expressed in baculovirus expression system using eIF4E-binding protein 1 peptide and ATP as substrate incubated for 30 mins by LANCE ultra kinase assay	ic50	0.0015	uM
8-[(1R,2R)-2-hydroxy-2-methylcyclopentyl]-2-[(1-methylsulfonylpiperidin-4-yl)amino]pyrido[2,3-d]pyrimidin-7-one	1685179: Inhibition of non-phosphorylated CDK4/Cyclin D3 (unknown origin) assessed as reduction in production of ADP using 5-FAM-RRRFRPASPLRGPPK peptide as substrate preincubated with enzyme for 12 mins and measured after 35 mins in presence of ATP by fluorescence-based microfluidic mobility shift assay	ki	0.0015	uM
Abemaciclib	1909254: Inhibition of recombinant N-terminal GST/His6-fusion tagged human CDK4/Cyclin D3 expressed in Sf9 insect cells using 5-FAM-IPTSPITTTYFFFKKK as substrate preincubated for 10 mins followed by substrate addition and incubated for 3 hrs in presence of ATP by caliper mobility shift analysis	ic50	0.0015	uM
6-(1-ethylpiperidin-4-yl)-N-[5-fluoro-4-(7-fluoro-2-methyl-3-propan-2-ylbenzimidazol-5-yl)pyrimidin-2-yl]-7,8-dihydro-5H-1,6-naphthyridin-2-amine	1382364: Inhibition of human CDK6/Cyclin-D3	ic50	0.0016	uM
6-[2-(dimethylamino)ethyl]-N-[5-fluoro-4-[7-fluoro-2-methyl-3-(1-methylcyclopropyl)benzimidazol-5-yl]pyrimidin-2-yl]-7,8-dihydro-5H-1,6-naphthyridin-2-amine	1509615: Inhibition of recombinant human full length N-terminal GST-tagged CDK6 (1 to 326 residues)/cyclin D3 (1 to 292 residues) expressed in baculovirus expression system using eIF4E-binding protein 1 peptide and ATP as substrate incubated for 30 mins by LANCE ultra kinase assay	ic50	0.0016	uM
6-[2-(dimethylamino)ethyl]-N-[5-fluoro-4-[7-fluoro-2-methyl-3-(4-methylcyclohexyl)benzimidazol-5-yl]pyrimidin-2-yl]-7,8-dihydro-5H-1,6-naphthyridin-2-amine	1509614: Inhibition of recombinant human full length N-terminal GST-tagged CDK4 (1 to 303 residues)/cyclin D3 (1 to 292 residues) expressed in baculovirus expression system using eIF4E-binding protein 1 peptide and ATP as substrate incubated for 30 mins by LANCE ultra kinase assay	ic50	0.0016	uM
N-[4-[3-(cyclopropylmethyl)-7-fluoro-2-methylbenzimidazol-5-yl]-5-fluoropyrimidin-2-yl]-6-[2-(dimethylamino)ethyl]-7,8-dihydro-5H-1,6-naphthyridin-2-amine	1509614: Inhibition of recombinant human full length N-terminal GST-tagged CDK4 (1 to 303 residues)/cyclin D3 (1 to 292 residues) expressed in baculovirus expression system using eIF4E-binding protein 1 peptide and ATP as substrate incubated for 30 mins by LANCE ultra kinase assay	ic50	0.0016	uM
6-[2-[dimethylphosphoryl(methyl)amino]ethyl]-N-[5-fluoro-4-(7-fluoro-2-methyl-3-propan-2-ylbenzimidazol-5-yl)pyrimidin-2-yl]-7,8-dihydro-5H-1,6-naphthyridin-2-amine	1509614: Inhibition of recombinant human full length N-terminal GST-tagged CDK4 (1 to 303 residues)/cyclin D3 (1 to 292 residues) expressed in baculovirus expression system using eIF4E-binding protein 1 peptide and ATP as substrate incubated for 30 mins by LANCE ultra kinase assay	ic50	0.0016	uM
N-[4-(3-tert-butyl-7-fluoro-2-methylbenzimidazol-5-yl)-5-fluoropyrimidin-2-yl]-6-[2-(dimethylamino)ethyl]-7,8-dihydro-5H-1,6-naphthyridin-2-amine	1509614: Inhibition of recombinant human full length N-terminal GST-tagged CDK4 (1 to 303 residues)/cyclin D3 (1 to 292 residues) expressed in baculovirus expression system using eIF4E-binding protein 1 peptide and ATP as substrate incubated for 30 mins by LANCE ultra kinase assay	ic50	0.0016	uM
5-fluoro-N-[5-(4-methylpiperazin-1-yl)-2-pyridinyl]-4-(5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a]azepin-3-yl)pyrimidin-2-amine	1588588: Inhibition of human full length GST-tagged CDK4 (1 to 303(end) amino acids)/Cyclin D3 (1 to 292(end) amino acids) expressed in baculovirus expression system assessed as inhibition constant using Ulight-4E-BP1 as substrate preincubated for 30 mins followed by substrate addition and incubated for 90 mins by TR-FRET assay	ki	0.0018	uM
N-[4-(3-cyclopropyl-7-fluoro-2-methylbenzimidazol-5-yl)-5-fluoropyrimidin-2-yl]-6-[2-(dimethylamino)ethyl]-7,8-dihydro-5H-1,6-naphthyridin-2-amine	1509614: Inhibition of recombinant human full length N-terminal GST-tagged CDK4 (1 to 303 residues)/cyclin D3 (1 to 292 residues) expressed in baculovirus expression system using eIF4E-binding protein 1 peptide and ATP as substrate incubated for 30 mins by LANCE ultra kinase assay	ic50	0.0019	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	1317364: Inhibition of CDK6/cyclin D3 (unknown origin)	ic50	0.0020	uM
N-cyclopentyl-5-[2-[(5-piperazin-1-yl-2-pyridinyl)amino]pyrimidin-4-yl]-4-(trifluoromethyl)-1,3-thiazol-2-amine	1438405: Inhibition of CDK6/cyclin D3 (unknown origin) in presence of [gamma-33P]-ATP by KINOMEscan assay	ki	0.0020	uM
N-[5-[(4-ethylpiperazin-1-yl)methyl]-2-pyridinyl]-5-fluoro-4-(7’-fluoro-2’-methylspiro[cyclopentane-1,3’-indole]-5’-yl)pyrimidin-2-amine	1402379: Inhibition of CDK6/Cyclin-D3 (unknown origin) using histoneH1 as substrate after 90 mins by ADP-Glo assay	ic50	0.0020	uM
1-[2-[2-[[5-fluoro-4-(7-fluoro-2-methyl-3-propan-2-ylbenzimidazol-5-yl)pyrimidin-2-yl]amino]-7,8-dihydro-5H-1,6-naphthyridin-6-yl]ethyl]-1-methylthiourea	1509614: Inhibition of recombinant human full length N-terminal GST-tagged CDK4 (1 to 303 residues)/cyclin D3 (1 to 292 residues) expressed in baculovirus expression system using eIF4E-binding protein 1 peptide and ATP as substrate incubated for 30 mins by LANCE ultra kinase assay	ic50	0.0020	uM
6-bromo-8-cyclopentyl-2-(4-piperazin-1-ylanilino)pyrido[2,3-d]pyrimidin-7-one	240709: Inhibition of Cyclin-dependent kinase 4-cyclinD	ic50	0.0020	uM
6-acetyl-8-cyclopentyl-5-methyl-2-(4-piperazin-1-ylanilino)pyrido[2,3-d]pyrimidin-7-one	240709: Inhibition of Cyclin-dependent kinase 4-cyclinD	ic50	0.0020	uM
1-[8-methyl-12-[[5-(piperazin-1-ylmethyl)-2-pyridinyl]amino]-4-propan-2-yl-2,5,11,13-tetrazatricyclo[7.4.0.02,6]trideca-1(13),3,5,7,9,11-hexaen-7-yl]ethanone	1737183: Inhibition of recombinant human full-length N-terminal GST-fused CDK4 (1 to 303 residues)/GST-tagged CyclinD3 (1 to 292 residues) expressed in baculovirus expression system using ULight-elF4E-binding protein 1 peptide as substrate measured after 30 mins by LANCE assay	ic50	0.0022	uM
6-[2-(dimethylamino)ethyl]-N-[4-(3-ethyl-7-fluoro-2-methylbenzimidazol-5-yl)-5-fluoropyrimidin-2-yl]-7,8-dihydro-5H-1,6-naphthyridin-2-amine	1509614: Inhibition of recombinant human full length N-terminal GST-tagged CDK4 (1 to 303 residues)/cyclin D3 (1 to 292 residues) expressed in baculovirus expression system using eIF4E-binding protein 1 peptide and ATP as substrate incubated for 30 mins by LANCE ultra kinase assay	ic50	0.0024	uM
7-cyclopentyl-2-[4-[2-(dimethylamino)ethylcarbamoyl]-2-fluoroanilino]-N,N-dimethylpyrrolo[2,3-d]pyrimidine-6-carboxamide	1921444: Inhibition of human CDK4/Cyclin D3 in presence of ATP	ic50	0.0025	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Estradiol	affects expression, increases expression, increases reaction	6
Benzo(a)pyrene	affects methylation, decreases methylation, increases expression, increases methylation	5
Tretinoin	decreases reaction, increases expression, increases reaction, decreases expression, increases degradation (+1 more)	5
sodium arsenite	affects expression, increases expression	4
Fluorouracil	affects response to substance, increases expression	4
Sirolimus	decreases stability, affects cotreatment, decreases reaction, increases expression, decreases expression	4
bisphenol A	decreases reaction, affects expression, affects cotreatment, decreases methylation, increases expression	3
Cisplatin	affects cotreatment, increases expression	3
Aflatoxin B1	increases expression, increases methylation	3
thymoquinone	decreases expression, decreases reaction	2
1-aminomethylphosphonic acid	affects cotreatment, decreases expression	2
4-(2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)-1-propenyl)benzoic acid	increases expression, increases reaction, decreases expression	2
2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one	decreases expression, affects cotreatment, decreases reaction, increases expression	2
alpha-cyano-(3,4-dihydroxy)-N-benzylcinnamide	decreases reaction, increases expression, decreases expression	2
U 0126	increases expression, decreases expression, decreases reaction	2
erucylphospho-N,N,N-trimethylpropylammonium	decreases expression, decreases reaction	2
palbociclib	affects binding, decreases reaction, increases phosphorylation, increases expression	2
(+)-JQ1 compound	decreases expression	2
Imatinib Mesylate	affects cotreatment, decreases expression	2
Sorafenib	affects cotreatment, decreases expression	2
Arsenic Trioxide	decreases expression, increases expression	2
Troglitazone	decreases expression, increases reaction	2
Silybin	affects cotreatment, decreases expression	2
Aspirin	decreases expression, increases reaction	2
Cannabidiol	decreases expression	2
Copper	affects binding, decreases expression	2
Drugs, Chinese Herbal	decreases expression	2
Furazolidone	increases expression, decreases reaction	2
Nickel	increases expression	2
Parathion	affects cotreatment, increases expression	2

ChEMBL screening assays

425 unique, capped per target: 422 binding, 2 admet, 1 toxicity

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4887807	Binding	CDK4/cyclinD Millipore kinase panel	Data for DCP probe BAY-091
CHEMBL4325186	ADMET	Inhibition of human CDK4/Cyclin D3 at 1 uM relative to control	Selectivity and Physicochemical Optimization of Repurposed Pyrazolo[1,5-b]pyridazines for the Treatment of Human African Trypanosomiasis. — J Med Chem
CHEMBL5229243	Toxicity	Binding affinity to human full length CDK4 (M1 to E303 residues) expressed in mammalian expression system/CyclinD3 by KdELECT kinase assay	Engineering Selectivity for Reduced Toxicity of Bacterial Kinase Inhibitors Using Structure-Guided Medicinal Chemistry. — ACS Med Chem Lett

Cellosaurus cell lines

6 cell lines: 4 cancer cell line, 2 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B2TM	Abcam HEK293T CCND3 KO	Transformed cell line	Female
CVCL_D7LX	Ubigene A-549 CCND3 KO	Cancer cell line	Male
CVCL_D8IL	Ubigene HCT 116 CCND3 KO	Cancer cell line	Male
CVCL_D9BD	Ubigene HEK293 CCND3 KO	Transformed cell line	Female
CVCL_D9ZL	Ubigene HeLa CCND3 KO	Cancer cell line	Female
CVCL_SH37	HAP1 CCND3 (-)	Cancer cell line	Male

Clinical trials (associated diseases)

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