CHEK2

Summary

CHEK2 (checkpoint kinase 2, HGNC:16627) is a protein-coding gene on chromosome 22q12.1, encoding Serine/threonine-protein kinase Chk2 (O96017). Serine/threonine-protein kinase which is required for checkpoint-mediated cell cycle arrest, activation of DNA repair and apoptosis in response to the presence of DNA double-strand breaks. In precision oncology, CHEK2 mutation confers sensitivity to Olaparib in Castration-resistant Prostate Carcinoma (CIViC Level A); 1 further curated variant–drug associations are listed below. It is haploinsufficient (ClinGen: sufficient evidence).

In response to DNA damage and replication blocks, cell cycle progression is halted through the control of critical cell cycle regulators. The protein encoded by this gene is a cell cycle checkpoint regulator and putative tumor suppressor. It contains a forkhead-associated protein interaction domain essential for activation in response to DNA damage and is rapidly phosphorylated in response to replication blocks and DNA damage. When activated, the encoded protein is known to inhibit CDC25C phosphatase, preventing entry into mitosis, and has been shown to stabilize the tumor suppressor protein p53, leading to cell cycle arrest in G1. In addition, this protein interacts with and phosphorylates BRCA1, allowing BRCA1 to restore survival after DNA damage. Mutations in this gene have been linked with Li-Fraumeni syndrome, a highly penetrant familial cancer phenotype usually associated with inherited mutations in TP53. Also, mutations in this gene are thought to confer a predisposition to sarcomas, breast cancer, and brain tumors. This nuclear protein is a member of the CDS1 subfamily of serine/threonine protein kinases. Several transcript variants encoding different isoforms have been found for this gene.

Source: NCBI Gene 11200 — RefSeq curated summary.

At a glance

• Gene–disease (curated): CHEK2-related cancer predisposition (Definitive, ClinGen) — +5 more curated relationships
• GWAS associations: 48
• Clinical variants (ClinVar): 4,714 total — 755 pathogenic, 254 likely-pathogenic
• Phenotypes (HPO): 101
• Druggable target: yes — 30 molecules with ChEMBL bioactivity
• Precision-oncology evidence (CIViC): 2 curated variant–drug associations
• Cancer driver (intOGen): activating (oncogene-like) across 1 cancer types
• Dosage sensitivity (ClinGen): haploinsufficiency sufficient evidence, triplosensitivity no evidence
• MANE Select transcript: NM_007194

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:16627
Approved symbol	CHEK2
Name	checkpoint kinase 2
Location	22q12.1
Locus type	gene with protein product
Status	Approved
Aliases	CDS1, CHK2, HuCds1, PP1425, bA444G7
Ensembl gene	ENSG00000183765
Ensembl biotype	protein_coding
OMIM	604373
Entrez	11200

Gene structure

Transcript identifiers

Ensembl transcripts: 42 — 31 protein_coding, 8 nonsense_mediated_decay, 2 retained_intron, 1 protein_coding_CDS_not_defined

ENST00000348295, ENST00000382580, ENST00000398017, ENST00000402731, ENST00000403642, ENST00000404276, ENST00000405598, ENST00000416671, ENST00000417588, ENST00000425190, ENST00000433028, ENST00000433728, ENST00000434810, ENST00000439200, ENST00000439346, ENST00000448511, ENST00000454252, ENST00000456369, ENST00000464581, ENST00000472807, ENST00000491919, ENST00000648295, ENST00000649563, ENST00000650233, ENST00000650281, ENST00000711048, ENST00000899937, ENST00000928683, ENST00000928684, ENST00000928685, ENST00000928686, ENST00000928687, ENST00000928688, ENST00000928689, ENST00000928690, ENST00000928691, ENST00000928692, ENST00000928693, ENST00000928694, ENST00000928695, ENST00000928696, ENST00000954618

RefSeq mRNA: 5 — MANE Select: NM_007194 NM_001005735, NM_001257387, NM_001349956, NM_007194, NM_145862

CCDS: CCDS13843, CCDS13844, CCDS33629, CCDS93141

Canonical transcript exons

ENST00000404276 — 15 exons

Exon	Start	End
ENSE00003478809	28734403	28734727
ENSE00003500761	28703505	28703566
ENSE00003527481	28719395	28719485
ENSE00003559542	28695710	28695873
ENSE00003566135	28710006	28710059
ENSE00003584101	28695127	28695242
ENSE00003621985	28689135	28689215
ENSE00003626468	28725243	28725367
ENSE00003632344	28724977	28725124
ENSE00003645901	28694032	28694117
ENSE00003668709	28687743	28687986
ENSE00003694540	28699838	28699937
ENSE00003787789	28711909	28712017
ENSE00003788575	28696901	28696987
ENSE00003831704	28741769	28741820

Expression profiles

Bgee: expression breadth ubiquitous, 183 present calls, max score 90.59.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 14.3740 / max 169.6474, expressed in 1762 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
193490	12.5074	1711
193491	1.2224	561
193489	0.3339	189
193488	0.3102	157

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	90.59	gold quality
lower esophagus mucosa	UBERON:0035834	89.41	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	88.61	gold quality
mucosa of transverse colon	UBERON:0004991	88.58	gold quality
tibial nerve	UBERON:0001323	88.55	gold quality
oocyte	CL:0000023	88.45	gold quality
secondary oocyte	CL:0000655	87.19	gold quality
rectum	UBERON:0001052	86.12	gold quality
ventricular zone	UBERON:0003053	85.90	gold quality
left ovary	UBERON:0002119	85.46	gold quality
right ovary	UBERON:0002118	85.30	gold quality
adrenal tissue	UBERON:0018303	84.63	gold quality
right adrenal gland cortex	UBERON:0035827	84.37	gold quality
right adrenal gland	UBERON:0001233	84.19	gold quality
ganglionic eminence	UBERON:0004023	83.97	gold quality
left adrenal gland cortex	UBERON:0035825	83.96	gold quality
ovary	UBERON:0000992	83.80	gold quality
left adrenal gland	UBERON:0001234	83.29	gold quality
esophagus mucosa	UBERON:0002469	83.13	gold quality
granulocyte	CL:0000094	81.90	gold quality
stromal cell of endometrium	CL:0002255	81.72	gold quality
embryo	UBERON:0000922	81.72	gold quality
adrenal gland	UBERON:0002369	81.43	gold quality
adrenal cortex	UBERON:0001235	81.30	gold quality
right lobe of liver	UBERON:0001114	81.22	gold quality
monocyte	CL:0000576	81.18	gold quality
transverse colon	UBERON:0001157	80.71	gold quality
mononuclear cell	CL:0000842	80.70	gold quality
endocervix	UBERON:0000458	80.70	gold quality
calcaneal tendon	UBERON:0003701	80.68	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	6.70
E-MTAB-7008	no	152.78

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): CTNNBL1, E2F1, E2F6, MYC, NCOR2, NFYA, PITX2, RARA, TP53, TP73, WT1, ZKSCAN7

miRNA regulators (miRDB)

8 targeting CHEK2, 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-548E-5P	99.89	72.73	4486
HSA-MIR-4276	99.56	67.66	2514
HSA-MIR-5190	99.15	67.76	1234
HSA-MIR-3938	98.72	66.07	834
HSA-MIR-5094	98.63	67.11	1062
HSA-MIR-134-5P	97.11	66.52	976
HSA-MIR-3118	97.11	66.58	984
HSA-MIR-759	96.16	66.77	873

Functional genomics

ClinGen dosage: haploinsufficiency 3 (sufficient evidence), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 40)

• Destabilization of CHK2 by a missense mutation associated with Li-Fraumeni Syndrome. (PMID:11719428)
• Mutations of the CHK2 gene are found in some osteosarcomas, but are rare in breast, lung, and ovarian tumors. (PMID:11746983)
• robust method for detecting CHK2/RAD53 mutations in genomic DNA (PMID:11793476)
• utilization of peptide library analyses to develop specific, highly preferred substrate motifs for hCds1/Chk2 and Chk1 (PMID:11821419)
• genetic changes in CHK2 occur in small proportion of vulval squamous cell carcinomas (PMID:11875739)
• Phosphorylation of threonine 68 promotes oligomerization and autophosphorylation of the Chk2 protein kinase via the forkhead-associated domain (PMID:11901158)
• Low-penetrance susceptibility to breast cancer due to CHEK2(*)1100delC in noncarriers of BRCA1 or BRCA2 mutations. (PMID:11967536)
• CHEKs and balances: accounting for breast cancer. (PMID:11984555)
• results suggest that Chk2 oligomerization regulates Chk2 activation, signal amplification, and transduction in DNA damage checkpoint pathways (PMID:12024051)
• Although phospho-dependent binding is important for Chk2 activity, previously uncharacterized phospho-independent FHA domain interactions appear to be the primary target of oncogenic lesions. (PMID:12049740)
• mutation is associated with familial breast cancer (PMID:12094328)
• function and regulation of Cds1 - review (PMID:12111733)
• phosphorylation of Thr-68 may be required for initial oligomerization and activation of Chk2, but it is not needed for maintenance of dimerization or kinase activity (PMID:12386164)
• CHK2 alterations are uncommon in malignant lymphomas but occur in a subset of aggressive tumors. The high number of chromosomal imbalances in tumors with complete absence of CHK2 protein suggests a role in chromosomal instability in human lymphomas. (PMID:12393693)
• checkpoint kinase hCds1/Chk2 has a role in regulating PML-dependent apoptosis after DNA damage (PMID:12402044)
• interaction with polo-like kinase 1 and localization to centrosomes and midbody (PMID:12493754)
• Mutations and CHEK2 protein levels were analyzed in prostatic neoplasms. CHEK2 mutations contributed to prostate cancer risk. (PMID:12533788)
• Plk3 is rapidly activated by reactive oxygen species fibroblasts cells, correlating with increased p53 protein levels. Plk3 physically interacts with Chk2 and the interaction is enhanced upon DNA damage. (PMID:12548019)
• Chk2 is regulated by NFBD1 and 53BP1 in human tumor cells (PMID:12551934)
• MDC1 is recruited through its FHA domain to the activated CHK2, and has a critical role in CHK2-mediated DNA damage responses (PMID:12607004)
• Variations in this enzyme other than 1100delC do not make a major contribution to breast cancer susceptibility. (PMID:12610780)
• although Chk2 purified from DNA damage sustaining cells has dramatically increased ability to phosphorylate Cdc25C when compared with untreated cells, its ability to phosphorylate p53 is weak (PMID:12654916)
• Chk2 kinase is not required for p53 activation in human cells and explain why CHK2 and TP53 mutations can jointly occur in human tumors. (PMID:12654917)
• Increased phosphate incorporation into serine residues generated by the combined action of CHK1 and CHK2 kinases correlated with the ionizing radiation-induced acceleration of Cdc25A proteolysis. (PMID:12676583)
• The 1100delC variant of the CHEK2 gene was present in 18% of 55 families with hereditary breast and colorectal cancer (HBCC) as compared with 4% of 380 families with non-HBCC and may act in synergy with unknown susceptibility gene(s) (PMID:12690581)
• Determination of substrate specificity and putative substrates of Chk2 kinase. (PMID:12711320)
• Expression of a dominant-negative Chk2 mutant blocks induction of E2F-1 and prevents E2F-1-dependent apoptosis. Moreover, E2F-1 is resistant to induction by etoposide in tumour cells expressing mutant chk2. (PMID:12717439)
• autophosphorylation of Chk2 can occur both in cis and in trans and suggest that oligomerization may regulate Chk2 activation by promoting these cis- and trans-phosphorylation events (PMID:12805407)
• chk2 is recruited into the PML nuclear bodies by PML along with p53 (PMID:12810724)
• Chk2 autophosphorylation is critical for Chk2 function following DNA damage (PMID:12855706)
• evidence that CHK2 can be activated allosterically towards some substrates by a novel docking interaction; identifed a potential regulatory switch that may channel CHK2 into distinct signalling pathways in vivo (PMID:12897801)
• the NLS-3 motif located at amino acids 515-522 acts indeed as Nuclear Localization Signal for Chk2 (PMID:12909615)
• study from South India, on BRCA1, BRCA2 & CHEK2 mutations in patients with a family history of breast and/or ovarian cancer and early onset breast/ovarian cancer (PMID:14507240)
• Zinc-finger protein transcription factors bind an 18-bp recognition sequence within the promoter of the endogenous CHK2 gene, giving a >10-fold reduction in CHK2 mRNA and protein (PMID:14514889)
• The CHEK2 1100delC allele was not over-represented in cases suggesting that this variant is not associated with an increased risk of colorectal disease. (PMID:14568168)
• CHEK2 variants are low-penetrance prostate cancer predisposition alleles that contribute significantly to familial clustering of prostate cancer at the population level (PMID:14612911)
• data reveal the very different mode of regulation between CHK1 and CHK2 (PMID:14681223)
• functional link between recombination control and breast cancer predisposition in carriers of Chk2 and BRCA1 germ line mutations (PMID:14701743)
• Results suggest that E2F1 plays a central role in signaling disturbances in the retinoblastoma growth control pathway and, by upregulation of Chk2 by Atm and Nbs1, may sensitize cells to undergo apoptosis. (PMID:15024084)
• p53 negatively regulates Chk2 gene transcription through modulation of NF-Y function and that this regulation may be important for reentry of cells into the cell cycle after DNA damage is repaired. (PMID:15044452)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	chek2	ENSDARG00000025820
mus_musculus	Chek2	ENSMUSG00000029521
rattus_norvegicus	Chek2	ENSRNOG00000037509
drosophila_melanogaster	lok	FBGN0019686
caenorhabditis_elegans		WBGENE00000499
caenorhabditis_elegans		WBGENE00011612

Protein

Protein identifiers

Serine/threonine-protein kinase Chk2 — O96017 (reviewed: O96017)

Alternative names: CHK2 checkpoint homolog, Cds1 homolog, Checkpoint kinase 2

All UniProt accessions (14): A0A087X102, A0A3B3ITA7, A0A7P0MUT5, A0AA34QVK6, B7ZBF2, B7ZBF7, B7ZBF8, C9JFD7, F8WCV2, O96017, H0Y4V6, H0Y820, H7BZ30, H7C0V7

UniProt curated annotations — full annotation on UniProt →

Function. Serine/threonine-protein kinase which is required for checkpoint-mediated cell cycle arrest, activation of DNA repair and apoptosis in response to the presence of DNA double-strand breaks. May also negatively regulate cell cycle progression during unperturbed cell cycles. Following activation, phosphorylates numerous effectors preferentially at the consensus sequence [L-X-R-X-X-S/T]. Regulates cell cycle checkpoint arrest through phosphorylation of CDC25A, CDC25B and CDC25C, inhibiting their activity. Inhibition of CDC25 phosphatase activity leads to increased inhibitory tyrosine phosphorylation of CDK-cyclin complexes and blocks cell cycle progression. May also phosphorylate NEK6 which is involved in G2/M cell cycle arrest. Regulates DNA repair through phosphorylation of BRCA2, enhancing the association of RAD51 with chromatin which promotes DNA repair by homologous recombination. Also stimulates the transcription of genes involved in DNA repair (including BRCA2) through the phosphorylation and activation of the transcription factor FOXM1. Regulates apoptosis through the phosphorylation of p53/TP53, MDM4 and PML. Phosphorylation of p53/TP53 at ‘Ser-20’ by CHEK2 may alleviate inhibition by MDM2, leading to accumulation of active p53/TP53. Phosphorylation of MDM4 may also reduce degradation of p53/TP53. Also controls the transcription of pro-apoptotic genes through phosphorylation of the transcription factor E2F1. Tumor suppressor, it may also have a DNA damage-independent function in mitotic spindle assembly by phosphorylating BRCA1. Its absence may be a cause of the chromosomal instability observed in some cancer cells. Promotes the CCAR2-SIRT1 association and is required for CCAR2-mediated SIRT1 inhibition. Under oxidative stress, promotes ATG7 ubiquitination by phosphorylating the E3 ubiquitin ligase TRIM32 at ‘Ser-55’ leading to positive regulation of the autophagosme assembly. (Microbial infection) Phosphorylates herpes simplex virus 1/HHV-1 protein ICP0 and thus activates its SUMO-targeted ubiquitin ligase activity.

Subunit / interactions. Homodimer. Homodimerization is part of the activation process but the dimer may dissociate following activation. Interacts with PML. Interacts with TP53. Interacts with RB1; phosphorylates RB1. Interacts with BRCA1. Interacts (phosphorylated at Thr-68) with MDC1; requires ATM-mediated phosphorylation of CHEK2. Interacts with TP53BP1; modulates CHEK2 phosphorylation at Thr-68 in response to ionizing radiation. Interacts with CDC25A; phosphorylates CDC25A and mediates its degradation in response to ionizing radiation. Interacts with CUL1; mediates CHEK2 ubiquitination and regulation. Interacts with CDKN2AIP. Interacts (via protein kinase domain) with CCAR2 (via N-terminus). Interacts with SIRT1.

Subcellular location. Nucleus Nucleus Nucleus Nucleus Nucleus Nucleus. PML body. Nucleus. Nucleoplasm.

Tissue specificity. High expression is found in testis, spleen, colon and peripheral blood leukocytes. Low expression is found in other tissues.

Post-translational modifications. Phosphorylated. Phosphorylated at Ser-73 by PLK3 in response to DNA damage, promoting phosphorylation at Thr-68 by ATM and the G2/M transition checkpoint. Phosphorylation at Thr-68 induces homodimerization. Autophosphorylates at Thr-383 and Thr-387 in the T-loop/activation segment upon dimerization to become fully active and phosphorylate its substrates like for instance CDC25C. DNA damage-induced autophosphorylation at Ser-379 induces CUL1-mediated ubiquitination and regulates the pro-apoptotic function. Phosphorylation at Ser-456 also regulates ubiquitination. Phosphorylated by PLK4. Ubiquitinated. CUL1-mediated ubiquitination regulates the pro-apoptotic function. Ubiquitination may also regulate protein stability. Ubiquitinated by RNF8 via ‘Lys-48’-linked ubiquitination.

Disease relevance. Tumor predisposition syndrome 4 (TPDS4) [MIM:609265] A disorder characterized by an increased risk for developing various types of benign and/or malignant neoplasms that arise at an accelerated rate and in different organs. The disease is caused by variants affecting the gene represented in this entry. Prostate cancer (PC) [MIM:176807] A malignancy originating in tissues of the prostate. Most prostate cancers are adenocarcinomas that develop in the acini of the prostatic ducts. Other rare histopathologic types of prostate cancer that occur in approximately 5% of patients include small cell carcinoma, mucinous carcinoma, prostatic ductal carcinoma, transitional cell carcinoma, squamous cell carcinoma, basal cell carcinoma, adenoid cystic carcinoma (basaloid), signet-ring cell carcinoma and neuroendocrine carcinoma. Disease susceptibility is associated with variants affecting the gene represented in this entry. Osteogenic sarcoma (OSRC) [MIM:259500] A sarcoma originating in bone-forming cells, affecting the ends of long bones. The gene represented in this entry may be involved in disease pathogenesis. Breast cancer (BC) [MIM:114480] A common malignancy originating from breast epithelial tissue. Breast neoplasms can be distinguished by their histologic pattern. Invasive ductal carcinoma is by far the most common type. Breast cancer is etiologically and genetically heterogeneous. Important genetic factors have been indicated by familial occurrence and bilateral involvement. Mutations at more than one locus can be involved in different families or even in the same case. Disease susceptibility is associated with variants affecting the gene represented in this entry.

Activity regulation. Activated through phosphorylation at Thr-68 by ATM in response to DNA double-strand breaks. Activation is modulated by several mediators including MDC1 and TP53BP1. Induces homodimerization with exchange of the T-loop/activation segment between protomers and transphosphorylation of the protomers. The autophosphorylated kinase dimer is fully active. Negatively regulated by PPM1D through dephosphorylation of Thr-68.

Miscellaneous. Lacks enzymatic activity. Lacks enzymatic activity. Lacks enzymatic activity. Retains low level of catalytic activity. Lacks enzymatic activity. Lacks enzymatic activity.

Similarity. Belongs to the protein kinase superfamily. CAMK Ser/Thr protein kinase family. CHK2 subfamily.

Isoforms (13)

UniProt ID	Names	Canonical?
O96017-1	1	yes
O96017-2	2, ins2
O96017-3	3, del2-12
O96017-4	4, del2-3
O96017-5	5, del4
O96017-6	6, sub3
O96017-7	7, del9-12
O96017-8	8, del7
O96017-9	9, insx
O96017-10	10, iso2
O96017-11	11, iso1
O96017-12	12, del9
O96017-13	13

RefSeq proteins (5): NP_001005735, NP_001244316, NP_001336885, NP_009125, NP_665861 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000253	FHA_dom	Domain
IPR000719	Prot_kinase_dom	Domain
IPR008271	Ser/Thr_kinase_AS	Active_site
IPR008984	SMAD_FHA_dom_sf	Homologous_superfamily
IPR011009	Kinase-like_dom_sf	Homologous_superfamily

Pfam: PF00069, PF00498

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)

Substrate kinetics (BRENDA)

8 substrates with measured Km, best-characterized 8. 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
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

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 (126 total): sequence variant 32, helix 21, strand 19, splice variant 19, mutagenesis site 8, modified residue 7, binding site 5, turn 4, compositionally biased region 4, region of interest 3, domain 2, chain 1, active site 1

Structure

Experimental structures (PDB)

38 structures, top 30 by resolution.

PDB	Method	Resolution (Å)
3VA4	X-RAY DIFFRACTION	1.54
2YCF	X-RAY DIFFRACTION	1.77
2YIQ	X-RAY DIFFRACTION	1.89
2W0J	X-RAY DIFFRACTION	2.05
2YCQ	X-RAY DIFFRACTION	2.05
2W7X	X-RAY DIFFRACTION	2.07
2WTJ	X-RAY DIFFRACTION	2.1
2YIR	X-RAY DIFFRACTION	2.1
2YCR	X-RAY DIFFRACTION	2.2
2YIT	X-RAY DIFFRACTION	2.2
2CN5	X-RAY DIFFRACTION	2.25
2XBJ	X-RAY DIFFRACTION	2.3
4BDI	X-RAY DIFFRACTION	2.32
2XK9	X-RAY DIFFRACTION	2.35
2YCS	X-RAY DIFFRACTION	2.35
4A9U	X-RAY DIFFRACTION	2.48
2WTI	X-RAY DIFFRACTION	2.5
2XM9	X-RAY DIFFRACTION	2.5
4BDB	X-RAY DIFFRACTION	2.5
4BDE	X-RAY DIFFRACTION	2.55
4BDA	X-RAY DIFFRACTION	2.6
4A9S	X-RAY DIFFRACTION	2.66
4BDD	X-RAY DIFFRACTION	2.67
1GXC	X-RAY DIFFRACTION	2.7
2CN8	X-RAY DIFFRACTION	2.7
4A9T	X-RAY DIFFRACTION	2.7
4BDF	X-RAY DIFFRACTION	2.7
4BDH	X-RAY DIFFRACTION	2.7
2WTD	X-RAY DIFFRACTION	2.75
4BDG	X-RAY DIFFRACTION	2.84

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O96017-F1	77.64	0.49

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): 347 (proton acceptor)

Ligand- & substrate-binding residues (5): 227–234; 249; 302–308; 351–352; 368

Post-translational modifications (7): 62, 68, 73, 379, 383, 387, 456

Mutagenesis-validated functional residues (8):

Position	Phenotype
68	loss of activation and phosphorylation.
73	impaired activation, phosphorylation by atm and g2/m transition checkpoint.
347	loss of kinase activity and of the ability to phosphorylate cdc25a.
368	loss of autophosphorylation activity.
379	abrogates autophosphorylation at ser-379 and prevents ubiquitination.
383	loss of phosphorylation in response to ionizing radiation.
387	loss of phosphorylation in response to ionizing radiation.
456	increased ubiquitination and degradation by the proteasome.

Function

Pathways and Gene Ontology

Reactome pathways

8 pathways

ID	Pathway
R-HSA-5693565	Recruitment and ATM-mediated phosphorylation of repair and signaling proteins at DNA double strand breaks
R-HSA-6804756	Regulation of TP53 Activity through Phosphorylation
R-HSA-6804757	Regulation of TP53 Degradation
R-HSA-6804760	Regulation of TP53 Activity through Methylation
R-HSA-69473	G2/M DNA damage checkpoint
R-HSA-69541	Stabilization of p53
R-HSA-69601	Ubiquitin-Mediated Degradation of Phosphorylated Cdc25A
R-HSA-75035	Chk1/Chk2(Cds1) mediated inactivation of Cyclin B:Cdk1 complex

MSigDB gene sets: 744 (showing top): GSE18804_SPLEEN_MACROPHAGE_VS_BRAIN_TUMORAL_MACROPHAGE_DN, GOBP_CHROMOSOME_ORGANIZATION, GOBP_RESPONSE_TO_IONIZING_RADIATION, GOBP_INTRINSIC_APOPTOTIC_SIGNALING_PATHWAY_IN_RESPONSE_TO_DNA_DAMAGE_BY_P53_CLASS_MEDIATOR, GOBP_PHOSPHOLIPID_METABOLIC_PROCESS, GOBP_REGULATION_OF_FAT_CELL_DIFFERENTIATION, GOBP_PHOSPHATIDYLCHOLINE_METABOLIC_PROCESS, GOBP_PHOSPHATIDYLINOSITOL_METABOLIC_PROCESS, GOBP_VACUOLE_ORGANIZATION, BIOCARTA_ATM_PATHWAY, GOBP_PHOSPHATIDYLCHOLINE_BIOSYNTHETIC_PROCESS, JAEGER_METASTASIS_DN, CROONQUIST_NRAS_SIGNALING_DN, REACTOME_G2_M_DNA_DAMAGE_CHECKPOINT, GOBP_POSITIVE_REGULATION_OF_FAT_CELL_DIFFERENTIATION

GO Biological Process (38): DNA damage checkpoint signaling (GO:0000077), G2/M transition of mitotic cell cycle (GO:0000086), double-strand break repair (GO:0006302), regulation of DNA-templated transcription (GO:0006355), protein phosphorylation (GO:0006468), DNA damage response (GO:0006974), intrinsic apoptotic signaling pathway in response to DNA damage (GO:0008630), protein catabolic process (GO:0030163), DNA damage response, signal transduction by p53 class mediator (GO:0030330), mitotic intra-S DNA damage checkpoint signaling (GO:0031573), cellular response to stress (GO:0033554), regulation of protein catabolic process (GO:0042176), signal transduction in response to DNA damage (GO:0042770), intrinsic apoptotic signaling pathway in response to DNA damage by p53 class mediator (GO:0042771), mitotic DNA damage checkpoint signaling (GO:0044773), positive regulation of DNA-templated transcription (GO:0045893), protein autophosphorylation (GO:0046777), protein stabilization (GO:0050821), cell division (GO:0051301), thymocyte apoptotic process (GO:0070242), cellular response to xenobiotic stimulus (GO:0071466), cellular response to gamma radiation (GO:0071480), mitotic spindle assembly (GO:0090307), replicative senescence (GO:0090399), regulation of signal transduction by p53 class mediator (GO:1901796), response to glycoside (GO:1903416), cellular response to bisphenol A (GO:1903926), negative regulation of DNA damage checkpoint (GO:2000002), positive regulation of anoikis (GO:2000210), regulation of autophagosome assembly (GO:2000785), autophagosome assembly (GO:0000045), DNA repair (GO:0006281), apoptotic process (GO:0006915), response to oxidative stress (GO:0006979), response to gamma radiation (GO:0010332), response to starvation (GO:0042594), protein K63-linked ubiquitination (GO:0070534), positive regulation of autophagosome assembly (GO:2000786)

GO Molecular Function (13): protein serine/threonine kinase activity (GO:0004674), ATP binding (GO:0005524), protein kinase binding (GO:0019901), ubiquitin protein ligase binding (GO:0031625), identical protein binding (GO:0042802), protein homodimerization activity (GO:0042803), metal ion binding (GO:0046872), protein serine kinase activity (GO:0106310), nucleotide binding (GO:0000166), protein kinase activity (GO:0004672), protein binding (GO:0005515), kinase activity (GO:0016301), transferase activity (GO:0016740)

GO Cellular Component (6): nucleus (GO:0005634), nucleoplasm (GO:0005654), cytoplasm (GO:0005737), Golgi apparatus (GO:0005794), PML body (GO:0016605), chromosome, telomeric region (GO:0000781)

Reactome top-level categories

Rollup of top-7 pathways:

Category	Pathways
Regulation of TP53 Activity	2
DNA Double Strand Break Response	1
Regulation of TP53 Expression and Degradation	1
G2/M Checkpoints	1
p53-Dependent G1 DNA Damage Response	1
p53-Independent G1/S DNA Damage Checkpoint	1
G2/M DNA damage checkpoint	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
signal transduction in response to DNA damage	2
mitotic cell cycle	2
DNA-templated transcription	2
DNA damage response	2
protein kinase activity	2
intracellular membrane-bounded organelle	2
cellular anatomical structure	2
DNA integrity checkpoint signaling	1
mitotic cell cycle phase transition	1
cell cycle G2/M phase transition	1
DNA repair	1
regulation of gene expression	1
regulation of RNA biosynthetic process	1
phosphorylation	1
protein modification process	1
cellular response to stress	1
intrinsic apoptotic signaling pathway	1
macromolecule catabolic process	1
protein metabolic process	1
signal transduction by p53 class mediator	1
mitotic S phase	1
mitotic DNA damage checkpoint signaling	1
response to stress	1
cellular response to stimulus	1
regulation of catabolic process	1
protein catabolic process	1
regulation of protein metabolic process	1
intracellular signal transduction	1
intrinsic apoptotic signaling pathway in response to DNA damage	1
intrinsic apoptotic signaling pathway by p53 class mediator	1
DNA damage checkpoint signaling	1
mitotic DNA integrity checkpoint signaling	1
regulation of DNA-templated transcription	1
positive regulation of RNA biosynthetic process	1
protein phosphorylation	1
regulation of protein stability	1
cellular process	1
T cell apoptotic process	1
adenyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1

Protein interactions and networks

STRING

4210 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CHEK2	ATM	Q13315	999
CHEK2	BRCA1	P38398	997
CHEK2	TP53	P04637	992
CHEK2	RAD9A	Q99638	974
CHEK2	BRCA2	P51587	969
CHEK2	MDC1	Q14676	965
CHEK2	ATR	Q13535	955
CHEK2	TP53BP1	Q12888	951
CHEK2	CDC25A	P30304	949
CHEK2	PALB2	Q86YC2	919
CHEK2	CDC25C	P30307	919
CHEK2	H2AX	P16104	911
CHEK2	RAD51	Q06609	883
CHEK2	MSH6	P52701	866
CHEK2	BARD1	Q99728	864

IntAct

163 interactions, top by confidence:

A	B	Type	Score
TP63	TP73	psi-mi:“MI:0914”(association)	0.770
CHEK2	KPNA2	psi-mi:“MI:0915”(physical association)	0.730
KPNA2	CHEK2	psi-mi:“MI:0915”(physical association)	0.730
PLK1	CHEK2	psi-mi:“MI:0915”(physical association)	0.720
PLK1	CHEK2	psi-mi:“MI:0217”(phosphorylation reaction)	0.720
CHEK2	PLK1	psi-mi:“MI:0217”(phosphorylation reaction)	0.720
PLK1	CHEK2	psi-mi:“MI:0403”(colocalization)	0.720
CHEK2	CHEK2	psi-mi:“MI:0407”(direct interaction)	0.720
CHEK2	CHEK2	psi-mi:“MI:0217”(phosphorylation reaction)	0.720
CHEK2	PPP2R5A	psi-mi:“MI:0915”(physical association)	0.660
PPP2R5A	CHEK2	psi-mi:“MI:0407”(direct interaction)	0.660
CHEK2	MDM2	psi-mi:“MI:0915”(physical association)	0.660
CHEK2	MDM2	psi-mi:“MI:0407”(direct interaction)	0.660
MDM2	CHEK2	psi-mi:“MI:0407”(direct interaction)	0.660
MDM2	CHEK2	psi-mi:“MI:0217”(phosphorylation reaction)	0.660
MDM2	CHEK2	psi-mi:“MI:0915”(physical association)	0.660
CHEK2	TP53	psi-mi:“MI:0217”(phosphorylation reaction)	0.650

BioGRID (422): CHEK2 (Biochemical Activity), CHEK2 (Affinity Capture-MS), SIRT1 (Affinity Capture-Western), CCAR2 (Affinity Capture-Western), CHEK2 (Affinity Capture-Western), CHEK2 (Affinity Capture-Western), CHEK2 (Biochemical Activity), CDC25C (Biochemical Activity), PSME3 (Biochemical Activity), CHEK2 (Co-fractionation), CHEK2 (Co-fractionation), CHEK2 (Co-fractionation), BEX1 (Two-hybrid), CCL5 (Two-hybrid), CDH13 (Two-hybrid)

ESM2 similar proteins: A7MBL8, F1QGZ6, O14757, O35099, O35280, O35942, O54785, O54863, O54992, O96017, P45983, P45984, P49186, P49187, P51955, P53350, P53666, P53668, P53669, P53670, P53671, P53779, P62205, P70032, Q07832, Q14680, Q15835, Q28GW8, Q2RAX3, Q2TA25, Q32L23, Q3SZW1, Q61241, Q61831, Q61846, Q62673, Q63651, Q6DE87, Q6NU47, Q8AYC9

Diamond homologs: A0A8I3S724, A2VDZ4, A4IGM9, A5GFW1, A7SNN5, A8BPK8, A8X6H1, B2GUY1, B3DL84, B3M6I4, B3NE99, B4HBU3, B4IAQ8, B4J3F1, B4KYX8, B4LDJ6, B4MXR8, B4PDM5, B4QK53, D7UQM5, O00444, O14965, O15865, O43293, O44997, O54784, O55099, O59790, O64629, O70126, O80902, O88445, O88764, O96017, O97143, P05131, P05132, P05383, P0C8M8, P12370

SIGNOR signaling

103 interactions.

A	Effect	B	Mechanism
CHEK2	“up-regulates quantity by stabilization”	E2F1	phosphorylation
CHEK2	“down-regulates activity”	CDC25C	phosphorylation
CHEK2	“up-regulates activity”	CHEK2	phosphorylation
CHEK2	“down-regulates quantity by destabilization”	CDC25A	phosphorylation
CHEK2	up-regulates	BRCA1	phosphorylation
CHEK2	up-regulates	PPP2R5C	phosphorylation
TTK	up-regulates	CHEK2	phosphorylation
PRKDC	up-regulates	CHEK2	phosphorylation
CHEK2	down-regulates	MDM4	phosphorylation
CHEK2	up-regulates	FOXM1	phosphorylation
CHEK2	down-regulates	RASGRF1	phosphorylation
CHEK2	“up-regulates quantity by stabilization”	TP53	phosphorylation
CHEK2	“up-regulates activity”	RB1	phosphorylation
3-(carbamoylamino)-5-(3-fluorophenyl)-N-[(3S)-3-piperidinyl]-2-thiophenecarboxamide	down-regulates	CHEK2	“chemical inhibition”
SCHEMBL14517914	down-regulates	CHEK2	“chemical inhibition”
CHEK2	down-regulates	MAPT	phosphorylation
CHEK2	up-regulates	VHL	phosphorylation
CHEK2	“down-regulates quantity by destabilization”	MDM4	phosphorylation
CHEK2	up-regulates	XRCC1	phosphorylation
CHEK2	unknown	TTK	phosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 108 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
Platelet sensitization by LDL	6	49.8×	4e-07
Signaling by GSK3beta mutants	5	47.0×	2e-06
CTNNB1 S33 mutants aren’t phosphorylated	5	47.0×	2e-06
CTNNB1 S37 mutants aren’t phosphorylated	5	47.0×	2e-06
CTNNB1 S45 mutants aren’t phosphorylated	5	47.0×	2e-06
CTNNB1 T41 mutants aren’t phosphorylated	5	47.0×	2e-06
Co-inhibition by CTLA4	7	44.9×	8e-08
Beta-catenin phosphorylation cascade	5	41.5×	3e-06

GO biological processes:

GO term	Partners	Fold	FDR
double-strand break repair	8	16.4×	3e-05
regulation of cell cycle	9	6.8×	3e-03

Disease & clinical

Cancer significance

From intOGen — cancer-driver classification: activating (oncogene-like) across 1 cancer types — BRCA.

Clinical variants and AI predictions

ClinVar

4714 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	755
Likely pathogenic	254
Uncertain significance	2111
Likely benign	785
Benign	100

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1049247	NM_007194.4(CHEK2):c.1009-100_1095+3del	Pathogenic
1050237	NM_007194.4(CHEK2):c.793-110_846+2del	Pathogenic
1050248	NM_007194.4(CHEK2):c.1324del (p.Ser442fs)	Pathogenic
1068535	NM_007194.4(CHEK2):c.830T>A (p.Leu277Ter)	Pathogenic
1068559	NM_007194.4(CHEK2):c.349del (p.Arg117fs)	Pathogenic
1068607	NC_000022.10:g.(?29082731)(29138822_?)del	Pathogenic
1068608	NC_000022.10:g.(?29083885)(29130709_?)del	Pathogenic
1068609	NC_000022.10:g.(?29091105)(29091240_?)del	Pathogenic
1068727	NC_000022.10:g.(?29115373)(29121365_?)del	Pathogenic
1068846	NM_007194.4(CHEK2):c.664del (p.Met222fs)	Pathogenic
1069072	NM_007194.4(CHEK2):c.1362del (p.Val455fs)	Pathogenic
1069073	NM_007194.4(CHEK2):c.788_789del (p.Glu263fs)	Pathogenic
1069084	NM_007194.4(CHEK2):c.400_403del (p.Asp134fs)	Pathogenic
1069315	NM_007194.4(CHEK2):c.471del (p.Ile157fs)	Pathogenic
1069809	NM_007194.4(CHEK2):c.919G>T (p.Gly307Ter)	Pathogenic
1070086	NM_007194.4(CHEK2):c.1067_1077del (p.Leu355_Ser356insTer)	Pathogenic
1070237	NM_007194.4(CHEK2):c.664_676del (p.Met222fs)	Pathogenic
1070866	NC_000022.10:g.(?29090010)(29115483_?)del	Pathogenic
1070867	NC_000022.10:g.(?29105988)(29115479_?)del	Pathogenic
1070868	NC_000022.10:g.(?29099483)(29108015_?)del	Pathogenic
1070869	NC_000022.10:g.(?29083885)(29099564_?)del	Pathogenic
1070996	NM_007194.4(CHEK2):c.548del (p.Pro182_Leu183insTer)	Pathogenic
1071123	NM_007194.4(CHEK2):c.663_664insGGAGCAGGAAGTGGCGGTGCGAGGGCTGCTACACAGCGAGCGGAGCCGCGGTCCGGACGGCAGCGCGTGCCCCGAGCTCTCCGCNNNNNNNNNNAAAAAAAAAAAAAAAAAAAAGAGATGAATACATC (p.Met222fs)	Pathogenic
1071295	NM_007194.4(CHEK2):c.1420del (p.Arg474fs)	Pathogenic
1071596	NM_007194.4(CHEK2):c.33del (p.Gln11fs)	Pathogenic
1071738	NM_007194.4(CHEK2):c.222del (p.Pro75fs)	Pathogenic
1071801	NM_007194.4(CHEK2):c.1432G>T (p.Glu478Ter)	Pathogenic
1072210	NM_007194.4(CHEK2):c.1248del (p.Leu417fs)	Pathogenic
1072359	NM_007194.4(CHEK2):c.55del (p.Ser19fs)	Pathogenic
1072632	NM_007194.4(CHEK2):c.1264dup (p.Ser422fs)	Pathogenic

SpliceAI

4093 predictions. Top by Δscore:

Variant	Effect	Δscore
22:28689131:ATAC:A	donor_loss	1.0000
22:28689133:A:T	donor_loss	1.0000
22:28689134:C:CA	donor_loss	1.0000
22:28689214:TCCT:T	acceptor_loss	1.0000
22:28689215:CCTGT:C	acceptor_loss	1.0000
22:28689216:C:CC	acceptor_gain	1.0000
22:28689217:T:G	acceptor_loss	1.0000
22:28694118:C:CC	acceptor_gain	1.0000
22:28694130:T:TC	acceptor_gain	1.0000
22:28694140:C:CT	acceptor_gain	1.0000
22:28694142:CAG:C	acceptor_gain	1.0000
22:28694143:A:T	acceptor_gain	1.0000
22:28694144:G:GC	acceptor_gain	1.0000
22:28695244:T:C	acceptor_gain	1.0000
22:28695247:A:C	acceptor_gain	1.0000
22:28695250:T:TC	acceptor_gain	1.0000
22:28695253:G:C	acceptor_gain	1.0000
22:28695253:G:GC	acceptor_gain	1.0000
22:28696988:C:CC	acceptor_gain	1.0000
22:28699832:TTTTA:T	donor_loss	1.0000
22:28699833:TTTA:T	donor_loss	1.0000
22:28699834:TTA:T	donor_loss	1.0000
22:28699835:TA:T	donor_loss	1.0000
22:28699836:ACCTG:A	donor_loss	1.0000
22:28699837:CCTGC:C	donor_loss	1.0000
22:28699933:CCATC:C	acceptor_gain	1.0000
22:28699934:CATCC:C	acceptor_gain	1.0000
22:28699936:TC:T	acceptor_gain	1.0000
22:28699937:CC:C	acceptor_gain	1.0000
22:28711901:GTAC:G	donor_loss	1.0000

AlphaMissense

0 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000066689 (22:28734962 C>G), RS1000124286 (22:28717372 C>T), RS1000127010 (22:28734143 A>G), RS1000211096 (22:28716273 T>C), RS1000243736 (22:28716018 G>GC), RS1000274016 (22:28709935 T>C), RS1000447233 (22:28704679 C>G,T), RS1000459574 (22:28715689 G>A,C), RS1000460177 (22:28704425 C>T), RS1000485332 (22:28709394 A>G), RS1000490811 (22:28734377 T>A,C), RS1000492071 (22:28715296 C>T), RS1000702193 (22:28708273 G>A,C), RS1000727447 (22:28709618 T>A), RS1000749804 (22:28710269 A>G)

Disease associations

OMIM: gene MIM:604373 | disease phenotypes: MIM:114480, MIM:176807, MIM:613659, MIM:259500, MIM:114500, MIM:120435, MIM:604370, MIM:151623, MIM:609266, MIM:211980, MIM:612555, MIM:614954, MIM:219700

GenCC curated gene-disease

Disease	Classification	Inheritance
CHEK2-related cancer predisposition	Definitive	Autosomal dominant
Li-Fraumeni syndrome 2	Definitive	Autosomal dominant
hereditary breast carcinoma	Strong	Autosomal dominant
acute myeloid leukemia	Moderate	Autosomal dominant
hereditary nonpolyposis colon cancer	Limited	Unknown

ClinGen Gene-Disease Validity (3)

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

Disease	Classification	Inheritance
CHEK2-related cancer predisposition	Definitive	AD
familial ovarian cancer	Refuted	AD
hereditary nonpolyposis colon cancer	Limited	AD

Mondo (46): hereditary breast carcinoma (MONDO:0016419), hereditary neoplastic syndrome (MONDO:0015356), prostate cancer, hereditary (MONDO:0700275), breast cancer (MONDO:0007254), familial ovarian cancer (MONDO:0016248), CHEK2-related cancer predisposition (MONDO:0700271), hereditary breast ovarian cancer syndrome (MONDO:0003582), gastric cancer (MONDO:0001056), bone osteosarcoma (MONDO:0002629), colorectal cancer (MONDO:0005575), prostate cancer (MONDO:0008315), exocrine pancreatic carcinoma (MONDO:0005192), hereditary nonpolyposis colon cancer (MONDO:0018630), breast carcinoma (MONDO:0004989), breast-ovarian cancer, familial, susceptibility to, 1 (MONDO:0011450)

Orphanet (21): Hereditary breast cancer (Orphanet:227535), Inherited cancer-predisposing syndrome (Orphanet:140162), Familial prostate cancer (Orphanet:1331), Li-Fraumeni syndrome (Orphanet:524), Hereditary breast and/or ovarian cancer syndrome (Orphanet:145), Osteosarcoma (Orphanet:668), Familial pancreatic carcinoma (Orphanet:1333), Rare carcinoma of pancreas (Orphanet:217074), Hereditary nonpolyposis colon cancer (Orphanet:443909), Leiomyosarcoma (Orphanet:64720), Familial colorectal cancer Type X (Orphanet:440437), Lynch syndrome (Orphanet:144), Nephroblastoma (Orphanet:654), Adrenocortical carcinoma (Orphanet:1501), Cystic fibrosis (Orphanet:586)

HPO phenotypes

101 total (30 of 101 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000505	Visual impairment
HP:0000708	Atypical behavior
HP:0000716	Depression
HP:0000737	Irritability
HP:0000738	Hallucinations
HP:0000739	Anxiety
HP:0000944	Abnormal metaphysis morphology
HP:0001123	Visual field defect
HP:0001250	Seizure
HP:0001252	Hypotonia
HP:0001260	Dysarthria
HP:0001276	Hypertonia
HP:0001288	Gait disturbance
HP:0001371	Flexion contracture
HP:0001386	Joint swelling
HP:0001402	Hepatocellular carcinoma
HP:0001442	Typified by somatic mosaicism
HP:0001824	Weight loss
HP:0001909	Leukemia
HP:0001945	Fever
HP:0002017	Nausea and vomiting
HP:0002019	Constipation
HP:0002024	Malabsorption
HP:0002027	Abdominal pain
HP:0002076	Migraine
HP:0002167	Abnormal speech pattern
HP:0002239	Gastrointestinal hemorrhage
HP:0002354	Memory impairment
HP:0002376	Developmental regression

GWAS associations

48 associations (top):

Study	Trait	p-value
GCST000700_2	Vertical cup-disc ratio	1.000000e-08
GCST000777_4	Esophageal cancer and gastric cancer	1.000000e-08
GCST001585_24	Breast size	4.000000e-07
GCST001674_7	Esophageal cancer (squamous cell)	2.000000e-22
GCST001937_28	Breast cancer	3.000000e-09
GCST002466_2	Lung cancer	3.000000e-11
GCST002466_4	Lung cancer	1.000000e-13
GCST002553_2	Pancreatic cancer	1.000000e-08
GCST002568_9	Esophageal squamous cell carcinoma	4.000000e-07
GCST002626_15	Vertical cup-disc ratio	5.000000e-20
GCST002762_21	Optic cup area	1.000000e-17
GCST002762_6	Optic cup area	4.000000e-16
GCST004075_30	Vertical cup-disc ratio	5.000000e-21
GCST004075_31	Vertical cup-disc ratio	1.000000e-20
GCST004076_10	Optic disc area	2.000000e-09
GCST004076_24	Optic disc area	1.000000e-08
GCST004137_30	Optic cup area	1.000000e-18
GCST004137_45	Optic cup area	8.000000e-22
GCST004607_192	Plateletcrit	6.000000e-09
GCST004982_2	Prostate cancer	8.000000e-10
GCST004988_275	Breast cancer	1.000000e-08
GCST005312_20	Menopause (age at onset)	6.000000e-09
GCST006065_36	Glaucoma (primary open-angle)	2.000000e-11
GCST006804_171	Red cell distribution width	3.000000e-09
GCST009404_2	Optic cup area	2.000000e-19
GCST009411_6	Optic disc area	2.000000e-09
GCST009412_6	Vertical cup-disc ratio	5.000000e-25
GCST009462_4	Optic disc size	8.000000e-33
GCST009723_28	Vertical cup-disc ratio (adjusted for vertical disc diameter)	2.000000e-38
GCST009723_38	Vertical cup-disc ratio (adjusted for vertical disc diameter)	8.000000e-15

EFO canonical traits (12, from GWAS)

EFO ID	Trait name
EFO:0006939	cup-to-disc ratio measurement
EFO:0007985	platelet crit
EFO:0004704	age at menopause
EFO:0009188	Red cell distribution width
EFO:0004918	age at diagnosis
EFO:0005670	smoking initiation
EFO:0004251	myeloproliferative disorder
EFO:0004528	mean corpuscular hemoglobin concentration
EFO:0010701	mean reticulocyte volume
EFO:0004533	alkaline phosphatase measurement
EFO:0004532	serum gamma-glutamyl transferase measurement
EFO:0004736	aspartate aminotransferase measurement

MeSH disease descriptors (19)

Descriptor	Name	Tree numbers
D001254	Astrocytoma	C04.557.465.625.600.380.080; C04.557.470.670.380.080; C04.557.580.625.600.380.080
D001943	Breast Neoplasms	C04.588.180; C17.800.090.500
D003110	Colonic Neoplasms	C04.588.274.476.411.307.180; C06.301.371.411.307.180; C06.405.249.411.307.180; C06.405.469.158.356.180; C06.405.469.491.307.180
D003550	Cystic Fibrosis	C06.689.202; C08.381.187; C16.320.190; C16.614.213
D061325	Hereditary Breast and Ovarian Cancer Syndrome	C04.588.180.483; C04.588.322.455.431; C04.700.517; C12.050.351.500.056.630.705.431; C12.050.351.937.418.685.431; C12.100.250.056.630.705.431; C12.900.418.685.431; C16.320.700.517; C17.800.090.500.483; C19.344.410.431; C19.391.630.705.431
D007890	Leiomyosarcoma	C04.557.450.590.455; C04.557.450.795.455
D015470	Leukemia, Myeloid, Acute	C04.557.337.539.275; C15.378.508.539.275
D016864	Li-Fraumeni Syndrome	C04.700.600; C16.320.700.600; C18.452.284.520
D016403	Lymphoma, Large B-Cell, Diffuse	C04.557.386.480.150.585; C15.604.515.569.480.150.585; C20.683.515.761.480.150.585
D008545	Melanoma	C04.557.465.625.650.510; C04.557.580.625.650.510; C04.557.665.510; C04.588.805.377; C17.800.882.445
D009386	Neoplastic Syndromes, Hereditary	C04.700; C16.320.700
D016649	Primary Ovarian Insufficiency	C12.050.351.500.056.630.750; C12.100.250.056.630.750; C19.391.630.750
D011471	Prostatic Neoplasms	C04.588.945.440.770; C12.100.500.260.750; C12.100.500.565.625; C12.200.294.260.750; C12.200.294.565.625; C12.200.758.409.750; C12.900.619.750
D012509	Sarcoma	C04.557.450.795
D009396	Wilms Tumor	C04.557.435.595; C04.588.945.947.535.585; C04.700.900; C12.050.351.937.820.535.585; C12.050.351.968.419.473.585; C12.200.758.820.750.585; C12.200.777.419.473.585; C12.900.820.535.585; C12.950.419.473.585; C12.950.983.535.585; C16.320.700.900
C562840	Breast Cancer, Familial (supp.)
C563755	Li-Fraumeni Syndrome 2 (supp.)
C537261	Lynch syndrome I (site-specific colonic cancer) (supp.)
C537243	Prostate cancer, familial (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (2): CHEMBL2527 (SINGLE PROTEIN), CHEMBL3883296 (PROTEIN FAMILY)

Molecules with ChEMBL bioactivity

30 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 261,713 (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
CHEMBL180022	NERATINIB	4	9,404
CHEMBL288441	BOSUTINIB	4	12,255
CHEMBL3545311	BRIGATINIB	4	5,634
CHEMBL535	SUNITINIB	4	79,020
CHEMBL939	GEFITINIB	4	117,814
CHEMBL38380	FASUDIL	3	11,953
CHEMBL491473	CEDIRANIB	3	9,098
CHEMBL522892	DOVITINIB	3	4,944
CHEMBL603469	LESTAURTINIB	3
CHEMBL91829	RUBOXISTAURIN	3	77
CHEMBL103667	DORAMAPIMOD	2	1,681
CHEMBL1230609	FORETINIB	2	3,096
CHEMBL1721885	SU-014813	2	363
CHEMBL1967878	CENISERTIB	2	358
CHEMBL1980297	ILORASERTIB	2	581
CHEMBL2010872	CEP-11981	2	1,252
CHEMBL215152	DEFOSBARASERTIB	2	372
CHEMBL3544911	PREXASERTIB	2	699
CHEMBL513909	BI-2536	2	895
CHEMBL574737	UCN-01	2	2,217
CHEMBL1084546	PF-00562271	1
CHEMBL1908397	KW-2449	1
CHEMBL1980391	RG-1530	1
CHEMBL259084	MLN-8054	1
CHEMBL3128043	PF-03758309	1
CHEMBL4169078	SRA-737	1
CHEMBL482767	SNS-314	1
CHEMBL482967	CYC-116	1
CHEMBL494089	GSK-690693	1
CHEMBL574738	AST-487	1

Clinical evidence (CIViC)

Drug × variant × indication: 2 predictive associations from 2 curated evidence items; also 5 predisposing, 1 functional, 1 prognostic.

Variant	Therapy	Indication	Effect	Level	CIViC
CHEK2 mutation	Olaparib	Castration-resistant Prostate Carcinoma	Sensitivity/Response	CIViC A	EID11205
CHEK2 mutation	Enzalutamide + Talazoparib	Castration-resistant Prostate Carcinoma	Sensitivity/Response	CIViC B	EID11737

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

GtoPdb / IUPHAR curated pharmacology

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

Target class: enzyme — CHK1 subfamily

Most potent curated ligand interactions (10 total), top 10:

Ligand	Action	Affinity	Parameter
CCT241533	Inhibition	8.52	pIC50
prexasertib	Inhibition	8.1	pIC50
AZD7762	Inhibition	8.0	pIC50
compound 25b [PMID: 22564207]	Inhibition	7.54	pIC50
Chk2 inhibitor II	Inhibition	7.43	pKi
PF-477736	Inhibition	7.33	pIC50
CDK inhibitor 4.35	Inhibition	6.28	pIC50
7-hydroxystaurosporine	Inhibition	5.98	pIC50
CCT245737	Inhibition	5.61	pIC50
isogranulatimide	Inhibition	5.52	pIC50

Binding affinities (BindingDB)

14 measured of 45 human assays (45 total across all organisms); most potent 14 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
Preparation of(S)-4-azaspiro[2.5]octan-6-amine	IC50	55 nM	US-20250188059: NOVEL COMPOUND AND USE THEREOF FOR INHIBITING CHECKPOINT KINASE 2
(S)-3-amino-6-(2-fluoro-5-(1-(2,2,2- trifluoroethyl)-1H-pyrazol-4- yl)phenyl)-N-(4-azaspiro[2.5]octan-6- yl)pyrazine-2-carboxamide	IC50	55 nM	US-20250188059: NOVEL COMPOUND AND USE THEREOF FOR INHIBITING CHECKPOINT KINASE 2
3-amino-6-(2-fluoro-5-(1-(2,2,2- trifluoroethyl)-1H-pyrazol-4- yl)phenyl)-N-((3S,5S)-5- fluoropiperidin-3-yl) pyrazine-2-carboxamide	IC50	55 nM	US-20250188059: NOVEL COMPOUND AND USE THEREOF FOR INHIBITING CHECKPOINT KINASE 2
3-amino-6-(2-fluoro-5-(1-(2,2,2- trifluoroethyl)-1H-pyrazol-4- yl)phenyl)-N-((3R,4R)-4- hydroxypiperidin-3-yl) pyrazine-2-carboxamide	IC50	55 nM	US-20250188059: NOVEL COMPOUND AND USE THEREOF FOR INHIBITING CHECKPOINT KINASE 2
3-amino-6-(2-fluoro-5-(1-(2,2,2- trifluoroethyl)-1H-pyrazol-4- yl)phenyl)-N-((3R,4R)-4- hydroxypyrrolidin-3-yl) pyrazine-2-carboxamide	IC50	55 nM	US-20250188059: NOVEL COMPOUND AND USE THEREOF FOR INHIBITING CHECKPOINT KINASE 2
3-amino-6-(5-(5,5-dimethyl-5,6-dihydro- 4H-pyrrolo[1,2-b]pyrazol-3-yl)-2- fluorophenyl)-N-((3R,4R)-4- hydroxypiperidine-3-yl) pyrazine-2-carboxamide	IC50	55 nM	US-20250188059: NOVEL COMPOUND AND USE THEREOF FOR INHIBITING CHECKPOINT KINASE 2
3-amino-6-(3-(5,5-dimethyl-5,6-dihydro- 4H-pyrrolo[1,2-b]pyrazol-3-yl)phenyl)-N- ((3R,4R)-4-hydroxypiperidine-3- yl)pyrazine-2-carboxamide	IC50	55 nM	US-20250188059: NOVEL COMPOUND AND USE THEREOF FOR INHIBITING CHECKPOINT KINASE 2
3-amino-6-(2-(5,5-dimethyl-5,6-dihydro- 4H-pyrrolo[1,2-b]pyrazol-3-yl)pyridin-4- yl)-N-((3R,4R)-4-hydroxypiperidin-3- yl)pyrazine-2-carboxamide	IC50	55 nM	US-20250188059: NOVEL COMPOUND AND USE THEREOF FOR INHIBITING CHECKPOINT KINASE 2
3-amino-6-(5-(5,5-dimethyl-5,6-dihydro- 4H-pyrrolo[1,2-b]pyrazol-3-yl)-2- hydroxyphenyl)-N-((3R,4R)-4- hydroxypyrrolidin-3-yl)pyrazine-2- carboxamide	IC50	55 nM	US-20250188059: NOVEL COMPOUND AND USE THEREOF FOR INHIBITING CHECKPOINT KINASE 2
3-amino-6-(3-(5,5-dimethyl-5,6-dihydro- 4H-pyrrolo[1,2-b]pyrazol-3-yl)phenyl)-N- ((3S,4S)-4-fluoropyrrolidin-3-yl) pyrazine-2-carboxamide	IC50	55 nM	US-20250188059: NOVEL COMPOUND AND USE THEREOF FOR INHIBITING CHECKPOINT KINASE 2
2-arylbenzimidazole	IC50	100 nM
DDUG	IC50	200 nM
(4Z)-4-(2-amino-5-oxo-3,5-dihydro-4H-imidazol-4-ylidene)-4,5,6,7-tetrahydropyrrolo[2,3-c]azepin-8(1H)-one	IC50	420 nM
(S)-3-amino-N-(5,5-difluoropiperidin- 3-yl)-6-(2-(1-(2,2,2-trifluoroethyl)- 1H-pyrazol-4-yl)pyridin-4- yl)pyrazine-2-carboxamide	IC50	550 nM	US-20250188059: NOVEL COMPOUND AND USE THEREOF FOR INHIBITING CHECKPOINT KINASE 2

ChEMBL bioactivities

880 potent at pChembl≥5 of 951 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
9.20	Ki	0.631	nM	CHEMBL1988594
8.90	Ki	1.259	nM	TAE-684
8.80	Ki	1.585	nM	CHEMBL1970203
8.70	IC50	2	nM	CHEMBL195041
8.70	IC50	2	nM	CHEMBL5812190
8.64	IC50	2.3	nM	CHEMBL195041
8.60	Ki	2.512	nM	CENISERTIB
8.52	IC50	3	nM	CHEMBL179717
8.52	IC50	3	nM	CHEMBL195177
8.52	IC50	3	nM	CHEMBL3980850
8.52	Ki	3	nM	PF-03758309
8.52	IC50	3	nM	CHEMBL1236782
8.50	Ki	3.162	nM	CHEMBL1980144
8.48	IC50	3.34	nM	STAUROSPORINE
8.47	IC50	3.4	nM	CHEMBL195177
8.44	IC50	3.6	nM	CHEMBL6165880
8.40	IC50	4	nM	CHEMBL359881
8.40	IC50	4	nM	CHEMBL3958697
8.40	IC50	4	nM	CHEMBL3894962
8.40	IC50	4	nM	CHEMBL3949796
8.40	IC50	4	nM	CHEMBL3935794
8.36	IC50	4.4	nM	CHEMBL359881
8.35	IC50	4.5	nM	CHEMBL179717
8.31	IC50	4.86	nM	STAUROSPORINE
8.30	IC50	5	nM	CHEMBL175553
8.30	IC50	5	nM	CHEMBL3917001
8.30	IC50	5	nM	CHEMBL3956891
8.30	IC50	5	nM	CHEMBL3904143
8.30	IC50	5	nM	CHEMBL3947096
8.30	IC50	5	nM	CHEMBL3933085
8.30	IC50	5	nM	CHEMBL3930129
8.30	IC50	5	nM	CHEMBL1650128
8.29	IC50	5.1	nM	CHEMBL5176837
8.26	IC50	5.5	nM	CHEMBL175553
8.26	IC50	5.5	nM	CHEMBL4072515
8.26	IC50	5.56	nM	CHEMBL4159805
8.26	IC50	5.55	nM	CHEMBL4171617
8.25	IC50	5.6	nM	BRIGATINIB
8.24	IC50	5.72	nM	STAUROSPORINE
8.22	IC50	6	nM	CHEMBL3916197
8.22	IC50	6	nM	CHEMBL3909679
8.22	IC50	6	nM	CHEMBL3931376
8.20	IC50	6.28	nM	STAUROSPORINE
8.19	IC50	6.5	nM	BRIGATINIB
8.18	IC50	6.6	nM	CHEMBL193990
8.17	IC50	6.7	nM	STAUROSPORINE
8.16	IC50	6.9	nM	CHEMBL4093249
8.15	IC50	7	nM	CHEMBL192161
8.15	IC50	7	nM	CHEMBL191969
8.15	IC50	7	nM	CHEMBL193990

PubChem BioAssay actives

396 with measured affinity, of 2312 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
2-[4-(4-hydroxyphenyl)sulfanylphenyl]-3H-benzimidazole-5-carboxamide	310503: Inhibition of human recombinant Chk2	ic50	0.0020	uM
4-fluoro-2-[4-[[(3S,4R)-4-(2-hydroxypropan-2-yl)pyrrolidin-3-yl]amino]-6,7-dimethoxyquinazolin-2-yl]phenol	566343: Inhibition of CHK2 by DELFIA assay	ic50	0.0030	uM
N-[(1S)-2-(dimethylamino)-1-phenylethyl]-6,6-dimethyl-3-[(2-methylthieno[3,2-d]pyrimidin-4-yl)amino]-1,4-dihydropyrrolo[3,4-d]pyrazole-5-carboxamide	2167980: Inhibition of human CHK2 assessed as inhibition constant in presence of ATP	ki	0.0030	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	627128: Inhibition of CHK2 using biotinylated substrate preincubated for 15 mins before substrate addition measured after 30 mins by fluorescence microplate analysis	ic50	0.0033	uM
2-[4-[(3,4-dichlorophenyl)sulfamoyl]phenyl]-3H-benzimidazole-5-carboxamide	241478: Inhibition of recombinant human Chk2 kinase	ic50	0.0034	uM
2-[4-(3-chloro-4-methylphenoxy)phenyl]-3H-benzimidazole-5-carboxamide	241478: Inhibition of recombinant human Chk2 kinase	ic50	0.0044	uM
2-[4-[4-chloro-3-(trifluoromethyl)phenoxy]phenyl]-3H-benzimidazole-5-carboxamide	241478: Inhibition of recombinant human Chk2 kinase	ic50	0.0045	uM
4-fluoro-2-[4-[[(3S,4R)-4-(2-hydroxypropan-2-yl)pyrrolidin-3-yl]amino]-6-methoxy-7-(2-methoxyethoxy)quinazolin-2-yl]phenol	566343: Inhibition of CHK2 by DELFIA assay	ic50	0.0050	uM
6-[7-methoxy-6-(1-methylpyrazol-4-yl)imidazo[1,2-a]pyridin-3-yl]-N-pyrrolidin-3-ylpyridin-2-amine	1894586: Inhibition of CHK2 (unknown origin)	ic50	0.0051	uM
2-[4-(3,4-dichlorophenoxy)phenyl]-3H-benzimidazole-5-carboxamide	241478: Inhibition of recombinant human Chk2 kinase	ic50	0.0055	uM
N-benzyl-2-[4-(3-methyl-4-nitro-1-phenylpyrazol-5-yl)oxyphenyl]-3H-benzimidazole-5-carboxamide	1452627: Inhibition of Chk2 (unknown origin) by ELISA based spectrophotometric analysis	ic50	0.0055	uM
ethyl 2-[4-[4-(6-carbamoyl-1H-benzimidazol-2-yl)phenyl]sulfanyl-6-(4-chlorophenyl)-5-cyanopyrimidin-2-yl]sulfanylacetate	1353280: Inhibition of Chk2 (unknown origin) assessed as decrease in Cdc25C phosphorylation at Ser216 by ELISA based spectrophotometric analysis	ic50	0.0056	uM
2-[4-[5-cyano-2-(2-ethoxy-2-oxoethyl)sulfanyl-6-(4-fluorophenyl)pyrimidin-4-yl]oxyphenyl]-3H-benzimidazole-5-carboxylic acid	1353280: Inhibition of Chk2 (unknown origin) assessed as decrease in Cdc25C phosphorylation at Ser216 by ELISA based spectrophotometric analysis	ic50	0.0056	uM
Brigatinib	2182800: Inhibition of human CHEK2 I157T mutant using KKKVSRSGLYRSPSMPENLNRPR as substrate in presence of [gamma33P]-ATP by HotSpot assay	ic50	0.0056	uM
2-[4-(4-chlorophenyl)sulfonylphenyl]-3H-benzimidazole-5-carboxamide	241478: Inhibition of recombinant human Chk2 kinase	ic50	0.0066	uM
N-cyclohexyl-2-[4-(3-methyl-4-nitro-1-phenylpyrazol-5-yl)oxyphenyl]-3H-benzimidazole-5-carboxamide	1452627: Inhibition of Chk2 (unknown origin) by ELISA based spectrophotometric analysis	ic50	0.0069	uM
1-[5-chloro-2-[(3-methyloxetan-3-yl)methoxy]phenyl]-3-(5-cyanopyrazin-2-yl)urea	241131: Inhibition of Serine/threonine-protein kinase Chk2	ic50	0.0070	uM
Sunitinib	507875: Binding affinity to CHEK2	kd	0.0071	uM
5-(2-amino-4-hydroxy-1H-imidazol-5-yl)-3,4-dihydro-2H-azepino[3,4-b]indol-1-one	1924350: Inhibition of Chk2 (unknown origin)	ic50	0.0080	uM
2-[4-[[(3S,4R)-4-(2-hydroxypropan-2-yl)pyrrolidin-3-yl]amino]quinazolin-2-yl]-4-(1H-pyrazol-5-yl)phenol	566343: Inhibition of CHK2 by DELFIA assay	ic50	0.0080	uM
5-[[5-[2-(3-aminopropoxy)-6-methoxyphenyl]-1H-pyrazol-3-yl]amino]pyrazine-2-carbonitrile	1872306: Inhibition of CHK2 (unknown origin)	ic50	0.0080	uM
2-[4-(4-chlorophenyl)sulfanylphenyl]-3H-benzimidazole-5-carboxamide	241478: Inhibition of recombinant human Chk2 kinase	ic50	0.0082	uM
4-(1H-pyrazol-5-yl)-2-[4-[[(3S)-pyrrolidin-3-yl]amino]quinazolin-2-yl]phenol	566343: Inhibition of CHK2 by DELFIA assay	ic50	0.0090	uM
2-[4-(4-chloro-3-hydroxyphenoxy)phenyl]-3H-benzimidazole-5-carboxamide	241478: Inhibition of recombinant human Chk2 kinase	ic50	0.0098	uM
3-(carbamoylamino)-5-(3-fluorophenyl)-N-[(3S)-piperidin-3-yl]thiophene-2-carboxamide	677585: Inhibition of CHK2	ic50	0.0100	uM
2-[4-[4-[(E)-[(4-methoxyphenyl)hydrazinylidene]methyl]-3-methyl-1-phenylpyrazol-5-yl]oxyphenyl]-1H-benzimidazole-5-carboxylic acid	1351720: Inhibition of Chk2 (unknown origin) by spectrophotometric analysis	ic50	0.0100	uM
(2S,3R,4R,6R,18S)-18-hydroxy-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	501668: Inhibition of CHK2	ic50	0.0100	uM
4-fluoro-2-[7-(2-methoxyethoxy)-4-[[(3S)-pyrrolidin-3-yl]amino]quinazolin-2-yl]phenol	566343: Inhibition of CHK2 by DELFIA assay	ic50	0.0110	uM
4-fluoro-2-[4-[[(3S,4R)-4-(hydroxymethyl)pyrrolidin-3-yl]amino]-6,7-dimethoxyquinazolin-2-yl]phenol	566343: Inhibition of CHK2 by DELFIA assay	ic50	0.0110	uM
2-[4-[4-[(E)-(carbamoylhydrazinylidene)methyl]-3-methyl-1-phenylpyrazol-5-yl]oxyphenyl]-3H-benzimidazole-5-carboxamide	1351720: Inhibition of Chk2 (unknown origin) by spectrophotometric analysis	ic50	0.0111	uM
[(E)-[3-methyl-5-[4-(6-nitro-1H-benzimidazol-2-yl)phenoxy]-1-phenylpyrazol-4-yl]methylideneamino]thiourea	1351720: Inhibition of Chk2 (unknown origin) by spectrophotometric analysis	ic50	0.0115	uM
N-[(E)-[3-methyl-5-[4-(6-nitro-1H-benzimidazol-2-yl)phenoxy]-1-phenylpyrazol-4-yl]methylideneamino]aniline	1351720: Inhibition of Chk2 (unknown origin) by spectrophotometric analysis	ic50	0.0117	uM
2-[4-(3,4-dimethylphenoxy)phenyl]-3H-benzimidazole-5-carboxamide	241478: Inhibition of recombinant human Chk2 kinase	ic50	0.0120	uM
2-[4-[2-fluoro-5-(trifluoromethyl)phenoxy]phenyl]-3H-benzimidazole-5-carboxamide	241478: Inhibition of recombinant human Chk2 kinase	ic50	0.0120	uM
2-(4-naphthalen-2-yloxyphenyl)-3H-benzimidazole-5-carboxamide	241478: Inhibition of recombinant human Chk2 kinase	ic50	0.0120	uM
2-[6,7-dimethoxy-4-[[(3S)-pyrrolidin-3-yl]amino]quinazolin-2-yl]-4-fluorophenol	566343: Inhibition of CHK2 by DELFIA assay	ic50	0.0120	uM
2-[4-[4-[(E)-(carbamothioylhydrazinylidene)methyl]-3-methyl-1-phenylpyrazol-5-yl]oxyphenyl]-3H-benzimidazole-5-carboxylic acid	1351720: Inhibition of Chk2 (unknown origin) by spectrophotometric analysis	ic50	0.0129	uM
2-[4-(4-chlorophenyl)sulfinylphenyl]-3H-benzimidazole-5-carboxamide	241478: Inhibition of recombinant human Chk2 kinase	ic50	0.0130	uM
5-(4-anilinoanilino)-N’-(1-hydroxypropan-2-yl)-3-oxo-1,2-thiazole-4-carboximidamide	273728: Inhibition of CHK2	ic50	0.0130	uM
2-[4-[(4-chlorophenyl)sulfamoyl]phenyl]-3H-benzimidazole-5-carboxamide	241478: Inhibition of recombinant human Chk2 kinase	ic50	0.0140	uM
2-[4-[[1-[(4-chlorophenyl)methyl]piperidin-3-yl]methoxy]phenyl]-3H-benzimidazole-5-carboxamide	310503: Inhibition of human recombinant Chk2	ic50	0.0140	uM
(4Z)-4-(2-amino-5-oxo-1H-imidazol-4-ylidene)-2-(3,4-dimethoxyphenyl)-1,5,6,7-tetrahydropyrrolo[2,3-c]azepin-8-one	1924350: Inhibition of Chk2 (unknown origin)	ic50	0.0140	uM
(4Z)-4-(2-amino-5-oxo-1H-imidazol-4-ylidene)-2-(4-methoxyphenyl)-1,5,6,7-tetrahydropyrrolo[2,3-c]azepin-8-one	644377: Inhibition of human Chk2 using STK1 as substrate after 10 mins by HTRF assay	ic50	0.0140	uM
2-[4-[[(3S,4R)-4-(2-hydroxypropan-2-yl)pyrrolidin-3-yl]amino]quinazolin-2-yl]-4-(1H-pyrazol-4-yl)phenol	566343: Inhibition of CHK2 by DELFIA assay	ic50	0.0140	uM
N-methyl-2-[4-(3-methyl-4-nitro-1-phenylpyrazol-5-yl)oxyphenyl]-3H-benzimidazole-5-carboxamide	1452627: Inhibition of Chk2 (unknown origin) by ELISA based spectrophotometric analysis	ic50	0.0149	uM
2-[4-(4-chlorophenoxy)phenyl]-3H-benzimidazole-5-carboxamide	241478: Inhibition of recombinant human Chk2 kinase	ic50	0.0150	uM
2-[4-[(5-cyano-6-phenyl-2-sulfanylidene-1H-pyrimidin-4-yl)oxy]phenyl]-3H-benzimidazole-5-carboxylic acid	1353280: Inhibition of Chk2 (unknown origin) assessed as decrease in Cdc25C phosphorylation at Ser216 by ELISA based spectrophotometric analysis	ic50	0.0154	uM
2-[4-(3-chlorophenoxy)phenyl]-3H-benzimidazole-5-carboxamide	241478: Inhibition of recombinant human Chk2 kinase	ic50	0.0170	uM
2-[4-(3-methyl-4-nitro-1-phenylpyrazol-5-yl)oxyphenyl]-N-propan-2-yl-3H-benzimidazole-5-carboxamide	1452627: Inhibition of Chk2 (unknown origin) by ELISA based spectrophotometric analysis	ic50	0.0179	uM
2-[4-(phenylsulfamoyl)phenyl]-3H-benzimidazole-5-carboxamide	241478: Inhibition of recombinant human Chk2 kinase	ic50	0.0180	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Cisplatin	decreases reaction, increases phosphorylation, affects reaction, decreases response to substance, increases expression (+2 more)	10
2-morpholin-4-yl-6-thianthren-1-yl-pyran-4-one	decreases reaction, increases phosphorylation, increases reaction, increases expression, increases activity (+2 more)	8
bisphenol A	increases phosphorylation, decreases reaction, affects cotreatment, decreases expression, decreases methylation (+1 more)	7
Resveratrol	increases phosphorylation, increases reaction, affects cotreatment, increases activity, increases expression (+1 more)	7
Doxorubicin	decreases expression, decreases reaction, increases phosphorylation, increases reaction, increases activity (+1 more)	7
Caffeine	decreases reaction, increases phosphorylation, affects cotreatment, increases activity, increases reaction (+1 more)	6
sodium arsenite	decreases expression, increases abundance, affects binding, decreases phosphorylation, affects reaction (+3 more)	5
Acetylcysteine	decreases reaction, increases expression, increases phosphorylation, increases reaction	5
Arsenic Trioxide	increases expression, increases activity, increases phosphorylation, increases reaction, affects cotreatment	4
Camptothecin	increases expression, increases phosphorylation, decreases reaction	4
usnic acid	decreases reaction, increases expression	3
Hydroxyurea	increases expression, increases phosphorylation	3
trichostatin A	affects cotreatment, decreases expression	2
2-chloroethyl ethyl sulfide	increases phosphorylation, decreases reaction, affects reaction	2
diacetyldiphenylurea bisguanylhydrazone	decreases reaction, increases expression, decreases activity	2
3-amino-6-(4-(methylsulfonyl)phenyl)-N-phenylpyrazine-2-carboxamide	affects response to substance, decreases expression, decreases reaction, increases phosphorylation	2
Wortmannin	decreases reaction, increases phosphorylation, decreases phosphorylation	2
Temozolomide	increases phosphorylation, affects cotreatment, decreases reaction	2
Silybin	decreases reaction, increases phosphorylation	2
Arsenic	affects phosphorylation, affects reaction, affects response to substance, decreases phosphorylation, increases abundance	2
Ascorbic Acid	increases expression, decreases reaction, increases phosphorylation	2
Benzo(a)pyrene	decreases expression	2
Cannabidiol	decreases expression, affects cotreatment	2
Copper	affects binding, decreases expression, increases phosphorylation	2
Etoposide	decreases reaction, increases phosphorylation	2
Floxuridine	increases activity, increases phosphorylation	2
Hydrogen Peroxide	decreases reaction, increases phosphorylation, increases reaction	2
Metribolone	affects cotreatment, increases phosphorylation	2
Aphidicolin	decreases phosphorylation, increases activity, increases phosphorylation, increases reaction	2
Cadmium Chloride	increases abundance, increases expression, increases phosphorylation	2

ChEMBL screening assays

690 unique, capped per target: 687 binding, 2 functional, 1 admet

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1000634	Binding	Inhibition of CHK2 at 1 uM relative to control	Novel potent BRAF inhibitors: toward 1 nM compounds through optimization of the central phenyl ring. — J Med Chem
CHEMBL1963720	Functional	PUBCHEM_BIOASSAY: Navigating the Kinome. (Class of assay: other) Panel member name: CHEK2	PubChem BioAssay data set
CHEMBL4407583	ADMET	Inhibition of recombinant human full-length His-tagged CHEK2 expressed in baculovirus expression system at 25 uM using FRET-labeled Ser/Thr 07 peptide as substrate measured after 1 hr by Z’-lyte assay relative to control	Optimization and Mechanistic Characterization of Pyridopyrimidine Inhibitors of Bacterial Biotin Carboxylase. — J Med Chem

Cellosaurus cell lines

20 cell lines: 14 cancer cell line, 3 induced pluripotent stem cell, 1 telomerase immortalized cell line, 1 finite cell line, 1 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_0292	HCT 15	Cancer cell line	Male
CVCL_1R50	OS 187	Cancer cell line	Male
CVCL_4Y02	HCT 15-Luc#1	Cancer cell line	Male
CVCL_5400	VACO 400	Cancer cell line	Male
CVCL_A4BZ	HCT-15-Luc2	Cancer cell line	Male
CVCL_A7KT	ZNHi001-A	Induced pluripotent stem cell	Male
CVCL_A7KU	ZNHi001-B	Induced pluripotent stem cell	Male
CVCL_B1NC	Abcam HeLa CHEK2 KO	Cancer cell line	Female
CVCL_B2ME	Abcam A-549 CHEK2 KO	Cancer cell line	Male
CVCL_C3K5	N/Tert-1 CHEK2	Telomerase immortalized cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00199147	PHASE4	UNKNOWN	Efficacy of G-CSF-Priming in Elderly AML Patients
NCT00304447	PHASE4	COMPLETED	Study Evaluating the Effect of Corticosteroids on Mylotarg® Infusion-Related Adverse Events in Patients With Leukemia
NCT00464217	PHASE4	COMPLETED	Treatment of the Acute Myeloblastic Leukaemia in Patients Over 65 Years
NCT00487448	PHASE4	COMPLETED	SMD_FLAG-IDA_98: FLAG-IDA in Induction Treatment of High Risk Myelodysplastic Syndromes or Secondary Acute Myeloblastic Leukemia
NCT00488709	PHASE4	COMPLETED	Fludarabine, Cytarabine, Topotecan in Treating Patients With Relapsed or Refractory Acute Myeloid Leukemia
NCT00686543	PHASE4	COMPLETED	Oral Posaconazole in High Risk Patients With Gastrointestinal Dysfunction (Study P05115)
NCT01041040	PHASE4	COMPLETED	LAM07: Study to Analyze the Efficacy of a Risk Adapted Treatment Strategy, Including Gemtuzumab Ozogamicin (GO) During Consolidation, for Patients With Acute Myeloid Leukemia (AML)
NCT01198054	PHASE4	TERMINATED	LENA-LMA-5:Lenalidomide in Acute Myeloid Leukemia (AML)
NCT01200355	PHASE4	COMPLETED	Posaconazole Versus Micafungin for Prophylaxis Against Invasive Fungal Infections During Neutropenia in Patients Undergoing Chemotherapy for Acute Myelogenous Leukemia, Acute Lymphocytic Leukemia or Myelodysplastic Syndrome
NCT01347996	PHASE4	COMPLETED	Maintenance Therapy With Ceplene® (Histamine) and IL-2 on Immune Response and MRD in Acute Myeloid Leukemia
NCT01587430	PHASE4	UNKNOWN	3 Anthracyclines, 2 Types of Consolidation With Different ARA-C Doses and Maintenance in Adult Acute Myeloid Leukemia
NCT01819792	PHASE4	COMPLETED	Respiratory Viral Infections During Acute Myeloid Leukemia (AML)Chemotherapy Related Aplasia
NCT02024308	PHASE4	UNKNOWN	AML1-ETO Acute Myeloid Leukemia With Fludarabine and Cytarabine Chemotherapy
NCT02027064	PHASE4	UNKNOWN	Interferon for the Intervention of Molecular Relapse in t (8; 21) AML After Allo-HSCT
NCT02277847	PHASE4	UNKNOWN	Idarubicin at Different Dosages as Induction Therapy for Newly Diagnosed Acute Myeloid Leukaemia
NCT02386800	PHASE4	ACTIVE_NOT_RECRUITING	CINC424A2X01B Rollover Protocol
NCT02926586	PHASE4	COMPLETED	Fludarabine and Cytarabine Versus High-dose Cytarabine for CBF-AML
NCT02933333	PHASE4	UNKNOWN	G-CSF Alone or Combination With GM-CSF on Prevention and Treatment of Infection in Children With Malignant Tumor
NCT03026842	PHASE4	UNKNOWN	Decitabine Versus Conventional Chemotherapy for Maintenance Therapy of Acute Myeloid Leukemia With t(8;21)
NCT03150134	PHASE4	UNKNOWN	Early Tapering of Immunosuppressive Agents to Immunomodulation to Improve Survival of AML Patients
NCT05144243	PHASE4	ACTIVE_NOT_RECRUITING	Study to Assess Adverse Events and Change in Disease State of Oral Venetoclax in Combination With Subcutaneous (SC) Azacitidine in Newly Diagnosed Adult Participants With Acute Myeloid Leukemia (AML) Who Are Ineligible for Intensive Chemotherapy in China
NCT06370000	PHASE4	RECRUITING	Oral Azacitidine in Transplant-Eligible Patients With Acute Myeloid Leukemia (AML) Suffering From Health-Inequality
NCT06571825	PHASE4	RECRUITING	RIC Allo-HSCT vs. Venetoclax-Based Consolidation in Elderly AML Patients After First CR
NCT07016165	PHASE4	RECRUITING	Ciprofloxacin vs Ceftazidime for Empirical Treatment of High-Risk Neutropenic Fever in Children With Hematologic Malignancies
NCT07044687	PHASE4	RECRUITING	Study to Assess Adverse Events and Change in Disease Activity of Oral Venetoclax in Combination With Subcutaneous (SC) or Intravenous (IV) Azacitidine in Newly Diagnosed Adult Participants With Acute Myeloid Leukemia (AML) Who Are Ineligible for Standard Induction Therapy in India
NCT07486713	PHASE4	RECRUITING	Olutasidenib DDI Study in Patients With IDH1 Mutation Positive Malignancies
NCT07561892	PHASE4	RECRUITING	Study of the Effectiveness and Safety of Daunorubicin /Idarubicin ± Silibinin in Treating Newly Diagnosed AML (Non-M3).
NCT00014638	PHASE4	COMPLETED	Letrozole in Treating Postmenopausal Women With Metastatic Breast Cancer
NCT00022386	PHASE4	COMPLETED	Epoetin Alfa in Treating Chemotherapy-Related Anemia in Women With Stage I, Stage II, or Stage III Breast Cancer
NCT00029224	PHASE4	COMPLETED	Treatment With Zoledronic Acid in Patients With Breast Cancer, Multiple Myeloma, and Prostate Cancer With Cancer Related Bone Lesions
NCT00030758	PHASE4	UNKNOWN	Filgrastim or Pegfilgrastim in Preventing Neutropenia in Women Receiving Chemotherapy Following Surgery for Breast Cancer
NCT00082277	PHASE4	COMPLETED	Anastrozole Biphosphonate Study in Postmenopausal Women With Hormone-Receptor-Positive Early Breast Cancer
NCT00087620	PHASE4	TERMINATED	A Study of Capecitabine In Combination With Docetaxel vs Capecitabine Followed by Docetaxel As First-Line Treatment For Metastatic Breast Cancer
NCT00121836	PHASE4	COMPLETED	A Study of Xeloda (Capecitabine) in Women With HER2-Negative Metastatic Breast Cancer
NCT00126360	PHASE4	UNKNOWN	STARS Breast Trial (Study of Anastrozole and Radiotherapy Sequencing Pilot)
NCT00127933	PHASE4	COMPLETED	XeNA Study - A Study of Xeloda (Capecitabine) in Patients With Invasive Breast Cancer
NCT00128297	PHASE4	COMPLETED	Pamidronate Administration in Breast Cancer Patients With Bone Metastases
NCT00129597	PHASE4	UNKNOWN	Effect of Ketalar to Prevent Postoperative Chronic Pain After Mastectomy
NCT00131170	PHASE4	COMPLETED	Paravertebral Block for Breast Surgery
NCT00156039	PHASE4	COMPLETED	Randomized Trial of Follow-up Strategies in Breast Cancer