CHEK1

Summary

CHEK1 (checkpoint kinase 1, HGNC:1925) is a protein-coding gene on chromosome 11q24.2, encoding Serine/threonine-protein kinase Chk1 (O14757). Serine/threonine-protein kinase which is required for checkpoint-mediated cell cycle arrest and activation of DNA repair in response to the presence of DNA damage or unreplicated DNA. In precision oncology, CHEK1 Mutation confers sensitivity to Olaparib in Castration-resistant Prostate Carcinoma (CIViC Level A); 1 further curated variant–drug associations are listed below. It is a common-essential gene (DepMap: required in 99.9% of cancer cell lines).

The protein encoded by this gene belongs to the Ser/Thr protein kinase family. It is required for checkpoint mediated cell cycle arrest in response to DNA damage or the presence of unreplicated DNA. This protein acts to integrate signals from ATM and ATR, two cell cycle proteins involved in DNA damage responses, that also associate with chromatin in meiotic prophase I. Phosphorylation of CDC25A protein phosphatase by this protein is required for cells to delay cell cycle progression in response to double-strand DNA breaks. Several alternatively spliced transcript variants have been found for this gene.

Source: NCBI Gene 1111 — RefSeq curated summary.

At a glance

• Gene–disease (curated): familial ovarian cancer (No Known Disease Relationship, ClinGen) — +1 more curated relationship
• GWAS associations: 2
• Clinical variants (ClinVar): 111 total — 4 pathogenic, 1 likely-pathogenic
• Phenotypes (HPO): 4
• Druggable target: yes — 36 molecules with ChEMBL bioactivity
• Precision-oncology evidence (CIViC): 2 curated variant–drug associations
• Cancer dependency (DepMap): dependent in 99.9% of screened cell lines (common-essential)
• Dosage sensitivity (ClinGen): haploinsufficiency no evidence, triplosensitivity no evidence
• MANE Select transcript: NM_001114122

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:1925
Approved symbol	CHEK1
Name	checkpoint kinase 1
Location	11q24.2
Locus type	gene with protein product
Status	Approved
Aliases	CHK1
Ensembl gene	ENSG00000149554
Ensembl biotype	protein_coding
OMIM	603078
Entrez	1111

Gene structure

Transcript identifiers

Ensembl transcripts: 24 — 21 protein_coding, 2 nonsense_mediated_decay, 1 retained_intron

ENST00000278916, ENST00000427383, ENST00000428830, ENST00000438015, ENST00000524737, ENST00000525396, ENST00000526937, ENST00000527013, ENST00000531062, ENST00000531607, ENST00000532449, ENST00000532669, ENST00000534070, ENST00000534685, ENST00000544373, ENST00000711049, ENST00000902656, ENST00000902657, ENST00000902658, ENST00000918645, ENST00000918646, ENST00000918647, ENST00000918648, ENST00000918649

RefSeq mRNA: 6 — MANE Select: NM_001114122 NM_001114121, NM_001114122, NM_001244846, NM_001274, NM_001330427, NM_001330428

CCDS: CCDS58191, CCDS81645, CCDS8459

Canonical transcript exons

ENST00000438015 — 13 exons

Exon	Start	End
ENSE00002198063	125655225	125657147
ENSE00002201597	125625163	125626012
ENSE00003490088	125644512	125644643
ENSE00003526480	125626749	125626833
ENSE00003559569	125653746	125653847
ENSE00003563982	125629232	125629296
ENSE00003580463	125644091	125644268
ENSE00003717945	125643792	125643900
ENSE00003731018	125627607	125627830
ENSE00003732867	125635429	125635533
ENSE00003746244	125629391	125629460
ENSE00003784684	125633163	125633351
ENSE00003788390	125637449	125637544

Expression profiles

Bgee: expression breadth ubiquitous, 210 present calls, max score 98.72.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 14.0108 / max 614.8629, expressed in 1598 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter ID	TPM avg	Samples expressed
117458	9.2963	1221
117459	2.7658	1080
117460	1.0861	526
117461	0.4371	186
117457	0.4254	234

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
secondary oocyte	CL:0000655	98.72	gold quality
oocyte	CL:0000023	98.40	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	94.54	gold quality
ventricular zone	UBERON:0003053	94.06	gold quality
ganglionic eminence	UBERON:0004023	91.22	gold quality
embryo	UBERON:0000922	90.47	gold quality
buccal mucosa cell	CL:0002336	85.77	silver quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	85.44	gold quality
seminal vesicle	UBERON:0000998	84.11	gold quality
stromal cell of endometrium	CL:0002255	81.27	gold quality
rectum	UBERON:0001052	81.13	gold quality
bone marrow	UBERON:0002371	80.60	gold quality
colonic epithelium	UBERON:0000397	79.25	gold quality
vermiform appendix	UBERON:0001154	79.25	gold quality
bone marrow cell	CL:0002092	78.62	gold quality
mucosa of transverse colon	UBERON:0004991	78.54	gold quality
bone element	UBERON:0001474	75.85	gold quality
lymph node	UBERON:0000029	75.40	gold quality
right testis	UBERON:0004534	75.36	gold quality
cortical plate	UBERON:0005343	75.29	gold quality
esophagus mucosa	UBERON:0002469	75.16	gold quality
popliteal artery	UBERON:0002250	75.12	gold quality
testis	UBERON:0000473	75.07	gold quality
tibial artery	UBERON:0007610	75.06	gold quality
adrenal tissue	UBERON:0018303	73.98	gold quality
left testis	UBERON:0004533	73.91	gold quality
caecum	UBERON:0001153	73.40	gold quality
aorta	UBERON:0000947	72.85	gold quality
body of pancreas	UBERON:0001150	72.72	gold quality
smooth muscle tissue	UBERON:0001135	72.62	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	13.87
E-MTAB-6108	no	57.95

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): BCL6, CREB1, E2F1, E2F2, E2F4, EZH2, FOXM1, MYC, TLX1, TP53

miRNA regulators (miRDB)

120 targeting CHEK1, 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-4795-3P	100.00	74.62	4024
HSA-MIR-188-3P	100.00	68.76	1240
HSA-MIR-6740-5P	100.00	65.64	932
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-4531	99.99	69.70	3181
HSA-MIR-4534	99.99	66.58	1907
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-19A-3P	99.98	75.33	2762
HSA-MIR-19B-3P	99.98	75.44	2754
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-5688	99.96	73.23	4504
HSA-MIR-495-3P	99.96	72.81	4197
HSA-MIR-548AT-5P	99.96	70.83	2666
HSA-MIR-497-5P	99.92	71.83	2674
HSA-MIR-338-5P	99.92	72.34	2951
HSA-MIR-1297	99.91	73.41	3162
HSA-MIR-16-5P	99.90	72.80	2780
HSA-MIR-195-5P	99.90	72.81	2805
HSA-MIR-15A-5P	99.90	72.80	2787
HSA-MIR-15B-5P	99.90	72.78	2798
HSA-MIR-3671	99.90	73.04	3897
HSA-MIR-424-5P	99.89	71.90	2641
HSA-MIR-6838-5P	99.89	71.94	2690
HSA-MIR-153-5P	99.89	73.86	6317
HSA-MIR-6857-5P	99.87	65.32	985
HSA-MIR-383-3P	99.85	65.84	1359
HSA-MIR-629-3P	99.85	67.99	1875
HSA-MIR-4307	99.82	70.45	3374
HSA-MIR-2052	99.79	69.37	2031

Functional genomics

ClinGen dosage: haploinsufficiency 0 (no evidence), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map DepMap (CRISPR cell-line fitness): dependent in 99.9% of screened cell lines, common-essential.

Literature-anchored findings (GeneRIF, showing 40)

• utilization of peptide library analyses to develop specific, highly preferred substrate motifs for hCds1/Chk2 and Chk1 (PMID:11821419)
• radiation induced phosphotylation of chK1 is associated with p53-dependent cell cycle arrest pathways in tumor (PMID:11896572)
• An ATM-independent S-phase checkpoint response involves CHK1 pathway. (PMID:11912127)
• role in mediating G(2)M checkpoint in relation to the cellular resistance to the novel topoisomerase I poison BNP1350 (PMID:12150968)
• findings indicate that Chk1 directly phosphorylates Cdc25A during an unperturbed cell cycle, and that phosphorylation of Cdc25A by Chk1 is required for cells to delay cell cycle progression in response to double-strand DNA breaks (PMID:12399544)
• Data suggest that the UVC-induced S checkpoint response of inhibition of replicon initiation is mediated by ATR signaling through Chk-1 and is independent of ATM, Nbs1, and Mre11. (PMID:12446774)
• Chk1 is phosphorylated by ATM and NBS1 and is essential for ionizing radiation-induced inhibition of DNA synthesis and the G(2)/M checkpoint (PMID:12588868)
• targets tousled like kinasese via DNA damage checkpoint (PMID:12660173)
• CHK1 regulates the S phase checkpoint by coupling the physiological turnover and ionizing radiation-induced accelerated proteolysis of Cdc25A. (PMID:12676583)
• Chk1 mediates both S and G2 checkpoint and is thus a more ubiquitous cell cycle checkpoint mediator than previously thought (PMID:12676925)
• Chk1 protein complexes bind to single-stranded DNA and DNA ends and has a role in the repair of double strand breaks (PMID:12756247)
• the G2 checkpoint in irradiated human cells derives from an overactivation of the ATR/CHK1 pathway. (PMID:12791699)
• Chk1 expression is dispensable for somatic cell death and critical for sustaining G2 DNA damage checkpoint (PMID:12813133)
• we show that Chk1 is essential for the suppression of TLK activity after replication block, but that ATR, Chk2 and BRCA1 are dispensable for TLK suppression. (PMID:12955071)
• hyperoxia activates the ATR-Chk1 pathway and phosphorylates p53 at multiple sites in an ATM-independent manner, which is different from other forms of oxidative stress such as H2O2 or UV light. (PMID:12959929)
• Data report the isolation and characterization of the 5’ flanking region of the Chk1 gene, and show that this region has promoter activity. (PMID:14504477)
• Data suggest that the Chk1/Cdc25A/14-3-3 pathway functions to prevent cells from entering into mitosis prior to replicating their genomes to ensure the fidelity of the cell division process. (PMID:14559997)
• Chk1 is a novel Hsp90 client with a role in sensitization of tumor cells to replication stress (PMID:14570880)
• data reveal the very different mode of regulation between CHK1 and CHK2 (PMID:14681223)
• CHEK1 interacts with XIAP protein during mitosis. (PMID:14759516)
• The transient slow-down of DNA synthesis was abolished in cells lacking ATR, whereas CHK1-siRNA-treated cells, NBS1 or Fanconi anemia cells showed partial S-phase arrest. (PMID:14988723)
• Brca1 and Chk1 are regulated by MCPH1 during DNA damage in tumor cell lines (PMID:15220350)
• Formation of a stable complex between protein kinase CK2beta and Chk1 is not affected by the modification of Thr213 but it does require the presence of an active Chk1 kinase. (PMID:15225637)
• the Chk1 pathway involves claspin, which functions in checkpoint control [review] (PMID:15279790)
• results suggest that centrosome-associated Chk1 shields centrosomal Cdk1 from unscheduled activation by cytoplasmic Cdc25B, thereby contributing to proper timing of the initial steps of cell division, including mitotic spindle formation. (PMID:15311285)
• These data further emphasise the role of Chk1 as a molecular target to inhibit in tumors with a defect in the G(1) checkpoint with the aim of increasing the selectivity and specificity of anticancer drug treatments. (PMID:15326376)
• CHK1 inactivation in non-hodgkin’s lymphoma occurs by loss of protein expression in a subset of aggressive variants alternatively to ATM, CHK2, and p53 alterations (PMID:15526025)
• role of Chk1 in maintaining tumor cell viability following activation of the replication checkpoint (PMID:15539958)
• Chk1 and Chk2 control the induction of the p53 related transcription factor p73 in response to DNA damage. (PMID:15601819)
• Chk1 and Chk2 have roles in mismatch repair-dependent G2 arrest (PMID:15647386)
• results indicate that the different radiosensitivities & G(2)checkpoint responses are independent of NHEJ, suggesting that CHK1-regulated checkpoint facilitates homologous recombination repair & protects cells from ionizing radiation-induced killing (PMID:15655357)
• possible interplay between tumor protein p53 C-terminal phosphorylation and acetylation, and they provide an additional mechanism for the control of the activity of p53 by Checkpoint kinase 1 and Checkpoint kinase 2 (PMID:15659650)
• Chk1 downregulation can not only potentiate DNA-damaging agents, but also enhance the toxicity of anti-microtubule agents. (PMID:15688426)
• Results show that the ATR/checkpoint kinase 1 pathway plays a predominant role in the response to topoisomerase I inhibitors in carcinoma cells. (PMID:15699047)
• Expression of Chk1 blunted induction of gammaH2AX foci by Cdk inhibitors, indicating that Chk1 down-regulation was necessary to elicit the full phenotype. (PMID:15705874)
• loss of PTEN and subsequent activation of AKT impair CHK1 through phosphorylation, ubiquitination, and reduced nuclear localization to promote genomic instability in tumor cells (PMID:15710331)
• ATR phosphorylates Chk1 in cells expressing only a mutant of ATRIP that does not bind to RPA-ssDNA. (PMID:15743907)
• Chk1 is required during normal S phase to avoid aberrantly increased initiation of DNA replication, thereby protecting against DNA breakage. (PMID:15831461)
• results of the present study suggest existence of a checkpoint kinase 1-dependent mechanism for diallyl trisulfide-induced mitotic arrest in human prostate cancer cells (PMID:15961392)
• Synthetized inhibitors are synthetically tractable and inhibit Chk1 by competing for its ATP site. (PMID:15974586)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	chek1	ENSDARG00000104765
mus_musculus	Chek1	ENSMUSG00000032113
rattus_norvegicus	Chek1	ENSRNOG00000071217
drosophila_melanogaster	grp	FBGN0261278

Protein

Protein identifiers

Serine/threonine-protein kinase Chk1 — O14757 (reviewed: O14757)

Alternative names: CHK1 checkpoint homolog, Cell cycle checkpoint kinase, Checkpoint kinase-1

All UniProt accessions (8): O14757, A0A087WT52, E7EPP6, E9PJI4, E9PKQ3, E9PPA5, E9PQW7, E9PRU7

UniProt curated annotations — full annotation on UniProt →

Function. Serine/threonine-protein kinase which is required for checkpoint-mediated cell cycle arrest and activation of DNA repair in response to the presence of DNA damage or unreplicated DNA. May also negatively regulate cell cycle progression during unperturbed cell cycles. This regulation is achieved by a number of mechanisms that together help to preserve the integrity of the genome. Recognizes the substrate consensus sequence [R-X-X-S/T]. Binds to and phosphorylates CDC25A, CDC25B and CDC25C. Phosphorylation of CDC25A at ‘Ser-178’ and ‘Thr-507’ and phosphorylation of CDC25C at ‘Ser-216’ creates binding sites for 14-3-3 proteins which inhibit CDC25A and CDC25C. Phosphorylation of CDC25A at ‘Ser-76’, ‘Ser-124’, ‘Ser-178’, ‘Ser-279’ and ‘Ser-293’ promotes proteolysis of CDC25A. Phosphorylation of CDC25A at ‘Ser-76’ primes the protein for subsequent phosphorylation at ‘Ser-79’, ‘Ser-82’ and ‘Ser-88’ by NEK11, which is required for polyubiquitination and degradation of CDCD25A. Inhibition of CDC25 leads to increased inhibitory tyrosine phosphorylation of CDK-cyclin complexes and blocks cell cycle progression. Also phosphorylates NEK6. Binds to and phosphorylates RAD51 at ‘Thr-309’, which promotes the release of RAD51 from BRCA2 and enhances the association of RAD51 with chromatin, thereby promoting DNA repair by homologous recombination. Phosphorylates multiple sites within the C-terminus of TP53, which promotes activation of TP53 by acetylation and promotes cell cycle arrest and suppression of cellular proliferation. Also promotes repair of DNA cross-links through phosphorylation of FANCE. Binds to and phosphorylates TLK1 at ‘Ser-743’, which prevents the TLK1-dependent phosphorylation of the chromatin assembly factor ASF1A. This may enhance chromatin assembly both in the presence or absence of DNA damage. May also play a role in replication fork maintenance through regulation of PCNA. May regulate the transcription of genes that regulate cell-cycle progression through the phosphorylation of histones. Phosphorylates histone H3.1 (to form H3T11ph), which leads to epigenetic inhibition of a subset of genes. May also phosphorylate RB1 to promote its interaction with the E2F family of transcription factors and subsequent cell cycle arrest. Phosphorylates SPRTN, promoting SPRTN recruitment to chromatin. Reduces replication stress and activates the G2/M checkpoint, by phosphorylating and inactivating PABIR1/FAM122A and promoting the serine/threonine-protein phosphatase 2A-mediated dephosphorylation and stabilization of WEE1 levels and activity. Endogenous repressor of isoform 1, interacts with, and antagonizes CHK1 to promote the S to G2/M phase transition.

Subunit / interactions. Interacts (phosphorylated by ATR) with RAD51. Interacts with and phosphorylates CLSPN, an adapter protein that regulates the ATR-dependent phosphorylation of CHEK1. Interacts with BRCA1. Interacts with and phosphorylates CDC25A, CDC25B and CDC25C. Interacts with FBXO6, which regulates CHEK1. Interacts with PPM1D, which regulates CHEK1 through dephosphorylation. Interacts with TIMELESS; DNA damage-dependent. Interacts with FEM1B; activates CHEK1 in response to stress. Interacts with TLK1. Interacts with XPO1 and YWHAZ. Interacts with CDK5RAP3; antagonizes CHEK1. Interacts with KRCC1; the interaction promotes CHEK1 phosphorylation at Ser-296. Isoform 1 associates with isoform 2, the interaction is disrupted upon phosphorylation by ATR.

Subcellular location. Nucleus. Chromosome. Cytoplasm. Cytoskeleton. Microtubule organizing center. Centrosome.

Tissue specificity. Expressed ubiquitously with the most abundant expression in thymus, testis, small intestine and colon.

Post-translational modifications. Phosphorylated by ATR in a RAD17-dependent manner in response to ultraviolet irradiation and inhibition of DNA replication. Phosphorylated by ATM in response to ionizing irradiation. ATM and ATR can both phosphorylate Ser-317 and Ser-345 and this results in enhanced kinase activity. Phosphorylation at Ser-345 induces a change in the conformation of the protein, activates the kinase activity and is a prerequisite for interaction with FBXO6 and subsequent ubiquitination at Lys-436. Phosphorylation at Ser-345 also increases binding to 14-3-3 proteins and promotes nuclear retention. Conversely, dephosphorylation at Ser-345 by PPM1D may contribute to exit from checkpoint mediated cell cycle arrest. Phosphorylation at Ser-280 by AKT1/PKB, may promote mono and/or diubiquitination. Also phosphorylated at undefined residues during mitotic arrest, resulting in decreased activity. Ubiquitinated. Mono or diubiquitination promotes nuclear exclusion. The activated form (phosphorylated on Ser-345) is polyubiquitinated at Lys-436 by some SCF-type E3 ubiquitin ligase complex containing FBXO6 promoting its degradation. Ubiquitination and degradation are required to terminate the checkpoint and ensure that activated CHEK1 does not accumulate as cells progress through S phase, when replication forks encounter transient impediments during normal DNA replication. ‘Lys-63’-mediated ubiquitination by TRAF4 at Lys-132 activates cell cycle arrest and activation of DNA repair. Proteolytically cleaved at the C-terminus by SPRTN during normal DNA replication, thereby promoting CHEK1 removal from chromatin and activating the protein kinase activity.

Disease relevance. Oocyte/zygote/embryo maturation arrest 21 (OZEMA21) [MIM:620610] An autosomal dominant, female infertility disorder characterized by zygote development arrest due to failure of pronuclei fusion. The disease is caused by variants affecting the gene represented in this entry.

Activity regulation. Activated through phosphorylation predominantly by ATR but also by ATM in response to DNA damage or inhibition of DNA replication. Activation is modulated by several mediators including CLSPN, BRCA1 and FEM1B. Proteolytic cleavage at the C-terminus by SPRTN during normal DNA replication activates the protein kinase activity.

Domain organisation. The autoinhibitory region (AIR) inhibits the activity of the kinase domain.

Similarity. Belongs to the protein kinase superfamily. CAMK Ser/Thr protein kinase family. NIM1 subfamily.

Isoforms (3)

UniProt ID	Names	Canonical?
O14757-1	1	yes
O14757-2	2, Chk1-short, Chk1-S
O14757-3	3

RefSeq proteins (6): NP_001107593, NP_001107594, NP_001231775, NP_001265, NP_001317356, NP_001317357 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000719	Prot_kinase_dom	Domain
IPR008271	Ser/Thr_kinase_AS	Active_site
IPR011009	Kinase-like_dom_sf	Homologous_superfamily
IPR017441	Protein_kinase_ATP_BS	Binding_site
IPR034670	Chk1_catalytic_dom	Domain

Pfam: PF00069

Enzyme classification (BRENDA):

• EC 2.7.11.1 — non-specific serine/threonine protein kinase (BRENDA: 71 organisms, 682 substrates, 228 inhibitors, 23 Km, 6 kcat entries)

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 (88 total): strand 18, helix 17, mutagenesis site 16, modified residue 9, sequence variant 7, turn 4, region of interest 3, splice variant 3, sequence conflict 3, cross-link 2, binding site 2, chain 1, domain 1, compositionally biased region 1, active site 1

Structure

Experimental structures (PDB)

164 structures, top 30 by resolution.

PDB	Method	Resolution (Å)
2YEX	X-RAY DIFFRACTION	1.3
9CE4	X-RAY DIFFRACTION	1.31
4HYI	X-RAY DIFFRACTION	1.4
3PA3	X-RAY DIFFRACTION	1.4
5OQ5	X-RAY DIFFRACTION	1.4
3OT3	X-RAY DIFFRACTION	1.44
7SUF	X-RAY DIFFRACTION	1.48
7SUG	X-RAY DIFFRACTION	1.48
8E80	X-RAY DIFFRACTION	1.49
5OPB	X-RAY DIFFRACTION	1.55
5OPU	X-RAY DIFFRACTION	1.55
8SIX	X-RAY DIFFRACTION	1.55
3PA4	X-RAY DIFFRACTION	1.59
2YDI	X-RAY DIFFRACTION	1.6
3TKI	X-RAY DIFFRACTION	1.6
6FC8	X-RAY DIFFRACTION	1.61
8E81	X-RAY DIFFRACTION	1.62
3OT8	X-RAY DIFFRACTION	1.65
7MCK	X-RAY DIFFRACTION	1.65
10HZ	X-RAY DIFFRACTION	1.67
1IA8	X-RAY DIFFRACTION	1.7
1ZYS	X-RAY DIFFRACTION	1.7
2HY0	X-RAY DIFFRACTION	1.7
2QHN	X-RAY DIFFRACTION	1.7
3PA5	X-RAY DIFFRACTION	1.7
4HYH	X-RAY DIFFRACTION	1.7
5OOP	X-RAY DIFFRACTION	1.7
10IA	X-RAY DIFFRACTION	1.74
1ZLT	X-RAY DIFFRACTION	1.74
4QYG	X-RAY DIFFRACTION	1.75

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O14757-F1	77.04	0.45

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): 130 (proton acceptor)

Ligand- & substrate-binding residues (2): 15–23; 38

Post-translational modifications (11): 286, 296, 301, 317, 331, 345, 467, 468, 132, 436, 280

Mutagenesis-validated functional residues (16):

Position	Phenotype
38	abolishes kinase activity.
130	abolishes kinase activity.
132	strong reduction of chromatin-associated chk1 ubiquitination.
317	abrogates interaction with rad51; when associated with a-345. reduces phosphorylation and impairs activation by hydroxyu
317	enhances interaction with rad51; when associated with e-345.
344	impairs nuclear export.
345	abrogates interaction with rad51; when associated with a-317. reduces phosphorylation and impairs activation by hydroxyu
345	enhances interaction with rad51; when associated with e-317.
353	impairs nuclear export.
357	no effect on phosphorylation induced by hydroxyurea.
366	no effect on phosphorylation induced by hydroxyurea.
372	in 3re mutant. disrupts the folding and/or conformation, allowing increased accessibility to fbxo6 component of scf-type
376	in 3re mutant. disrupts the folding and/or conformation, allowing increased accessibility to fbxo6 component of scf-type
379	in 3re mutant. disrupts the folding and/or conformation, allowing increased accessibility to fbxo6 component of scf-type
436	enhances stability of the protein, probably by preventing ubiquitination at this site.
468	no effect on phosphorylation induced by hydroxyurea.

Function

Pathways and Gene Ontology

Reactome pathways

10 pathways

ID	Pathway
R-HSA-1433557	Signaling by SCF-KIT
R-HSA-176187	Activation of ATR in response to replication stress
R-HSA-5693607	Processing of DNA double-strand break ends
R-HSA-5693616	Presynaptic phase of homologous DNA pairing and strand exchange
R-HSA-6796648	TP53 Regulates Transcription of DNA Repair Genes
R-HSA-6804756	Regulation of TP53 Activity through Phosphorylation
R-HSA-69473	G2/M DNA damage checkpoint
R-HSA-69601	Ubiquitin-Mediated Degradation of Phosphorylated Cdc25A
R-HSA-75035	Chk1/Chk2(Cds1) mediated inactivation of Cyclin B:Cdk1 complex
R-HSA-8953750	Transcriptional Regulation by E2F6

MSigDB gene sets: 474 (showing top): PID_FANCONI_PATHWAY, GOBP_REGULATION_OF_DOUBLE_STRAND_BREAK_REPAIR, SA_G2_AND_M_PHASES, GOBP_REGULATION_OF_DNA_RECOMBINATION, RODRIGUES_THYROID_CARCINOMA_ANAPLASTIC_UP, GOBP_EMBRYO_DEVELOPMENT_ENDING_IN_BIRTH_OR_EGG_HATCHING, RODRIGUES_THYROID_CARCINOMA_POORLY_DIFFERENTIATED_UP, GOBP_REGULATION_OF_NUCLEAR_DIVISION, BIOCARTA_ATM_PATHWAY, TGCTGCT_MIR15A_MIR16_MIR15B_MIR195_MIR424_MIR497, FISCHER_G1_S_CELL_CYCLE, GOBP_CELLULAR_RESPONSE_TO_EXTERNAL_STIMULUS, CROONQUIST_NRAS_SIGNALING_DN, REACTOME_G2_M_DNA_DAMAGE_CHECKPOINT, GOBP_CELL_CYCLE_PHASE_TRANSITION

GO Biological Process (30): DNA damage checkpoint signaling (GO:0000077), G2/M transition of mitotic cell cycle (GO:0000086), inner cell mass cell proliferation (GO:0001833), DNA replication (GO:0006260), DNA repair (GO:0006281), chromatin remodeling (GO:0006338), protein phosphorylation (GO:0006468), apoptotic process (GO:0006915), DNA damage response (GO:0006974), nucleus organization (GO:0006997), mitotic G2 DNA damage checkpoint signaling (GO:0007095), regulation of double-strand break repair via homologous recombination (GO:0010569), peptidyl-threonine phosphorylation (GO:0018107), regulation of cell population proliferation (GO:0042127), signal transduction in response to DNA damage (GO:0042770), mitotic G2/M transition checkpoint (GO:0044818), positive regulation of cell cycle (GO:0045787), negative regulation of gene expression, epigenetic (GO:0045814), negative regulation of mitotic nuclear division (GO:0045839), regulation of mitotic centrosome separation (GO:0046602), negative regulation of G0 to G1 transition (GO:0070317), cellular response to mechanical stimulus (GO:0071260), replicative senescence (GO:0090399), regulation of signal transduction by p53 class mediator (GO:1901796), apoptotic process involved in development (GO:1902742), nuclear envelope organization (GO:0006998), mitotic nuclear membrane disassembly (GO:0007077), regulation of gene expression (GO:0010468), positive regulation of G2/M transition of mitotic cell cycle (GO:0010971), negative regulation of cell cycle phase transition (GO:1901988)

GO Molecular Function (10): protein kinase activity (GO:0004672), protein serine/threonine kinase activity (GO:0004674), ATP binding (GO:0005524), protein domain specific binding (GO:0019904), histone H3T11 kinase activity (GO:0035402), protein serine kinase activity (GO:0106310), nucleotide binding (GO:0000166), protein binding (GO:0005515), kinase activity (GO:0016301), transferase activity (GO:0016740)

GO Cellular Component (13): chromatin (GO:0000785), condensed nuclear chromosome (GO:0000794), obsolete extracellular space (GO:0005615), nucleus (GO:0005634), nucleoplasm (GO:0005654), replication fork (GO:0005657), cytoplasm (GO:0005737), centrosome (GO:0005813), cytosol (GO:0005829), protein-containing complex (GO:0032991), chromosome, telomeric region (GO:0000781), chromosome (GO:0005694), cytoskeleton (GO:0005856)

Reactome top-level categories

Rollup of top-9 pathways:

Category	Pathways
G2/M Checkpoints	2
Signaling by Receptor Tyrosine Kinases	1
HDR through Homologous Recombination (HRR) or Single Strand Annealing (SSA)	1
Homologous DNA Pairing and Strand Exchange	1
Transcriptional Regulation by TP53	1
Regulation of TP53 Activity	1
p53-Independent G1/S DNA Damage Checkpoint	1
G2/M DNA damage checkpoint	1
Generic Transcription Pathway	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	5
cell population proliferation	2
DNA metabolic process	2
DNA damage response	2
protein kinase activity	2
chromosome	2
intracellular membraneless organelle	2
DNA integrity checkpoint signaling	1
signal transduction in response to DNA damage	1
mitotic cell cycle	1
mitotic cell cycle phase transition	1
cell cycle G2/M phase transition	1
blastocyst growth	1
DNA biosynthetic process	1
chromatin organization	1
phosphorylation	1
protein modification process	1
programmed cell death	1
apoptotic signaling pathway	1
execution phase of apoptosis	1
cellular response to stress	1
organelle organization	1
mitotic G2 phase	1
mitotic DNA damage checkpoint signaling	1
mitotic G2/M transition checkpoint	1
regulation of DNA recombination	1
double-strand break repair via homologous recombination	1
regulation of double-strand break repair	1
protein phosphorylation	1
peptidyl-threonine modification	1
regulation of cellular process	1
intracellular signal transduction	1
mitotic cell cycle checkpoint signaling	1
negative regulation of G2/M transition of mitotic cell cycle	1
cell cycle	1
positive regulation of cellular process	1
regulation of cell cycle	1
negative regulation of gene expression	1
epigenetic regulation of gene expression	1
regulation of mitotic nuclear division	1

Protein interactions and networks

STRING

4300 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CHEK1	CLSPN	Q9HAW4	998
CHEK1	ATM	Q13315	975
CHEK1	RAD51	Q06609	973
CHEK1	TIMELESS	Q9UNS1	972
CHEK1	BRCA1	P38398	965
CHEK1	RAD17	O75943	955
CHEK1	ATR	Q13535	947
CHEK1	CDC25A	P30304	944
CHEK1	CDC25C	P30307	939
CHEK1	RAD9A	Q99638	930
CHEK1	ATRIP	Q8WXE1	927
CHEK1	HUS1	O60921	924
CHEK1	TOPBP1	Q92547	917
CHEK1	CDC45	O75419	914
CHEK1	TP53	P04637	906

IntAct

181 interactions, top by confidence:

A	B	Type	Score
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
CHEK1	YWHAG	psi-mi:“MI:0915”(physical association)	0.700
YWHAG	CHEK1	psi-mi:“MI:0915”(physical association)	0.700
CHEK1	YWHAG	psi-mi:“MI:0407”(direct interaction)	0.700
CHEK1	YWHAB	psi-mi:“MI:0915”(physical association)	0.670
HSP90AB1	CHEK1	psi-mi:“MI:0915”(physical association)	0.660
CHEK1	HSP90AB1	psi-mi:“MI:0915”(physical association)	0.660
YWHAG	BLTP3B	psi-mi:“MI:0914”(association)	0.640
IL13RA2	CHEK1	psi-mi:“MI:0914”(association)	0.640
CDC25C	CHEK1	psi-mi:“MI:0217”(phosphorylation reaction)	0.620
CHEK1	SMURF1	psi-mi:“MI:0915”(physical association)	0.610
SMURF1	CHEK1	psi-mi:“MI:0915”(physical association)	0.610
CHEK1	SMURF1	psi-mi:“MI:0407”(direct interaction)	0.610
CHEK1	SMURF1	psi-mi:“MI:0217”(phosphorylation reaction)	0.610
CLSPN	CHEK1	psi-mi:“MI:0217”(phosphorylation reaction)	0.600
CLSPN	CHEK1	psi-mi:“MI:0915”(physical association)	0.600
CHEK1	CLSPN	psi-mi:“MI:0915”(physical association)	0.600
YWHAH	BLTP3B	psi-mi:“MI:0914”(association)	0.570
CHEK1	TP53	psi-mi:“MI:2364”(proximity)	0.570
TP53	CHEK1	psi-mi:“MI:0217”(phosphorylation reaction)	0.570
HLA-DRB5	CHEK1	psi-mi:“MI:0914”(association)	0.560

BioGRID (458): CHEK1 (Biochemical Activity), CHEK1 (Affinity Capture-Western), CHEK1 (Affinity Capture-Western), CHEK1 (Biochemical Activity), LATS2 (Biochemical Activity), FUS (Affinity Capture-MS), CHEK1 (Affinity Capture-MS), CHEK1 (Affinity Capture-MS), CHEK1 (Affinity Capture-MS), CHEK1 (Affinity Capture-MS), CHEK1 (Affinity Capture-MS), CHEK1 (Affinity Capture-MS), CHEK1 (Affinity Capture-MS), CHEK1 (Co-fractionation), CHEK1 (Co-fractionation)

ESM2 similar proteins: A0A8I3NFE2, A0JM59, A2RT67, A5PK16, A5PN09, A7Z056, D3YZI9, D7PF45, F1QGZ6, O14757, O15357, O35710, O81360, P36195, P41002, P51944, Q0JCU7, Q32NJ2, Q32NM1, Q5E9N5, Q5F3G0, Q5R5Z6, Q5T447, Q5XGG5, Q6DI92, Q6P549, Q6ZN16, Q7T0L6, Q7TN16, Q7ZUM8, Q80TA6, Q80WG7, Q8AYC9, Q8BRH3, Q8C6M1, Q8K4F8, Q8N414, Q8N6K7, Q8W519, Q94K49

Diamond homologs: A0A5B9GBF0, A0AAR7, A1IVT7, A2XUW1, A6ZQG7, A6ZZF6, A7TGR2, A8WYE4, A8XQD5, A8XWC4, B1H3E1, B2DD29, D3ZML2, D3ZSZ3, E1BMN8, E2QWQ2, G1XJZ4, O14019, O14328, O14757, O45818, O54949, O59763, O61661, O64812, O88866, O96821, P0CP69, P0DP15, P22211, P25333, P32485, P34117, P34208, P34244, P36002, P36004, P38970, P45894, P53233

SIGNOR signaling

110 interactions.

A	Effect	B	Mechanism
CHEK1	“up-regulates activity”	FANCD2	phosphorylation
CHEK1	up-regulates	TP73	phosphorylation
AKT1	down-regulates	CHEK1	phosphorylation
CHEK1	up-regulates	RAD51	phosphorylation
ATR	up-regulates	CHEK1	phosphorylation
PPM1D	down-regulates	CHEK1	dephosphorylation
CHEK1	up-regulates	CLSPN	phosphorylation
CHEK1	“down-regulates activity”	CDC25B	phosphorylation
CHEK1	up-regulates	AURKB	phosphorylation
CHEK1	up-regulates	FANCE	phosphorylation
CHEK1	“up-regulates activity”	RB1	phosphorylation
CHEK1	“down-regulates activity”	H3-3A	phosphorylation
CHEK1	up-regulates	E2F3	phosphorylation
ATM	up-regulates	CHEK1	phosphorylation
CHEK1	down-regulates	CDC25A	phosphorylation
CHEK1	“down-regulates quantity by destabilization”	CDC25C	phosphorylation
CHEK1	up-regulates	CDC7	phosphorylation
CHEK1	up-regulates	WEE1	phosphorylation
7-Hydroxystaurosporine	down-regulates	CHEK1	“chemical inhibition”
SCHEMBL14517914	down-regulates	CHEK1	“chemical inhibition”
CHEK1	up-regulates	BLM	phosphorylation
MUTYH	up-regulates	CHEK1

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 138 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
Chk1/Chk2(Cds1) mediated inactivation of Cyclin B:Cdk1 complex	7	46.6×	8e-09
Activation of BAD and translocation to mitochondria	6	45.2×	1e-07
SARS-CoV-1 targets host intracellular signalling and regulatory pathways	6	39.9×	3e-07
Activation of BH3-only proteins	6	29.5×	2e-06
Diseases of DNA repair	5	28.3×	2e-05
Homologous DNA Pairing and Strand Exchange	6	22.6×	7e-06
Impaired BRCA2 binding to RAD51	7	21.4×	2e-06
HDR through Single Strand Annealing (SSA)	7	20.3×	2e-06

GO biological processes:

GO term	Partners	Fold	FDR
protein targeting	6	17.4×	3e-04
positive regulation of miRNA transcription	5	11.5×	8e-03
intracellular protein localization	10	8.3×	2e-04
DNA repair	14	7.1×	1e-05
regulation of cell cycle	11	6.5×	3e-04
DNA damage response	11	4.7×	4e-03

Disease & clinical

Cancer significance

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	4
Likely pathogenic	1
Uncertain significance	50
Likely benign	38
Benign	10

Top pathogenic / likely-pathogenic (5)

Variant ID	HGVS	Classification
2663865	NM_001114122.3(CHEK1):c.1136G>A (p.Arg379Gln)	Pathogenic
2663866	NM_001114122.3(CHEK1):c.1324del (p.Arg442fs)	Pathogenic
2663867	NM_001114122.3(CHEK1):c.1325G>A (p.Arg442Gln)	Pathogenic
2663868	NM_001114122.3(CHEK1):c.1259G>A (p.Arg420Lys)	Pathogenic
2576413	NM_001114122.3(CHEK1):c.1036C>T (p.Gln346Ter)	Likely pathogenic

SpliceAI

1896 predictions. Top by Δscore:

Variant	Effect	Δscore
11:125626729:T:A	acceptor_gain	1.0000
11:125626730:G:A	acceptor_gain	1.0000
11:125626737:T:A	acceptor_gain	1.0000
11:125626747:A:AG	acceptor_gain	1.0000
11:125626748:G:GC	acceptor_gain	1.0000
11:125626748:GCC:G	acceptor_gain	1.0000
11:125626748:GCCGA:G	acceptor_gain	1.0000
11:125626829:GGAGA:G	donor_gain	1.0000
11:125626830:GAGA:G	donor_gain	1.0000
11:125626830:GAGAG:G	donor_gain	1.0000
11:125626831:A:T	donor_gain	1.0000
11:125626831:AGA:A	donor_gain	1.0000
11:125626832:GA:G	donor_gain	1.0000
11:125626832:GAG:G	donor_gain	1.0000
11:125626833:AGTG:A	donor_loss	1.0000
11:125626834:G:GG	donor_gain	1.0000
11:125626834:GTGA:G	donor_loss	1.0000
11:125626835:TGA:T	donor_loss	1.0000
11:125626836:GAGT:G	donor_loss	1.0000
11:125627602:TTTA:T	acceptor_loss	1.0000
11:125627604:TA:T	acceptor_loss	1.0000
11:125627605:A:AG	acceptor_gain	1.0000
11:125627605:A:G	acceptor_loss	1.0000
11:125627606:G:GG	acceptor_gain	1.0000
11:125627606:GA:G	acceptor_gain	1.0000
11:125627606:GAGTT:G	acceptor_gain	1.0000
11:125627701:A:T	donor_gain	1.0000
11:125627706:GATCT:G	donor_gain	1.0000
11:125627707:A:G	donor_gain	1.0000
11:125629230:A:AG	acceptor_gain	1.0000

AlphaMissense

0 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000038745 (11:125671484 G>A,T), RS1000059945 (11:125633075 AT>A,ATT), RS1000152883 (11:125670893 G>A,T), RS1000164198 (11:125634042 C>G,T), RS1000218137 (11:125672747 A>C), RS1000279834 (11:125633799 G>A), RS1000387485 (11:125677823 C>T), RS1000406530 (11:125648886 T>G), RS1000415373 (11:125662799 C>A), RS1000422066 (11:125656634 C>T), RS1000532128 (11:125659143 T>C), RS1000559980 (11:125641836 A>G), RS1000591109 (11:125641393 C>T), RS1000626153 (11:125626327 G>A), RS1000692078 (11:125652269 T>A)

Disease associations

OMIM: gene MIM:603078 | disease phenotypes: MIM:620610

GenCC curated gene-disease

Disease	Classification	Inheritance
familial ovarian cancer	No Known Disease Relationship	Unknown
hereditary breast carcinoma	No Known Disease Relationship	Unknown

ClinGen Gene-Disease Validity (2)

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

Disease	Classification	Inheritance
familial ovarian cancer	No Known Disease Relationship	AD
hereditary breast carcinoma	No Known Disease Relationship	AD

Mondo (4): hereditary neoplastic syndrome (MONDO:0015356), oocyte/zygote/embryo maturation arrest 21 (MONDO:0957961), familial ovarian cancer (MONDO:0016248), hereditary breast carcinoma (MONDO:0016419)

Orphanet (2): Inherited cancer-predisposing syndrome (Orphanet:140162), Male infertility due to gonadal dysgenesis or sperm disorder (Orphanet:399764)

HPO phenotypes

4 total (4 of 4 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0008222	Female infertility
HP:0011462	Young adult onset
HP:0033336	Zygotic cleavage failure

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST002861_2	Breast cancer (survival)	1.000000e-09
GCST004750_33	Squamous cell lung carcinoma	7.000000e-06

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0000714	survival time

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D009386	Neoplastic Syndromes, Hereditary	C04.700; C16.320.700
C562840	Breast Cancer, Familial (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (2): CHEMBL3883296 (PROTEIN FAMILY), CHEMBL4630 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

36 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 158,863 (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
CHEMBL1287853	FEDRATINIB	4	3,554
CHEMBL180022	NERATINIB	4	9,404
CHEMBL189963	PALBOCICLIB	4	13,102
CHEMBL288441	BOSUTINIB	4	12,255
CHEMBL3545311	BRIGATINIB	4	5,634
CHEMBL502835	NINTEDANIB	4	8,545
CHEMBL535	SUNITINIB	4	79,020
CHEMBL608533	MIDOSTAURIN	4	7,259
CHEMBL1879463	DACTOLISIB	3	7,988
CHEMBL522892	DOVITINIB	3	4,944
CHEMBL603469	LESTAURTINIB	3
CHEMBL91829	RUBOXISTAURIN	3	77
CHEMBL1230165	SILMITASERTIB	2	593
CHEMBL1236682	REFAMETINIB	2	3,223
CHEMBL1721885	SU-014813	2	363
CHEMBL1967878	CENISERTIB	2	358
CHEMBL2386889	SCH-900776	2	740
CHEMBL3039517	RABUSERTIB	2	538
CHEMBL3544911	PREXASERTIB	2	699
CHEMBL3545396	BMS-690514	2	567
CHEMBL3979920	MIVAVOTINIB	2
CHEMBL4116008	CERDULATINIB	2
CHEMBL475251	R-406	2
CHEMBL495727	AT-9283	2
CHEMBL572878	TOZASERTIB	2
CHEMBL574737	UCN-01	2
CHEMBL607707	PELITINIB	2
CHEMBL1908397	KW-2449	1
CHEMBL1980391	RG-1530	1
CHEMBL2041933	AZD-7762	1

Clinical evidence (CIViC)

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

Variant	Therapy	Indication	Effect	Level	CIViC
CHEK1 Mutation	Olaparib	Castration-resistant Prostate Carcinoma	Sensitivity/Response	CIViC A	EID11210
CHEK1 Overexpression	Prexasertib + Cisplatin + Olaparib	Lung Small Cell Carcinoma	Sensitivity/Response	CIViC D	EID4874

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 (18 total), top 18:

Ligand	Action	Affinity	Parameter
CHIR-124	Inhibition	9.49	pIC50
PF-477736	Inhibition	9.31	pIC50
prexasertib	Inhibition	9.05	pIC50
CCT245737	Inhibition	8.89	pIC50
MK-8776	Inhibition	8.52	pIC50
BEN-28010	Inhibition	8.4	pIC50
compound 25 [PMID: 17935989]	Inhibition	8.4	pIC50
AZD7762	Inhibition	8.3	pIC50
7-hydroxystaurosporine	Inhibition	8.15	pIC50
rabusertib	Inhibition	8.15	pIC50
CCT244747	Inhibition	8.11	pIC50
SB 218078	Inhibition	7.82	pIC50
compound 33 [PMID: 19364658]	Inhibition	7.05	pIC50
isogranulatimide	Inhibition	7.0	pIC50
compound 25 [PMID: 20855207]	Inhibition	6.85	pIC50
CCT241533	Inhibition	6.72	pIC50
BX-795	Inhibition	6.29	pIC50
BX-912	Inhibition	6.08	pIC50

Binding affinities (BindingDB)

689 measured of 779 human assays (779 total across all organisms); most potent 50 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
5-[[5-[2-methoxy-4-[(1-propan-2-ylpiperidin-4-yl)amino]phenyl]pyrazolidin-3-yl]amino]pyrazine-2-carbonitrile	IC50	0.004 nM	US-10010547: Pharmaceutical compounds
5-[[5-[4-[(1-ethylpiperidin-4-yl)amino]-2-methoxyphenyl]pyrazolidin-3-yl]amino]pyrazine-2-carbonitrile	IC50	0.005 nM	US-10010547: Pharmaceutical compounds
5-[[5-[2-methoxy-4-[(1-methylpiperidin-4-yl)amino]phenyl]pyrazolidin-3-yl]amino]pyrazine-2-carbonitrile	IC50	0.007 nM	US-10010547: Pharmaceutical compounds
5-[[5-[4-[(1-ethylpiperidin-4-yl)methyl-methylamino]-2-methoxyphenyl]pyrazolidin-3-yl]amino]pyrazine-2-carbonitrile	IC50	0.008 nM	US-10010547: Pharmaceutical compounds
5-[[5-[2-methoxy-4-[(2-methylpropylamino)methyl]phenyl]pyrazolidin-3-yl]amino]pyrazine-2-carbonitrile	IC50	0.012 nM	US-10010547: Pharmaceutical compounds
5-[[5-[2-methoxy-4-[(3R)-3-methylpiperazin-1-yl]phenyl]pyrazolidin-3-yl]amino]pyrazine-2-carbonitrile	IC50	0.016 nM	US-10010547: Pharmaceutical compounds
5-[[5-[4-[(3R)-3,4-dimethylpiperazin-1-yl]-2-methoxyphenyl]pyrazolidin-3-yl]amino]pyrazine-2-carbonitrile	IC50	0.016 nM	US-10010547: Pharmaceutical compounds
5-[[5-[4-[(3R)-4-ethyl-3-methylpiperazin-1-yl]-2-methoxyphenyl]pyrazolidin-3-yl]amino]pyrazine-2-carbonitrile	IC50	0.016 nM	US-10010547: Pharmaceutical compounds
5-[[5-[2-methoxy-4-[[(3R)-1-propan-2-ylpyrrolidin-3-yl]oxymethyl]phenyl]pyrazolidin-3-yl]amino]pyrazine-2-carbonitrile	IC50	0.019 nM	US-10010547: Pharmaceutical compounds
5-[[5-[4-[[(3R)-1-ethylpyrrolidin-3-yl]oxymethyl]-2-methoxyphenyl]pyrazolidin-3-yl]amino]pyrazine-2-carbonitrile	IC50	0.021 nM	US-10010547: Pharmaceutical compounds
5-[[5-[4-[(1-ethylpiperidin-4-yl)methyl]-2-methoxyphenyl]pyrazolidin-3-yl]amino]pyrazine-2-carbonitrile	IC50	0.021 nM	US-10010547: Pharmaceutical compounds
5-[[5-[2-methoxy-4-(1-methylazetidin-3-yl)phenyl]pyrazolidin-3-yl]amino]pyrazine-2-carbonitrile	IC50	0.022 nM	US-10010547: Pharmaceutical compounds
5-[[5-[4-[(2R)-4-ethylmorpholin-2-yl]-2-methoxyphenyl]pyrazolidin-3-yl]amino]pyrazine-2-carbonitrile	IC50	0.022 nM	US-10010547: Pharmaceutical compounds
5-[[5-[4-[[(2S)-1-ethylpyrrolidin-2-yl]methoxy]-2-methoxyphenyl]pyrazolidin-3-yl]amino]pyrazine-2-carbonitrile	IC50	0.023 nM	US-10010547: Pharmaceutical compounds
5-[[5-[4-[(cyclopropylmethylamino)methyl]-2-methoxyphenyl]pyrazolidin-3-yl]amino]pyrazine-2-carbonitrile	IC50	0.025 nM	US-10010547: Pharmaceutical compounds
5-[[5-[2-methoxy-4-[(oxan-4-ylamino)methyl]phenyl]pyrazolidin-3-yl]amino]pyrazine-2-carbonitrile	IC50	0.026 nM	US-10010547: Pharmaceutical compounds
5-[[5-[2-methoxy-4-(4-methylpiperazin-1-yl)phenyl]pyrazolidin-3-yl]amino]pyrazine-2-carbonitrile	IC50	0.026 nM	US-10010547: Pharmaceutical compounds
5-[[5-[2-methoxy-4-[(1-propan-2-ylpiperidin-4-yl)methyl]phenyl]pyrazolidin-3-yl]amino]pyrazine-2-carbonitrile	IC50	0.026 nM	US-10010547: Pharmaceutical compounds
5-[[5-[2-methoxy-4-[(2R)-4-methylmorpholin-2-yl]phenyl]pyrazolidin-3-yl]amino]pyrazine-2-carbonitrile	IC50	0.027 nM	US-10010547: Pharmaceutical compounds
5-[[5-[2-methoxy-4-[[(3S)-1-propan-2-ylpyrrolidin-3-yl]oxymethyl]phenyl]pyrazolidin-3-yl]amino]pyrazine-2-carbonitrile	IC50	0.027 nM	US-10010547: Pharmaceutical compounds
1-[5-chloro-2-methoxy-4-[2-[(4-piperazin-1-ylphenyl)methylamino]ethyl]phenyl]-3-(5-cyanopyrazin-2-yl)urea	IC50	0.03 nM	US-8716287: Pharmaceutical compounds
5-[[5-[2-methoxy-4-[methyl-[(1-propan-2-ylpiperidin-4-yl)methyl]amino]phenyl]pyrazolidin-3-yl]amino]pyrazine-2-carbonitrile	IC50	0.031 nM	US-10010547: Pharmaceutical compounds
5-[[5-[4-[[[1-(cyclopropanecarbonyl)piperidin-4-yl]methylamino]methyl]-2-methoxyphenyl]pyrazolidin-3-yl]amino]pyrazine-2-carbonitrile	IC50	0.034 nM	US-10010547: Pharmaceutical compounds
5-[[5-[4-[[(3S)-1-ethylpyrrolidin-3-yl]oxymethyl]-2-methoxyphenyl]pyrazolidin-3-yl]amino]pyrazine-2-carbonitrile	IC50	0.041 nM	US-10010547: Pharmaceutical compounds
5-[[5-[4-[(1-ethylpiperidin-4-yl)methylamino]-2-methoxyphenyl]pyrazolidin-3-yl]amino]pyrazine-2-carbonitrile	IC50	0.043 nM	US-10010547: Pharmaceutical compounds
5-[[5-[2-methoxy-4-[[(2R)-1-propan-2-ylpyrrolidin-2-yl]methoxy]phenyl]pyrazolidin-3-yl]amino]pyrazine-2-carbonitrile	IC50	0.044 nM	US-10010547: Pharmaceutical compounds
5-[[5-[2-methoxy-4-[[(2S)-1-propan-2-ylpyrrolidin-2-yl]methoxy]phenyl]pyrazolidin-3-yl]amino]pyrazine-2-carbonitrile	IC50	0.046 nM	US-10010547: Pharmaceutical compounds
5-[[5-[2-methoxy-4-(1-methylpiperidin-4-yl)phenyl]pyrazolidin-3-yl]amino]pyrazine-2-carbonitrile	IC50	0.048 nM	US-10010547: Pharmaceutical compounds
5-[[5-[2-fluoro-6-methoxy-4-(4-propan-2-ylpiperazin-1-yl)phenyl]pyrazolidin-3-yl]amino]pyrazine-2-carbonitrile	IC50	0.048 nM	US-10010547: Pharmaceutical compounds
1-[5-chloro-2-methoxy-4-[2-[[(2S)-morpholin-2-yl]methylamino]ethyl]phenyl]-3-(5-cyanopyrazin-2-yl)urea	IC50	0.05 nM	US-9630931: Pharmaceutically active pyrazine derivatives
5-[[5-[2-methoxy-4-[1-(2-methoxyethyl)piperidin-4-yl]phenyl]pyrazolidin-3-yl]amino]pyrazine-2-carbonitrile	IC50	0.051 nM	US-10010547: Pharmaceutical compounds
5-[[5-[2-methoxy-4-[[methyl(oxan-4-yl)amino]methyl]phenyl]pyrazolidin-3-yl]amino]pyrazine-2-carbonitrile	IC50	0.052 nM	US-10010547: Pharmaceutical compounds
5-[[5-[2-methoxy-4-[[methyl(propan-2-yl)amino]methyl]phenyl]pyrazolidin-3-yl]amino]pyrazine-2-carbonitrile	IC50	0.053 nM	US-10010547: Pharmaceutical compounds
5-[[5-[4-(4-ethylpiperazin-1-yl)-2-fluoro-6-methoxyphenyl]pyrazolidin-3-yl]amino]pyrazine-2-carbonitrile	IC50	0.053 nM	US-10010547: Pharmaceutical compounds
5-[[5-(2-hydroxy-4-piperazin-1-ylphenyl)pyrazolidin-3-yl]amino]pyrazine-2-carbonitrile	IC50	0.054 nM	US-10010547: Pharmaceutical compounds
5-[[5-[2-methoxy-4-(1-propan-2-ylpiperidin-4-yl)oxyphenyl]pyrazolidin-3-yl]amino]pyrazine-2-carbonitrile	IC50	0.054 nM	US-10010547: Pharmaceutical compounds
5-[[5-[2-methoxy-4-(pyrrolidin-1-ylmethyl)phenyl]pyrazolidin-3-yl]amino]pyrazine-2-carbonitrile	IC50	0.055 nM	US-10010547: Pharmaceutical compounds
5-[[5-[4-[[(2R)-1-ethylpyrrolidin-2-yl]methoxy]-2-methoxyphenyl]pyrazolidin-3-yl]amino]pyrazine-2-carbonitrile	IC50	0.056 nM	US-10010547: Pharmaceutical compounds
5-[[5-[4-[[(4-fluorophenyl)methylamino]methyl]-2-methoxyphenyl]pyrazolidin-3-yl]amino]pyrazine-2-carbonitrile	IC50	0.058 nM	US-10010547: Pharmaceutical compounds
5-[[5-[4-(ethylaminomethyl)-2-methoxyphenyl]pyrazolidin-3-yl]amino]pyrazine-2-carbonitrile	IC50	0.058 nM	US-10010547: Pharmaceutical compounds
5-[[5-[4-(1-ethyl-3-fluoropiperidin-4-yl)-2-methoxyphenyl]pyrazolidin-3-yl]amino]pyrazine-2-carbonitrile	IC50	0.059 nM	US-10010547: Pharmaceutical compounds
1-[5-chloro-2-methoxy-4-[2-[[(3S)-piperidin-3-yl]methylamino]ethyl]phenyl]-3-(5-cyanopyrazin-2-yl)urea	IC50	0.06 nM	US-9630931: Pharmaceutically active pyrazine derivatives
5-[[5-[2-methoxy-4-[(1-methylpiperidin-4-yl)methoxy]phenyl]pyrazolidin-3-yl]amino]pyrazine-2-carbonitrile	IC50	0.068 nM	US-10010547: Pharmaceutical compounds
5-[[5-(2-methoxy-4-piperidin-4-yloxyphenyl)pyrazolidin-3-yl]amino]pyrazine-2-carbonitrile	IC50	0.071 nM	US-10010547: Pharmaceutical compounds
5-[[5-[2-methoxy-4-[(propan-2-ylamino)methyl]phenyl]pyrazolidin-3-yl]amino]pyrazine-2-carbonitrile	IC50	0.071 nM	US-10010547: Pharmaceutical compounds
5-[[5-[2-methoxy-4-[(3S)-pyrrolidin-3-yl]oxyphenyl]pyrazolidin-3-yl]amino]pyrazine-2-carbonitrile	IC50	0.074 nM	US-10010547: Pharmaceutical compounds
5-[[5-[2-methoxy-4-[(2-morpholin-4-ylethylamino)methyl]phenyl]pyrazolidin-3-yl]amino]pyrazine-2-carbonitrile	IC50	0.077 nM	US-10010547: Pharmaceutical compounds
5-[[5-(2-fluoro-6-methoxy-4-piperazin-1-ylphenyl)pyrazolidin-3-yl]amino]pyrazine-2-carbonitrile	IC50	0.077 nM	US-10010547: Pharmaceutical compounds
5-[[5-[4-(3-fluoro-1-propan-2-ylpiperidin-4-yl)-2-methoxyphenyl]pyrazolidin-3-yl]amino]pyrazine-2-carbonitrile	IC50	0.079 nM	US-10010547: Pharmaceutical compounds
5-[[5-[2-methoxy-4-[(1-methylpiperidin-4-yl)methylamino]phenyl]pyrazolidin-3-yl]amino]pyrazine-2-carbonitrile	IC50	0.081 nM	US-10010547: Pharmaceutical compounds

ChEMBL bioactivities

3294 potent at pChembl≥5 of 3428 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
10.92	IC50	0.012	nM	CHEMBL5747621
10.80	IC50	0.016	nM	CHEMBL5812486
10.80	IC50	0.016	nM	CHEMBL5944770
10.80	IC50	0.016	nM	CHEMBL6027444
10.72	IC50	0.019	nM	CHEMBL5935192
10.68	IC50	0.021	nM	CHEMBL5861249
10.68	IC50	0.021	nM	CHEMBL5777143
10.66	IC50	0.022	nM	CHEMBL5773272
10.66	IC50	0.022	nM	CHEMBL5893031
10.64	IC50	0.023	nM	CHEMBL6047287
10.60	IC50	0.025	nM	CHEMBL5956681
10.59	IC50	0.026	nM	CHEMBL5842815
10.59	IC50	0.026	nM	CHEMBL5824984
10.59	IC50	0.026	nM	CHEMBL5855043
10.57	IC50	0.027	nM	CHEMBL5931629
10.57	IC50	0.027	nM	CHEMBL5845949
10.52	IC50	0.03	nM	CHEMBL2011352
10.52	IC50	0.03	nM	CHEMBL2011353
10.52	IC50	0.03	nM	CHEMBL3694397
10.51	IC50	0.031	nM	CHEMBL6053351
10.47	IC50	0.034	nM	CHEMBL5995631
10.39	IC50	0.041	nM	CHEMBL5839557
10.37	IC50	0.043	nM	CHEMBL5750986
10.36	IC50	0.044	nM	CHEMBL5912614
10.34	IC50	0.046	nM	CHEMBL5796222
10.32	IC50	0.048	nM	CHEMBL6002144
10.32	IC50	0.048	nM	CHEMBL5956287
10.30	IC50	0.05	nM	CHEMBL2010809
10.30	IC50	0.05	nM	CHEMBL2013170
10.30	IC50	0.05	nM	CHEMBL2011350
10.30	IC50	0.05	nM	CHEMBL2011354
10.30	IC50	0.05	nM	CHEMBL5795859
10.29	IC50	0.051	nM	CHEMBL5796100
10.28	IC50	0.052	nM	CHEMBL5772293
10.28	IC50	0.053	nM	CHEMBL5962917
10.28	IC50	0.053	nM	CHEMBL5802846
10.27	IC50	0.054	nM	CHEMBL5977891
10.27	IC50	0.054	nM	CHEMBL5907466
10.27	IC50	0.054	nM	CHEMBL5963288
10.26	IC50	0.055	nM	CHEMBL5904385
10.25	IC50	0.056	nM	CHEMBL5847574
10.24	IC50	0.058	nM	CHEMBL5936666
10.24	IC50	0.058	nM	CHEMBL5959878
10.23	IC50	0.059	nM	CHEMBL5750451
10.22	IC50	0.06	nM	CHEMBL6040237
10.17	IC50	0.068	nM	CHEMBL5785658
10.15	IC50	0.07	nM	CHEMBL2013169
10.15	IC50	0.071	nM	CHEMBL5983291
10.15	IC50	0.071	nM	CHEMBL5926704
10.13	IC50	0.074	nM	CHEMBL5836251

PubChem BioAssay actives

2502 with measured affinity, of 5218 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
5-[2-[[4-(4-acetylpiperazin-1-yl)-2-pyridinyl]amino]-1,3-thiazol-5-yl]-N-(2-aminoethyl)pyridine-3-carboxamide	654776: Inhibition of CHK1 by time resolved fluorescence assay	ic50	<0.0001	uM
N-(2-aminoethyl)-5-[2-[[4-(4-methylsulfonylpiperazin-1-yl)-2-pyridinyl]amino]-1,3-thiazol-5-yl]pyridine-3-carboxamide	654776: Inhibition of CHK1 by time resolved fluorescence assay	ic50	<0.0001	uM
[5-[3-[5-[(4-fluoropiperidin-1-yl)methyl]-1H-indol-2-yl]-1H-indazol-6-yl]-2H-triazol-4-yl]methanamine	1796853: Homogeneous Time-resolved Fluorescence (HTRF) Assay from Article 10.1016/j.bmcl.2006.08.118: “3-(Indol-2-yl)indazoles as Chek1 kinase inhibitors: Optimization of potency and selectivity via substitution at C6.”	ic50	0.0001	uM
(2R)-3-[[3-[4-(4-hydroxyphenyl)phenyl]-7-methoxy-1,4-dihydroindeno[2,1-d]pyrazol-6-yl]oxy]propane-1,2-diol	308318: Inhibition of Chk1	ic50	0.0001	uM
2-[[3-[4-(4-hydroxyphenyl)phenyl]-7-methoxy-1,4-dihydroindeno[2,1-d]pyrazol-6-yl]oxy]propane-1,3-diol	308318: Inhibition of Chk1	ic50	0.0001	uM
(2S)-3-[[3-[4-(4-hydroxyphenyl)phenyl]-7-methoxy-1,4-dihydroindeno[2,1-d]pyrazol-6-yl]oxy]propane-1,2-diol	308318: Inhibition of Chk1	ic50	0.0001	uM
N-(2-aminoethyl)-5-[2-[(4-piperazin-1-yl-2-pyridinyl)amino]-1,3-thiazol-5-yl]pyridine-3-carboxamide	655390: Competitive inhibition of Chk1 in presence of higher ATP levels	ic50	0.0001	uM
N-(2-aminoethyl)-5-[2-[(4-morpholin-4-yl-2-pyridinyl)amino]-1,3-thiazol-5-yl]pyridine-3-carboxamide	654776: Inhibition of CHK1 by time resolved fluorescence assay	ic50	0.0001	uM
N-(2-aminoethyl)-5-[2-[[4-(4,4-difluoropiperidin-1-yl)-2-pyridinyl]amino]-1,3-thiazol-5-yl]pyridine-3-carboxamide	655390: Competitive inhibition of Chk1 in presence of higher ATP levels	ic50	0.0001	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	1715399: Inhibition of human CHK1 using KKKVSRSGLYRSPSMPENLNRPR as substrate by [gamma-33P]-ATP assay	ic50	0.0001	uM
5-methyl-8-(1H-pyrrol-2-yl)-2H-[1,2,4]triazolo[4,3-a]quinolin-1-one	501658: Inhibition of His6-CHK1 expressed in baculovirus infected Sf9 cells	ic50	0.0001	uM
N-(aminomethyl)-5-[2-[[4-(4-fluoropiperidin-1-yl)-2-pyridinyl]amino]-1,3-thiazol-5-yl]pyridine-3-carboxamide	654776: Inhibition of CHK1 by time resolved fluorescence assay	ic50	0.0001	uM
N-(aminomethyl)-5-[2-[[4-(4,4-difluoropiperidin-1-yl)-2-pyridinyl]amino]-1,3-thiazol-5-yl]pyridine-3-carboxamide	654776: Inhibition of CHK1 by time resolved fluorescence assay	ic50	0.0001	uM
N-(4-hydroxycyclohexyl)-3-[4-(4-hydroxyphenyl)phenyl]-7-methoxy-1,4-dihydroindeno[2,1-d]pyrazole-6-carboxamide	299280: Inhibition of recombinant CHK-mediated Cdc25C phosphorylation after 30 mins	ic50	0.0002	uM
2-amino-2-cyclohexyl-N-[2-(1-methylpyrazol-4-yl)-9-oxo-3,10,11-triazatricyclo[6.4.1.04,13]trideca-1,4,6,8(13),11-pentaen-6-yl]acetamide	1424953: Kinobeads (epsilon), multiple immobilized ATP-competitive broad spectrum kinase inhibitors, used to assess residual binding of ~300 proteins simultaneously from cell lysate in the presence of a compound. Quantitative readout performed by mass spectrometry.	kd	0.0002	uM
4-[4-[3-[4-(pyrrolidin-1-ylmethyl)anilino]-1H-pyrazol-5-yl]phenyl]benzene-1,3-diol	301952: Inhibition of human CHK1 expressed in baculovirus/insect cell system	ki	0.0002	uM
4-[4-[3-[[6-[(butan-2-ylamino)methyl]-3-pyridinyl]amino]-1H-pyrazol-5-yl]phenyl]benzene-1,3-diol	301952: Inhibition of human CHK1 expressed in baculovirus/insect cell system	ki	0.0002	uM
[3-[4-(4-hydroxyphenyl)phenyl]-7-methoxy-1,4-dihydroindeno[2,1-d]pyrazol-6-yl]-(4-hydroxypiperidin-1-yl)methanone	299280: Inhibition of recombinant CHK-mediated Cdc25C phosphorylation after 30 mins	ic50	0.0002	uM
4-[4-[7-methoxy-6-[(2-pyrrolidin-1-ylethylamino)methyl]-1,4-dihydroindeno[2,1-d]pyrazol-3-yl]phenyl]phenol	299280: Inhibition of recombinant CHK-mediated Cdc25C phosphorylation after 30 mins	ic50	0.0002	uM
4-[4-[3-[4-[(dimethylamino)methyl]anilino]-1H-pyrazol-5-yl]phenyl]benzene-1,3-diol	301952: Inhibition of human CHK1 expressed in baculovirus/insect cell system	ki	0.0002	uM
4-[4-[6-methoxy-7-[3-(4-methylpiperazin-1-yl)propoxy]-1,4-dihydroindeno[2,1-d]pyrazol-3-yl]phenyl]phenol	308318: Inhibition of Chk1	ic50	0.0002	uM
4-[4-[7-methoxy-6-(oxan-4-yloxy)-1,4-dihydroindeno[2,1-d]pyrazol-3-yl]phenyl]phenol	308318: Inhibition of Chk1	ic50	0.0002	uM
4-[[(3S)-1-azabicyclo[2.2.2]octan-3-yl]amino]-3-(1H-benzimidazol-2-yl)-6-chloro-1H-quinolin-2-one	1859470: Inhibition of Chk1 (unknown origin) expressed in Sf9 insect cells using biotinylated cdc25c peptide as substrate in presence of 33P-gamma-labeled ATP by radioactive method	ic50	0.0003	uM
4-[[(3S)-1-azabicyclo[2.2.2]octan-3-yl]amino]-3-(1H-benzimidazol-2-yl)-6-methyl-1H-quinolin-2-one	265582: Inhibition of CHK1	ic50	0.0003	uM
[5-[3-[5-(piperidin-1-ylmethyl)-1H-indol-2-yl]-1H-indazol-6-yl]-2H-triazol-4-yl]methanol	1796853: Homogeneous Time-resolved Fluorescence (HTRF) Assay from Article 10.1016/j.bmcl.2006.08.118: “3-(Indol-2-yl)indazoles as Chek1 kinase inhibitors: Optimization of potency and selectivity via substitution at C6.”	ic50	0.0003	uM
2-methoxy-4-[3-[5-(piperidin-1-ylmethyl)-1H-indol-2-yl]-1H-indazol-6-yl]phenol	1796853: Homogeneous Time-resolved Fluorescence (HTRF) Assay from Article 10.1016/j.bmcl.2006.08.118: “3-(Indol-2-yl)indazoles as Chek1 kinase inhibitors: Optimization of potency and selectivity via substitution at C6.”	ic50	0.0003	uM
[5-[3-[5-[(4-fluoropiperidin-1-yl)methyl]-1H-indol-2-yl]-1H-indazol-6-yl]-2H-triazol-4-yl]methanol	1796853: Homogeneous Time-resolved Fluorescence (HTRF) Assay from Article 10.1016/j.bmcl.2006.08.118: “3-(Indol-2-yl)indazoles as Chek1 kinase inhibitors: Optimization of potency and selectivity via substitution at C6.”	ic50	0.0003	uM
4-[4-[3-[[6-(piperidin-1-ylmethyl)-3-pyridinyl]amino]-1H-pyrazol-5-yl]phenyl]benzene-1,3-diol	301952: Inhibition of human CHK1 expressed in baculovirus/insect cell system	ki	0.0003	uM
4-[5-(6,7-dimethoxy-1,4-dihydroindeno[2,1-d]pyrazol-3-yl)-2-pyridinyl]phenol	419415: Inhibition of Chk1	ki	0.0003	uM
(13Z)-7-chloro-8-hydroxy-3-oxo-11,16-dioxa-2,4,19,21-tetrazatricyclo[15.3.1.05,10]henicosa-1(20),5,7,9,13,17(21),18-heptaene-18-carbonitrile	310362: Inhibition of Chk1	ic50	0.0003	uM
7-chloro-8-hydroxy-3-oxo-11,16-dioxa-2,4,19,21-tetrazatricyclo[15.3.1.05,10]henicosa-1(20),5,7,9,17(21),18-hexaene-18-carbonitrile	310362: Inhibition of Chk1	ic50	0.0003	uM
6-(3-aminopropyl)-4-(4-hydroxyphenyl)-9-(1H-pyrazol-4-yl)-2H-benzo[h]isoquinolin-1-one	310149: Inhibition of human Chk1 expressed in baculovirus by time-resolved fluorescence assay	ic50	0.0003	uM
5-[(Z)-[6-(4-hydroxy-3-methoxyphenyl)-2-oxo-1H-indol-3-ylidene]methyl]-2-methyl-N-(2-pyrrolidin-1-ylethyl)selenophene-3-carboxamide	501927: Inhibition of human recombinant GST-Chk1after 30 mins	ic50	0.0003	uM
2-oxo-3-[5-(piperidin-1-ylmethyl)-1H-indol-2-yl]-1H-quinoline-6-carboxamide	276807: Inhibition of human CHEK1	ic50	0.0003	uM
(13Z)-8-amino-7-chloro-3-oxo-11,16-dioxa-2,4,19,21-tetrazatricyclo[15.3.1.05,10]henicosa-1(20),5(10),6,8,13,17(21),18-heptaene-18-carbonitrile	310362: Inhibition of Chk1	ic50	0.0003	uM
(13Z)-7-chloro-8-(3-morpholin-4-ylpropoxy)-3-oxo-11,16-dioxa-2,4,19,21-tetrazatricyclo[15.3.1.05,10]henicosa-1(20),5,7,9,13,17(21),18-heptaene-18-carbonitrile	310362: Inhibition of Chk1	ic50	0.0003	uM
N-(2-aminoethyl)-5-[2-[(3-chloro-2-pyridinyl)amino]-1,3-thiazol-5-yl]pyridine-3-carboxamide	654776: Inhibition of CHK1 by time resolved fluorescence assay	ic50	0.0003	uM
4-(1-methylpyrazol-4-yl)-12-[4-(piperidin-1-ylmethyl)phenyl]-5,8,10-triazatricyclo[7.4.0.02,7]trideca-1(9),2,4,6,10,12-hexaene	1228931: Inhibition of human recombinant Chk1 using biotinylated AKT substrate after 30 mins by Alphascreen biochemical assay	ic50	0.0003	uM
3-amino-1-[5-[2-[(4-morpholin-4-yl-2-pyridinyl)amino]-1,3-thiazol-5-yl]-3-pyridinyl]propan-1-one	655390: Competitive inhibition of Chk1 in presence of higher ATP levels	ic50	0.0003	uM
4-[4-[3-[4-[(propan-2-ylamino)methyl]anilino]-1H-pyrazol-5-yl]phenyl]benzene-1,3-diol	301952: Inhibition of human CHK1 expressed in baculovirus/insect cell system	ki	0.0004	uM
4-[4-[3-[4-[(cyclopropylamino)methyl]anilino]-1H-pyrazol-5-yl]phenyl]benzene-1,3-diol	301952: Inhibition of human CHK1 expressed in baculovirus/insect cell system	ki	0.0004	uM
4-[4-[6-[(2-hydroxyethylamino)methyl]-7-methoxy-1,4-dihydroindeno[2,1-d]pyrazol-3-yl]phenyl]phenol	299280: Inhibition of recombinant CHK-mediated Cdc25C phosphorylation after 30 mins	ic50	0.0004	uM
4-[4-[7-methoxy-6-(oxolan-3-yloxy)-1,4-dihydroindeno[2,1-d]pyrazol-3-yl]phenyl]phenol	308318: Inhibition of Chk1	ic50	0.0004	uM
5-[[4-(methylamino)-5-(1-methylpyrazol-4-yl)pyrimidin-2-yl]amino]-3-[(3R)-piperidin-3-yl]oxypyridine-2-carbonitrile	1595809: Inhibition of recombinant human N-terminal GST-tagged CHK1 (M1 to T476 residues) expressed in baculovirus infected insect cells using biotin-labelled STK substrate-1 as substrate incubated for 60 mins by HTRF assay	ic50	0.0004	uM
acetic acid;5-[[4-(methylamino)-5-(1-methylpyrazol-4-yl)pyrimidin-2-yl]amino]-3-[(3R)-piperidin-3-yl]oxypyridine-2-carbonitrile	1595809: Inhibition of recombinant human N-terminal GST-tagged CHK1 (M1 to T476 residues) expressed in baculovirus infected insect cells using biotin-labelled STK substrate-1 as substrate incubated for 60 mins by HTRF assay	ic50	0.0004	uM
N-(2-aminoethyl)-5-[2-[[4-(morpholin-4-ylmethyl)-2-pyridinyl]amino]-1,3-thiazol-5-yl]pyridine-3-carboxamide	655390: Competitive inhibition of Chk1 in presence of higher ATP levels	ic50	0.0004	uM
N-[2-(diethylamino)ethyl]-5-[(Z)-[6-(4-hydroxyphenyl)-2-oxo-1H-indol-3-ylidene]methyl]-2-methylselenophene-3-carboxamide	501927: Inhibition of human recombinant GST-Chk1after 30 mins	ic50	0.0004	uM
5-[(Z)-[6-(4-hydroxyphenyl)-2-oxo-1H-indol-3-ylidene]methyl]-2-methyl-N-(2-pyrrolidin-1-ylethyl)selenophene-3-carboxamide	501927: Inhibition of human recombinant GST-Chk1after 30 mins	ic50	0.0004	uM
N-(2-aminoethyl)-5-[2-[(3-methyl-2-pyridinyl)amino]-1,3-thiazol-5-yl]pyridine-3-carboxamide	654776: Inhibition of CHK1 by time resolved fluorescence assay	ic50	0.0004	uM
3-(1H-benzimidazol-2-yl)-6-chloro-4-[[(3S)-pyrrolidin-3-yl]amino]-1H-quinolin-2-one	265582: Inhibition of CHK1	ic50	0.0005	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Doxorubicin	increases activity, decreases activity, increases response to substance, affects reaction, decreases reaction (+6 more)	14
bisphenol A	affects cotreatment, decreases expression, increases expression, increases phosphorylation, decreases reaction	9
Cisplatin	affects reaction, decreases reaction, increases phosphorylation, increases activity, increases reaction (+2 more)	9
Benzo(a)pyrene	increases expression, increases phosphorylation, affects reaction, increases reaction, affects methylation (+1 more)	7
Caffeine	decreases reaction, increases activity, increases phosphorylation, increases reaction, affects cotreatment (+1 more)	6
Valproic Acid	affects expression, decreases expression	5
Camptothecin	increases phosphorylation, decreases response to substance, decreases reaction, increases expression	4
Fluorouracil	affects response to substance, increases activity, decreases expression, decreases reaction, affects cotreatment (+3 more)	4
Hydrogen Peroxide	increases expression, increases phosphorylation, decreases reaction, decreases expression	4
Cyclosporine	decreases expression	4
lasiocarpine	affects expression, decreases expression, increases metabolic processing, increases expression, affects cotreatment	3
cobaltous chloride	increases phosphorylation, increases reaction, decreases expression	3
7-hydroxystaurosporine	decreases activity	3
Go 6976	increases phosphorylation, decreases reaction, decreases activity	3
3-amino-6-(4-(methylsulfonyl)phenyl)-N-phenylpyrazine-2-carboxamide	decreases reaction, increases expression, increases phosphorylation, affects response to substance, decreases phosphorylation	3
(+)-JQ1 compound	affects cotreatment, decreases expression	3
Irinotecan	increases activity, increases phosphorylation, decreases reaction	3
Resveratrol	increases activity, increases expression, affects expression, decreases expression, increases phosphorylation (+2 more)	3
Wortmannin	increases phosphorylation, decreases expression, decreases reaction, increases activity	3
Vehicle Emissions	decreases expression, decreases reaction, increases phosphorylation, increases abundance	3
Curcumin	decreases response to substance, decreases reaction, increases expression, increases activity, increases phosphorylation	3
Hydroxyurea	increases activity, increases phosphorylation, increases reaction, decreases reaction	3
Mustard Gas	decreases reaction, increases phosphorylation, decreases expression	3
Tretinoin	affects expression, decreases expression	3
7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide	decreases expression, increases expression	3
Cadmium Chloride	decreases expression, increases abundance, increases expression, increases phosphorylation	3
sodium arsenite	decreases expression, increases phosphorylation	2
fludarabine	increases phosphorylation, decreases expression, affects cotreatment	2
10-decarbamoylmitomycin C	decreases expression, decreases stability, decreases reaction, affects response to substance	2
usnic acid	increases expression	2

ChEMBL screening assays

1086 unique, capped per target: 1039 binding, 44 functional, 3 admet

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL3863738	Binding	Induction of CHK1/2 phosphorylation in human MDA-MB-231 cells assessed as increase in p53 phosphorylation at 10 uM after 6 to 24 hrs by Western blot method	Synthesis and biological evaluation of lovastatin-derived aliphatic hydroxamates that induce reactive oxygen species. — Bioorg Med Chem Lett
CHEMBL1963782	Functional	PUBCHEM_BIOASSAY: Navigating the Kinome. (Class of assay: other) Panel member name: CHEK1	PubChem BioAssay data set
CHEMBL4407593	ADMET	Inhibition of recombinant human full-length His-tagged CHEK1 expressed in baculovirus expression system at 25 uM using FRET-labeled Ser/Thr 19 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

1 cell lines: 1 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B1EV	Abcam A-549 CHEK1 KO	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00040222	Not specified	COMPLETED	Clinical, Genetic, Behavioral, Laboratory and Epidemiologic Characterization of Individuals and Families at High Risk of Breast/Ovarian Cancer
NCT02557776	Not specified	COMPLETED	Written Genetic Counseling and Mutation Analysis of BRCA1 and BRCA2 to Patients With Breast Cancer
NCT03495544	Not specified	UNKNOWN	Study Estimating Association Between Germline Mutations and PD-L1 Expression in Breast Cancer
NCT03959267	Not specified	COMPLETED	Testing a Culturally Adapted Telephone Genetic Counseling Intervention
NCT04058418	Not specified	COMPLETED	Specialist Recommendation on FBC (Familial Breast Cancer) Chemoprevention Prescribing
NCT04125914	Not specified	ACTIVE_NOT_RECRUITING	Weight Management and Health Behavior Intervention in Lowering Cancer Risk for BRCA Positive and Lynch Syndrome Families
NCT04169542	Not specified	RECRUITING	Impact of COVID-19 Pandemic on Out-of-Pocket Costs, Lost Wages, and Unemployment in Patients With Breast Cancer Undergoing Breast Surgery
NCT04197856	Not specified	ACTIVE_NOT_RECRUITING	Direct Information to At-risk Relatives
NCT07292246	Not specified	RECRUITING	A Prospective CohorT Study of HandX - Assisted ENdoscopic MAstectomy: Feasibility and Safety (ATHENA I Study)
NCT07307664	Not specified	RECRUITING	Increasing Germline Genetic Testing for Patients With Cancer
NCT00001496	Not specified	COMPLETED	Establishment of Normal Breast Epithelial Cell Lines From Patients at High Risk for Breast Cancer
NCT00001898	Not specified	COMPLETED	Microarray Analysis for Human Genetic Disease
NCT00026884	Not specified	RECRUITING	Collection of Serum and Tissue Samples From Patients With Biopsy-Proved or Suspected Malignant Disease
NCT02289326	Not specified	COMPLETED	Biomarker Monitoring in TP53 Mutation Carriers
NCT02958462	Not specified	RECRUITING	Pre-myeloid Cancer and Bone Marrow Failure Clinic Study
NCT03160274	Not specified	RECRUITING	Genetic Analysis of Pheochromocytomas, Paragangliomas and Associated Conditions
NCT03426878	Not specified	COMPLETED	Cancer Health Assessments Reaching Many
NCT03857594	Not specified	ACTIVE_NOT_RECRUITING	Integrative Sequencing In Germline and Hereditary Tumours
NCT03973450	Not specified	UNKNOWN	Epidemiology of Pituitary Tumours: Prevalence of Associated Neoplasia
NCT03979612	Not specified	UNKNOWN	Evaluation of the Adhesion to the GENEPY Network
NCT04261972	Not specified	ACTIVE_NOT_RECRUITING	Cell-free DNA in Hereditary And High-Risk Malignancies 1
NCT04494945	Not specified	RECRUITING	Identifying and Caring for Individuals With Inherited Cancer Syndrome
NCT04541654	Not specified	RECRUITING	Li-Fraumeni & TP53 (LiFT UP): Understanding and Progress
NCT04763915	Not specified	ACTIVE_NOT_RECRUITING	Improving Care After Inherited Cancer Testing
NCT05562778	Not specified	RECRUITING	Chatbot to Maximize Hereditary Cancer Genetic Risk Assessment
NCT05664867	Not specified	RECRUITING	Implementation of Population Cancer Genetic Services in Federally Qualified Health Centers (FQHC)
NCT05721326	Not specified	COMPLETED	Sequential EHR Based Interventions to Increase Genetic Testing for Breast and Ovarian Cancer Predisposition
NCT06096688	Not specified	RECRUITING	Discovering New Targets for Colorectal and Endometrial Cancer Risk Reduction
NCT06654466	Not specified	RECRUITING	Closing the GAPS: Guideline Adherence, Prevention and Surveillance in Hereditary Cancer
NCT06708429	Not specified	RECRUITING	Lynch Syndrome X-Talk of Enteral Mucosa With Immune System
NCT06726642	Not specified	RECRUITING	CfDNA in Hereditary And High-risk Malignancies 2
NCT06914726	Not specified	ENROLLING_BY_INVITATION	Patient Centered Clinical Decision Support for Hereditary Cancer Syndromes
NCT06927947	Not specified	RECRUITING	Navigation Interventions to Improve Cascade Genetic Testing Among Relatives of Patients With Hereditary Cancer Syndromes
NCT06999954	Not specified	RECRUITING	Shwachman-Diamond Syndrome Global Patient Survey and Partnering Platform
NCT07052266	Not specified	RECRUITING	Trial of Combined Obstetric Carrier Screening and Hereditary Cancer Screening
NCT07195071	Not specified	RECRUITING	Feasibility Trial of Combination of Obstetrical Carrier Screening and Hereditary Cancer Screening
NCT07378423	Not specified	RECRUITING	Questionnaire on Congenital Cancer Signs Through Self-Assessment
NCT07381985	Not specified	ENROLLING_BY_INVITATION	Strategy for Management of Patients With Hereditary Cancer Syndromes (HCS) in a Rural Environment
NCT07542405	Not specified	NOT_YET_RECRUITING	A Web-Based Program (Kindred) to Improve the Understanding of Genetic Cancer Risk and Cancer Genetic Testing in African American Families