TLK2

Summary

TLK2 (tousled like kinase 2, HGNC:11842) is a protein-coding gene on chromosome 17q23.2, encoding Serine/threonine-protein kinase tousled-like 2 (Q86UE8). Serine/threonine-protein kinase involved in the process of chromatin assembly and probably also DNA replication, transcription, repair, and chromosome segregation. In precision oncology, TLK2 Amplification confers sensitivity to GF109203X + Go6983 in Breast Cancer (CIViC Level D). It is a selective cancer dependency (DepMap: 62.5% of cell lines).

This gene encodes a nuclear serine/threonine kinase that was first identified in Arabidopsis. The encoded protein is thought to function in the regulation of chromatin assembly in the S phase of the cell cycle by regulating the levels of a histone H3/H4 chaperone. This protein is associated with double-strand break repair of DNA damage caused by radiation. Pseudogenes of this gene are present on chromosomes 10 and 17. Alternate splicing results in multiple transcript variants.

Source: NCBI Gene 11011 — RefSeq curated summary.

At a glance

• Gene–disease (curated): complex neurodevelopmental disorder (Definitive, ClinGen) — +1 more curated relationship
• GWAS associations: 8
• Clinical variants (ClinVar): 286 total — 40 pathogenic, 36 likely-pathogenic
• Phenotypes (HPO): 53
• Druggable target: yes — 11 molecules with ChEMBL bioactivity
• Precision-oncology evidence (CIViC): 1 curated variant–drug association
• Cancer dependency (DepMap): dependent in 62.5% of screened cell lines
• MANE Select transcript: NM_006852

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:11842
Approved symbol	TLK2
Name	tousled like kinase 2
Location	17q23.2
Locus type	gene with protein product
Status	Approved
Aliases	PKU-ALPHA, MGC44450
Ensembl gene	ENSG00000146872
Ensembl biotype	protein_coding
OMIM	608439
Entrez	11011

Gene structure

Transcript identifiers

Ensembl transcripts: 64 — 50 protein_coding, 9 retained_intron, 3 nonsense_mediated_decay, 2 protein_coding_CDS_not_defined

ENST00000326270, ENST00000343388, ENST00000346027, ENST00000577616, ENST00000578931, ENST00000579450, ENST00000580203, ENST00000580705, ENST00000581041, ENST00000581286, ENST00000582195, ENST00000582660, ENST00000582809, ENST00000583310, ENST00000583690, ENST00000583843, ENST00000584367, ENST00000682075, ENST00000682085, ENST00000682149, ENST00000682203, ENST00000682274, ENST00000682827, ENST00000683104, ENST00000683536, ENST00000683737, ENST00000684012, ENST00000684133, ENST00000684213, ENST00000684440, ENST00000684553, ENST00000684772, ENST00000902349, ENST00000902350, ENST00000902351, ENST00000902352, ENST00000902353, ENST00000902354, ENST00000902355, ENST00000931871, ENST00000931872, ENST00000931873, ENST00000931874, ENST00000931875, ENST00000931876, ENST00000931877, ENST00000931878, ENST00000931879, ENST00000931880, ENST00000963455, ENST00000963456, ENST00000963457, ENST00000963458, ENST00000963459, ENST00000963460, ENST00000963461, ENST00000963462, ENST00000963463, ENST00000963464, ENST00000963465, ENST00000963466, ENST00000963467, ENST00000963468, ENST00000963469

RefSeq mRNA: 10 — MANE Select: NM_006852 NM_001284333, NM_001284363, NM_001330418, NM_001375269, NM_001375270, NM_001375271, NM_001375272, NM_001375273, NM_001411074, NM_006852

CCDS: CCDS11633, CCDS45753, CCDS62283, CCDS82182, CCDS92374

Canonical transcript exons

ENST00000346027 — 22 exons

Exon	Start	End
ENSE00001181136	62586135	62586226
ENSE00001181139	62580111	62580192
ENSE00001181142	62578477	62578574
ENSE00001181144	62576709	62576775
ENSE00001181147	62573215	62573367
ENSE00001181150	62565001	62565137
ENSE00001635332	62481121	62481206
ENSE00002458635	62552302	62552397
ENSE00002472645	62600651	62600820
ENSE00002527627	62560016	62560126
ENSE00002530141	62553663	62553755
ENSE00003473758	62520773	62520844
ENSE00003503571	62536170	62536337
ENSE00003505997	62524236	62524331
ENSE00003619493	62596585	62596674
ENSE00003663845	62608041	62608148
ENSE00003670766	62602042	62602180
ENSE00003679960	62522204	62522273
ENSE00003786926	62523134	62523177
ENSE00003789599	62606130	62606241
ENSE00003899996	62612392	62615481
ENSE00003903915	62478825	62479290

Expression profiles

Bgee: expression breadth ubiquitous, 185 present calls, max score 97.26.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.3497 / max 14.3536, expressed in 154 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
208301	0.3082	127
162111	0.0416	24

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
calcaneal tendon	UBERON:0003701	97.26	gold quality
sural nerve	UBERON:0015488	96.68	gold quality
colonic epithelium	UBERON:0000397	95.38	gold quality
bone marrow cell	CL:0002092	95.08	gold quality
ventricular zone	UBERON:0003053	94.79	gold quality
adrenal tissue	UBERON:0018303	94.49	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	93.89	gold quality
ganglionic eminence	UBERON:0004023	93.76	gold quality
left testis	UBERON:0004533	93.30	gold quality
endometrium epithelium	UBERON:0004811	93.18	gold quality
right testis	UBERON:0004534	92.95	gold quality
cortical plate	UBERON:0005343	92.87	gold quality
stromal cell of endometrium	CL:0002255	92.09	gold quality
testis	UBERON:0000473	91.16	gold quality
hindlimb stylopod muscle	UBERON:0004252	90.97	gold quality
gastrocnemius	UBERON:0001388	89.92	gold quality
muscle of leg	UBERON:0001383	89.89	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	89.73	gold quality
islet of Langerhans	UBERON:0000006	88.98	gold quality
popliteal artery	UBERON:0002250	88.50	gold quality
tibial artery	UBERON:0007610	88.49	gold quality
granulocyte	CL:0000094	87.89	gold quality
tibial nerve	UBERON:0001323	87.84	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	87.79	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	87.66	gold quality
smooth muscle tissue	UBERON:0001135	87.62	gold quality
leukocyte	CL:0000738	87.60	gold quality
monocyte	CL:0000576	87.47	gold quality
body of uterus	UBERON:0009853	87.34	gold quality
skin of leg	UBERON:0001511	87.30	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	7.43

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

135 targeting TLK2, 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-6867-5P	100.00	82.21	3464
HSA-MIR-1193	100.00	65.93	529
HSA-MIR-432-3P	100.00	67.86	705
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-513A-5P	100.00	69.77	2465
HSA-MIR-4747-5P	100.00	67.90	2681
HSA-MIR-5196-5P	100.00	67.98	2761
HSA-MIR-12121	99.99	66.64	255
HSA-MIR-27A-3P	99.98	72.13	2955
HSA-MIR-27B-3P	99.98	72.13	2955
HSA-MIR-9985	99.98	72.11	2939
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-551B-5P	99.96	71.28	3493
HSA-MIR-5688	99.96	73.23	4504
HSA-MIR-495-3P	99.96	72.81	4197
HSA-MIR-559	99.95	72.28	3609
HSA-MIR-548AB	99.95	71.31	3488
HSA-MIR-6755-5P	99.95	65.59	464
HSA-MIR-548A-5P	99.94	71.27	3482
HSA-MIR-548AD-5P	99.94	71.23	3502
HSA-MIR-548AE-5P	99.94	71.23	3502
HSA-MIR-548AK	99.94	71.24	3488
HSA-MIR-548AM-5P	99.94	71.24	3488
HSA-MIR-548AP-5P	99.94	71.14	3489
HSA-MIR-548AQ-5P	99.94	71.34	3426
HSA-MIR-548AR-5P	99.94	71.28	3515
HSA-MIR-548AS-5P	99.94	71.22	3482

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 62.5% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 13)

• ASF1 cellular levels are tightly controlled by distinct pathways and provide a molecular mechanism for post-translational regulation of dASF1 and hASF1a by TLK kinases. (PMID:20016786)
• TLKs appear to be intimately linked to the pattern of resistance to DNA damage, and specifically double-strand breaks. (PMID:21647934)
• TLK2 plays a role in Kaposi’s sarcoma-associated herpesvirus reactivation. (PMID:23414760)
• Tlk2 promotes Asf1A function during the DNA damage response in G2 to allow for proper restoration of chromatin structure at the break site and subsequent recovery from the arrest. (PMID:26931568)
• Results show that TLK2 overexpression correlates with increased genome-wide copy number aberrations in breast cancer cells, impairs cell-cycle checkpoint signaling in response to DNA damage. (PMID:27489360)
• TLK2 is amplified in aggressive luminal breast neoplasms (PMID:27694828)
• haploinsufficiency of TLK2 is the most likely underlying disease mechanism, leading to a consistent neurodevelopmental phenotype. (PMID:29861108)
• Molecular basis of TLK2 activation and inhibition has been dissected. (PMID:29955062)
• Study shows that TLK2 expression is increased in glioblastoma. Furthermore, TLK2 overexpression resulted in tumor growth and metastasis via SRC signaling pathway. (PMID:30207834)
• Tousled-Like Kinases Suppress Innate Immune Signaling Triggered by Alternative Lengthening of Telomeres. (PMID:32755577)
• Functional analysis of TLK2 variants and their proximal interactomes implicates impaired kinase activity and chromatin maintenance defects in their pathogenesis. (PMID:33323470)
• Tousled-like kinase 2 targets ASF1 histone chaperones through client mimicry. (PMID:35136069)
• [Effect of TLK2 Expression Regulated by MiR-21 on Proliferation and Apoptosis of Acute Myeloid Leukemia Cells]. (PMID:38926950)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	tlk2	ENSDARG00000010779
mus_musculus	Tlk2	ENSMUSG00000020694
rattus_norvegicus	Tlk2	ENSRNOG00000006285
drosophila_melanogaster	Tlk	FBGN0283657
caenorhabditis_elegans		WBGENE00006579

Paralogs (2): TTK (ENSG00000112742), TLK1 (ENSG00000198586)

Protein

Protein identifiers

Serine/threonine-protein kinase tousled-like 2 — Q86UE8 (reviewed: Q86UE8)

Alternative names: HsHPK, PKU-alpha, Tousled-like kinase 2

All UniProt accessions (14): Q86UE8, A0A804HIB4, A0A804HJM7, A0A804HJX3, A0A804HJZ9, A0A804HK10, A0A804HKD4, A0A804HKF1, J3KRK0, J3QLK5, J3QQN4, J3QR10, J3QS44, J3QS73

UniProt curated annotations — full annotation on UniProt →

Function. Serine/threonine-protein kinase involved in the process of chromatin assembly and probably also DNA replication, transcription, repair, and chromosome segregation. Phosphorylates the chromatin assembly factors ASF1A and ASF1B. Phosphorylation of ASF1A prevents its proteasome-mediated degradation, thereby enhancing chromatin assembly. Negative regulator of amino acid starvation-induced autophagy.

Subunit / interactions. Monomer. May form homodimers; homodimerization may enhance autophosphoylation and enzymatic activity. Heterodimer with TLK1. Interacts with YWHAZ; association with 14-3-3 proteins such as YWHAZ regulates subcellular location. May also interact with FEZ1/LZTS1 and FEZ2. Interacts with CHD7 and CHD8. Interacts with DYNLL1/LC8.

Subcellular location. Nucleus. Nucleoplasm. Cytoplasm. Perinuclear region. Cytoskeleton.

Tissue specificity. Detected in placenta, fetal liver, kidney, pancreas, heart and skeletal muscle. Highly expressed in testis. Detected in spleen, thymus, colon, ovary, small intestine, prostate and peripheral blood leukocytes. Almost undetectable in liver and lung.

Post-translational modifications. Phosphorylated at Ser-750, probably by CHEK1. Autophosphorylated; phosphorylation promotes the assembly of higher order oligomers and enzymatic activity.

Disease relevance. Intellectual developmental disorder, autosomal dominant 57 (MRD57) [MIM:618050] A disorder characterized by significantly below average general intellectual functioning associated with impairments in adaptive behavior and manifested during the developmental period. MRD57 is characterized by delayed psychomotor development apparent in infancy or early childhood, and a variety of behavioral abnormalities. Affected individuals may have severe gastro-intestinal problems, and facial dysmorphism. The disease is caused by variants affecting the gene represented in this entry.

Activity regulation. Cell cycle-regulated, with maximal activity in the S-phase. Rapidly and transiently inhibited by phosphorylation following the generation of DNA double-stranded breaks during S-phase, probably by CHEK1, possibly at Ser-750. This inhibition is cell cycle checkpoint- and ATM-dependent.

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

Isoforms (3)

UniProt ID	Names	Canonical?
Q86UE8-1	1	yes
Q86UE8-2	2
Q86UE8-3	3

RefSeq proteins (10): NP_001271262, NP_001271292, NP_001317347, NP_001362198, NP_001362199, NP_001362200, NP_001362201, NP_001362202, NP_001398003, NP_006843* (*=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

Pfam: PF00069

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 (99 total): sequence variant 29, strand 14, helix 13, mutagenesis site 10, modified residue 7, sequence conflict 5, region of interest 4, turn 4, compositionally biased region 3, coiled-coil region 3, binding site 2, splice variant 2, chain 1, domain 1, active site 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
7LO0	X-RAY DIFFRACTION	2.71
5O0Y	X-RAY DIFFRACTION	2.86

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q86UE8-F1	73.15	0.50

Functional residue map

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

Catalytic / active sites (1): 592 (proton acceptor)

Ligand- & substrate-binding residues (2): 468–476; 491

Post-translational modifications (7): 73, 94, 99, 115, 117, 134, 750

Mutagenesis-validated functional residues (10):

Position	Phenotype
518	reduced kinase activity.
592	loss of kinase activity. no impact on interaction with asf1a.
613	loss of kinase activity.
617	increase in autophosphorylation.
617	loss of kinase activity.
659	reduced kinase activity.
686	reduced kinase activity.
695	reduced kinase activity.
720	reduced phosphorylation of asf1a.

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 410 (showing top): WENDT_COHESIN_TARGETS_UP, RNGTGGGC_UNKNOWN, GOBP_RESPONSE_TO_IONIZING_RADIATION, GOBP_REGULATION_OF_AUTOPHAGY, GOBP_NEGATIVE_REGULATION_OF_PROTEOLYSIS, GOBP_REGULATION_OF_PROTEASOMAL_UBIQUITIN_DEPENDENT_PROTEIN_CATABOLIC_PROCESS, GOBP_PEPTIDYL_SERINE_MODIFICATION, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, AREB6_01, GOBP_CELLULAR_RESPONSE_TO_GAMMA_RADIATION, ATGCAGT_MIR217, CCATCCA_MIR432, GOBP_NEGATIVE_REGULATION_OF_PROTEIN_CATABOLIC_PROCESS, AGGCACT_MIR5153P, GOBP_NEGATIVE_REGULATION_OF_AUTOPHAGY

GO Biological Process (11): chromatin organization (GO:0006325), protein phosphorylation (GO:0006468), DNA damage response (GO:0006974), chromosome segregation (GO:0007059), negative regulation of autophagy (GO:0010507), peptidyl-serine phosphorylation (GO:0018105), negative regulation of proteasomal ubiquitin-dependent protein catabolic process (GO:0032435), intracellular signal transduction (GO:0035556), nucleus localization (GO:0051647), cellular response to gamma radiation (GO:0071480), regulation of chromatin organization (GO:1902275)

GO Molecular Function (9): protein serine/threonine kinase activity (GO:0004674), ATP binding (GO:0005524), identical protein binding (GO:0042802), 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), intermediate filament (GO:0005882), perinuclear region of cytoplasm (GO:0048471), cytoplasm (GO:0005737), cytoskeleton (GO:0005856)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
intracellular anatomical structure	2
protein kinase activity	2
cellular component organization	1
phosphorylation	1
protein modification process	1
cellular response to stress	1
cell cycle process	1
autophagy	1
negative regulation of catabolic process	1
regulation of autophagy	1
protein phosphorylation	1
peptidyl-serine modification	1
regulation of proteasomal ubiquitin-dependent protein catabolic process	1
proteasome-mediated ubiquitin-dependent protein catabolic process	1
negative regulation of proteasomal protein catabolic process	1
negative regulation of ubiquitin-dependent protein catabolic process	1
signal transduction	1
organelle localization	1
response to gamma radiation	1
cellular response to ionizing radiation	1
chromatin organization	1
regulation of cellular component organization	1
adenyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1
protein binding	1
nucleoside phosphate binding	1
heterocyclic compound binding	1
kinase activity	1
phosphotransferase activity, alcohol group as acceptor	1
catalytic activity, acting on a protein	1
binding	1
transferase activity, transferring phosphorus-containing groups	1
catalytic activity	1
intracellular membrane-bounded organelle	1
nuclear lumen	1
intermediate filament cytoskeleton	1
polymeric cytoskeletal fiber	1
cytoplasm	1
intracellular membraneless organelle	1

Protein interactions and networks

STRING

1702 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
TLK2	ASF1B	Q9NVP2	856
TLK2	ASF1A	Q9Y294	836
TLK2	SRSF1	Q07955	801
TLK2	USP39	Q53GS9	557
TLK2	H3-7	Q5TEC6	551
TLK2	H3-5	Q6NXT2	551
TLK2	H3-3A	P06351	550
TLK2	H3-4	Q16695	549
TLK2	H3C14	Q71DI3	549
TLK2	H3C1	P02295	548
TLK2	H1-0	P07305	547
TLK2	TMUB2	Q71RG4	535
TLK2	MBP	P02686	515
TLK2	FCF1	Q9Y324	514
TLK2	DNAJC14	Q6Y2X3	499
TLK2	ZKSCAN5	Q9Y2L8	499

IntAct

84 interactions, top by confidence:

A	B	Type	Score
TLK2	DYNLL1	psi-mi:“MI:0914”(association)	0.890
ASF1A	TLK2	psi-mi:“MI:0217”(phosphorylation reaction)	0.740
TLK1	DYNLL1	psi-mi:“MI:0914”(association)	0.730
DYNLL1	BLTP3B	psi-mi:“MI:0914”(association)	0.730
ASF1A	HAT1	psi-mi:“MI:0914”(association)	0.640
ASF1B	HAT1	psi-mi:“MI:0914”(association)	0.640
DYNLL2	BLTP3B	psi-mi:“MI:0914”(association)	0.640
TLK2	FRMD6	psi-mi:“MI:0915”(physical association)	0.560
TLK2	DMAP1	psi-mi:“MI:0915”(physical association)	0.560
TLK2	UBE2I	psi-mi:“MI:0915”(physical association)	0.560
PAX6	TLK2	psi-mi:“MI:0915”(physical association)	0.560
TLK2	TLK2	psi-mi:“MI:0915”(physical association)	0.560
TLK2	CEP70	psi-mi:“MI:0915”(physical association)	0.560
TLK2	GMCL1	psi-mi:“MI:0915”(physical association)	0.560
PAX5	TLK2	psi-mi:“MI:0915”(physical association)	0.560
UBE2I	TLK2	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (220): TLK2 (Affinity Capture-MS), TLK2 (Affinity Capture-MS), TLK2 (Affinity Capture-MS), TLK2 (Co-fractionation), TLK2 (Affinity Capture-MS), TLK2 (Affinity Capture-MS), TLK2 (Affinity Capture-MS), TLK2 (Affinity Capture-MS), TLK2 (Affinity Capture-MS), TLK2 (Affinity Capture-MS), TLK1 (Affinity Capture-MS), TLK2 (Affinity Capture-MS), TLK2 (Affinity Capture-MS), TLK2 (Affinity Capture-MS), RPS27A (Affinity Capture-MS)

ESM2 similar proteins: A0A8C0TYJ0, A0A8I5ZNK2, A5D7H2, O55047, O88506, O94806, O95747, P00535, P11273, P32298, P34947, P43249, P49137, Q08CW1, Q12959, Q13033, Q15139, Q15700, Q16644, Q1ECX4, Q28C55, Q3SYZ2, Q3UMW7, Q5PYH5, Q5PYH6, Q5R372, Q5R495, Q5RCW6, Q5XIS9, Q62101, Q62696, Q62833, Q63622, Q66H84, Q6P9R2, Q811D0, Q863I2, Q86UE8, Q8BZ03, Q8C0V0

Diamond homologs: A0A2I0BVG8, A0A509AHB6, A0A509AQE6, A0A5K1K8H0, A7SNN5, A8WXF6, B4HBU3, B4J3F1, B4KYX8, D3ZHP7, F4IRW0, O01427, O15865, O22932, O34507, O55047, O59790, O60285, O62305, O64629, O74536, O75385, O77708, O88445, O96017, P06782, P0C8M8, P11275, P11730, P11798, P15791, P23647, P31749, P31751, P32562, P34314, P47197, P50528, P53351, P62343

SIGNOR signaling

3 interactions.

A	Effect	B	Mechanism
TLK2	“up-regulates quantity by stabilization”	ASF1A	phosphorylation
TLK2	unknown	ASF1B	phosphorylation
CHEK1	“down-regulates activity”	TLK2	phosphorylation

Disease & clinical

Cancer significance

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	40
Likely pathogenic	36
Uncertain significance	152
Likely benign	27
Benign	2

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1098335	NM_006852.6(TLK2):c.1369-2A>G	Pathogenic
1217689	NM_006852.6(TLK2):c.665del (p.Asn222fs)	Pathogenic
1285495	NM_006852.6(TLK2):c.36del (p.Gln13fs)	Pathogenic
1675684	NM_006852.6(TLK2):c.1052dup (p.Gln352fs)	Pathogenic
1699127	NM_006852.6(TLK2):c.1366A>T (p.Lys456Ter)	Pathogenic
2231467	NM_006852.6(TLK2):c.1189-2A>G	Pathogenic
2570996	NM_006852.6(TLK2):c.1726dup (p.Ile576fs)	Pathogenic
2692575	NM_006852.6(TLK2):c.267+1G>A	Pathogenic
3337452	NM_006852.6(TLK2):c.839_840del (p.Gln280fs)	Pathogenic
3376137	NM_006852.6(TLK2):c.1415del (p.Gln472fs)	Pathogenic
3382792	NM_006852.6(TLK2):c.154-1G>A	Pathogenic
3456890	NM_006852.6(TLK2):c.1397dup (p.Ala467fs)	Pathogenic
3544389	NM_006852.6(TLK2):c.1286+1G>A	Pathogenic
3572904	NM_006852.6(TLK2):c.1865del (p.Leu622fs)	Pathogenic
3766074	NM_006852.6(TLK2):c.78_81del (p.Ser26fs)	Pathogenic
4056443	NM_006852.6(TLK2):c.2079+1G>A	Pathogenic
4528367	NM_006852.6(TLK2):c.865_866insTT (p.Ser289fs)	Pathogenic
4633167	NM_006852.6(TLK2):c.1929G>A (p.Trp643Ter)	Pathogenic
4685552	NM_006852.6(TLK2):c.1187_1188+18del	Pathogenic
4813044	NM_006852.6(TLK2):c.736A>T (p.Arg246Ter)	Pathogenic
521637	NM_006852.6(TLK2):c.1746del (p.Ala583fs)	Pathogenic
548933	NM_006852.6(TLK2):c.1720+1G>T	Pathogenic
548935	NM_006852.6(TLK2):c.989C>A (p.Ser330Ter)	Pathogenic
548936	NM_006852.6(TLK2):c.1460+2T>G	Pathogenic
617919	NM_006852.6(TLK2):c.784C>T (p.Arg262Ter)	Pathogenic
617923	NM_006852.6(TLK2):c.202G>T (p.Glu68Ter)	Pathogenic
617928	NM_006852.6(TLK2):c.181C>T (p.Arg61Ter)	Pathogenic
617935	NM_006852.6(TLK2):c.37C>T (p.Gln13Ter)	Pathogenic
617937	NM_006852.6(TLK2):c.1651C>T (p.Gln551Ter)	Pathogenic
620161	NM_006852.6(TLK2):c.1928G>A (p.Trp643Ter)	Pathogenic

SpliceAI

3377 predictions. Top by Δscore:

Variant	Effect	Δscore
17:62481115:TTTCA:T	acceptor_loss	1.0000
17:62481116:TTCAG:T	acceptor_loss	1.0000
17:62481117:TCA:T	acceptor_loss	1.0000
17:62481118:CA:C	acceptor_loss	1.0000
17:62481119:A:AC	acceptor_loss	1.0000
17:62481119:A:AG	acceptor_gain	1.0000
17:62481120:G:GA	acceptor_gain	1.0000
17:62481120:GC:G	acceptor_gain	1.0000
17:62481120:GCA:G	acceptor_gain	1.0000
17:62481120:GCAGA:G	acceptor_gain	1.0000
17:62481123:GAA:G	acceptor_gain	1.0000
17:62481202:GTAAG:G	donor_gain	1.0000
17:62481204:AAGGT:A	donor_loss	1.0000
17:62481205:AGGTG:A	donor_loss	1.0000
17:62481207:GTGA:G	donor_loss	1.0000
17:62520768:TTCA:T	acceptor_loss	1.0000
17:62520769:TCA:T	acceptor_loss	1.0000
17:62520770:CA:C	acceptor_loss	1.0000
17:62520771:A:AG	acceptor_gain	1.0000
17:62520771:A:C	acceptor_loss	1.0000
17:62520771:AG:A	acceptor_gain	1.0000
17:62520771:AGG:A	acceptor_gain	1.0000
17:62520772:G:A	acceptor_gain	1.0000
17:62520772:G:GT	acceptor_gain	1.0000
17:62520772:GGG:G	acceptor_gain	1.0000
17:62520772:GGGA:G	acceptor_gain	1.0000
17:62520772:GGGAC:G	acceptor_gain	1.0000
17:62520841:AGAG:A	donor_loss	1.0000
17:62520845:G:C	donor_loss	1.0000
17:62522190:AT:A	acceptor_gain	1.0000

AlphaMissense

4926 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
17:62481181:G:T	R19M	1.000
17:62560113:T:C	L273P	1.000
17:62560116:T:C	L274P	1.000
17:62565001:T:C	S278P	1.000
17:62565026:G:C	R286T	1.000
17:62565027:A:C	R286S	1.000
17:62565027:A:T	R286S	1.000
17:62565047:G:C	R293P	1.000
17:62565056:T:A	L296Q	1.000
17:62565056:T:C	L296P	1.000
17:62565058:G:A	G297S	1.000
17:62565058:G:C	G297R	1.000
17:62565058:G:T	G297C	1.000
17:62565059:G:A	G297D	1.000
17:62565059:G:C	G297A	1.000
17:62565059:G:T	G297V	1.000
17:62565064:T:C	F299L	1.000
17:62565066:T:A	F299L	1.000
17:62565066:T:G	F299L	1.000
17:62565083:G:A	G305E	1.000
17:62565103:T:A	W312R	1.000
17:62565103:T:C	W312R	1.000
17:62565104:G:C	W312S	1.000
17:62565105:G:C	W312C	1.000
17:62565105:G:T	W312C	1.000
17:62565112:G:C	G315R	1.000
17:62565112:G:T	G315C	1.000
17:62565113:G:A	G315D	1.000
17:62565113:G:T	G315V	1.000
17:62565121:T:C	F318L	1.000

dbSNP variants (sampled 300 via entrez): RS1000015598 (17:62469948 G>A), RS1000073188 (17:62604719 G>A), RS1000093135 (17:62498468 C>T), RS1000094671 (17:62471361 A>G), RS1000149610 (17:62492618 G>A,C,T), RS1000155801 (17:62571528 A>G), RS1000205913 (17:62547189 A>T), RS1000249159 (17:62608213 G>A,T), RS1000305221 (17:62540484 A>C), RS1000321835 (17:62475666 A>G), RS1000331971 (17:62521275 C>G,T), RS1000371513 (17:62601452 C>T), RS1000386738 (17:62515832 T>C), RS1000404865 (17:62559291 A>G), RS1000439132 (17:62515534 A>G)

Disease associations

OMIM: gene MIM:608439 | disease phenotypes: MIM:618050, MIM:162200, MIM:309800

GenCC curated gene-disease

Disease	Classification	Inheritance
intellectual disability, autosomal dominant 57	Definitive	Autosomal dominant

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
complex neurodevelopmental disorder	Definitive	AD

Mondo (5): intellectual disability, autosomal dominant 57 (MONDO:0054837), neurodevelopmental disorder (MONDO:0700092), neurofibromatosis type 1 (MONDO:0018975), syndromic microphthalmia (MONDO:0016073), intellectual disability (MONDO:0001071)

Orphanet (4): Neurofibromatosis type 1 (Orphanet:636), Syndromic microphthalmia-anophthalmia-coloboma (Orphanet:202948), Rare genetic intellectual disability (Orphanet:183757), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658)

HPO phenotypes

53 total (30 of 53 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000160	Narrow mouth
HP:0000218	High palate
HP:0000219	Thin upper lip vermilion
HP:0000252	Microcephaly
HP:0000276	Long face
HP:0000286	Epicanthus
HP:0000307	Pointed chin
HP:0000316	Hypertelorism
HP:0000358	Posteriorly rotated ears
HP:0000388	Otitis media
HP:0000426	Prominent nasal bridge
HP:0000455	Broad nasal tip
HP:0000486	Strabismus
HP:0000506	Telecanthus
HP:0000508	Ptosis
HP:0000545	Myopia
HP:0000581	Blepharophimosis
HP:0000582	Upslanted palpebral fissure
HP:0000722	Compulsive behaviors
HP:0000729	Autistic behavior
HP:0000739	Anxiety
HP:0000750	Delayed speech and language development
HP:0000998	Hypertrichosis
HP:0001156	Brachydactyly
HP:0001195	Single umbilical artery
HP:0001249	Intellectual disability
HP:0001250	Seizure
HP:0001263	Global developmental delay
HP:0001270	Motor delay

GWAS associations

8 associations (top):

Study	Trait	p-value
GCST002846_1	Lifespan	5.000000e-20
GCST006979_513	Heel bone mineral density	9.000000e-14
GCST006979_514	Heel bone mineral density	5.000000e-10
GCST90000025_605	Appendicular lean mass	3.000000e-16
GCST90020025_1485	Waist-to-hip ratio adjusted for BMI	2.000000e-08
GCST90020027_435	Waist-hip index	2.000000e-08
GCST90020028_1427	Hip circumference adjusted for BMI	1.000000e-09
GCST90020028_1437	Hip circumference adjusted for BMI	1.000000e-08

EFO canonical traits (4, from GWAS)

EFO ID	Trait name
EFO:0009270	heel bone mineral density
EFO:0004980	appendicular lean mass
EFO:0007788	BMI-adjusted waist-hip ratio
EFO:0008039	BMI-adjusted hip circumference

MeSH disease descriptors (3)

Descriptor	Name	Tree numbers
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539
D065886	Neurodevelopmental Disorders	F03.625
D009456	Neurofibromatosis 1	C04.557.580.600.580.590.650; C04.700.631.650; C10.562.600.500; C10.574.500.549.400; C10.668.829.675; C16.320.400.560.400; C16.320.700.633.650

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL5404 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

11 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 105,971 (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
CHEMBL288441	BOSUTINIB	4	12,255
CHEMBL535	SUNITINIB	4	79,020
CHEMBL300138	ENZASTAURIN	3	3,209
CHEMBL522892	DOVITINIB	3	4,944
CHEMBL603469	LESTAURTINIB	3
CHEMBL13608	TOCERANIB	2	1,166
CHEMBL1721885	SU-014813	2	363
CHEMBL475251	R-406	2	762
CHEMBL1908397	KW-2449	1	622
CHEMBL258805	SU-9516	1	76

Clinical evidence (CIViC)

Drug × variant × indication: 1 predictive associations from 1 curated evidence items.

Variant	Therapy	Indication	Effect	Level	CIViC
TLK2 Amplification	GF109203X + Go6983	Breast Cancer	Sensitivity/Response	CIViC D	EID6000

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

GtoPdb / IUPHAR curated pharmacology

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

Target class: enzyme — Tousled-like kinase (TLK) family

Binding affinities (BindingDB)

5 measured of 5 human assays (5 total across all organisms); most potent 5 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value
Staurosporine	KD	1.7 nM
(3Z)-4-amino-5-fluoro-3-[5-(4-methylpiperazino)-1,3-dihydrobenzimidazol-2-ylidene]carbostyril	KD	520 nM
5-[(Z)-(5-fluoranyl-2-oxidanylidene-1H-indol-3-ylidene)methyl]-2,4-dimethyl-N-[(2S)-3-morpholin-4-yl-2-oxidanyl-propyl]-1H-pyrrole-3-carboxamide	KD	2600 nM
1-Acyl-1H-[1,2,4]triazole-3,5-diamine Analogue 3b	KD	3100 nM
N-[2-(diethylamino)ethyl]-5-[(Z)-(5-fluoro-2-oxo-1,2-dihydro-3H-indol-3-ylidene)methyl]-2,4-dimethyl-1H-pyrrole-3-carboxamide	KD	3500 nM

ChEMBL bioactivities

119 potent at pChembl≥5 of 119 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
8.57	IC50	2.71	nM	STAUROSPORINE
8.47	IC50	3.37	nM	STAUROSPORINE
8.44	IC50	3.66	nM	STAUROSPORINE
8.04	IC50	9.1	nM	CHEMBL5549938
7.92	IC50	12	nM	CHEMBL5505789
7.82	IC50	15	nM	CHEMBL5555013
7.82	IC50	15	nM	CHEMBL5505914
7.80	Kd	16	nM	STAUROSPORINE
7.75	IC50	18	nM	CHEMBL5555697
7.73	IC50	18.65	nM	CHEMBL5204542
7.64	IC50	23	nM	CHEMBL5556475
7.58	IC50	26	nM	CHEMBL5505934
7.57	IC50	27	nM	CHEMBL5556322
7.48	IC50	33.15	nM	CHEMBL5188455
7.47	IC50	34	nM	CHEMBL5523411
7.44	IC50	36	nM	CHEMBL5512470
7.34	IC50	46	nM	CHEMBL5556177
7.33	IC50	47	nM	CHEMBL5559472
7.32	IC50	48	nM	CHEMBL5518017
7.21	IC50	62	nM	CHEMBL107225
7.21	IC50	61	nM	CHEMBL235641
7.19	Kd	64	nM	LESTAURTINIB
7.17	IC50	67	nM	CHEMBL5542619
7.11	IC50	77	nM	CHEMBL5558307
7.06	IC50	88	nM	CHEMBL5517951
7.02	IC50	95	nM	CHEMBL5555801
7.01	IC50	97	nM	CHEMBL5555013
7.00	IC50	100	nM	CHEMBL5559206
7.00	IC50	100	nM	CHEMBL5555012
7.00	IC50	100	nM	CHEMBL5555855
6.96	IC50	110	nM	CHEMBL5556090
6.96	IC50	110	nM	CHEMBL5523653
6.96	IC50	110	nM	CHEMBL5555911
6.92	IC50	120	nM	CHEMBL5542185
6.92	IC50	120	nM	CHEMBL5505767
6.89	IC50	130	nM	CHEMBL5558654
6.89	IC50	130	nM	CHEMBL5517792
6.85	IC50	140	nM	CHEMBL5505761
6.85	IC50	140	nM	CHEMBL5518089
6.82	IC50	150	nM	CHEMBL5559521
6.82	IC50	150	nM	CHEMBL5523551
6.80	IC50	160	nM	CHEMBL5523586
6.79	IC50	163.4	nM	CHEMBL5173181
6.77	IC50	170	nM	CHEMBL5542171
6.75	IC50	180	nM	CHEMBL5556812
6.72	IC50	190	nM	CHEMBL5505927
6.72	IC50	190	nM	CHEMBL5542948
6.70	IC50	200	nM	CHEMBL5556132
6.66	IC50	220	nM	CHEMBL5556373
6.64	IC50	230	nM	CHEMBL5555777

PubChem BioAssay actives

119 with measured affinity, of 747 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
(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	2198444: Inhibition of human TLK2 using casein as substrate preincubated for 20 mins followed by [gamma-33P]-ATP addition and measured after 120 mins by radiometric Hot-SpotSM Kinase assay	ic50	0.0027	uM
N-[(3Z)-3-(1H-imidazol-5-ylmethylidene)-2-oxo-1H-indol-5-yl]-2-methoxybenzamide	2062918: Inhibition of human TLK2 preincubated for 20 mins followed by 33P-ATP addition and measured after 120 mins by hotspot assay	ic50	0.0091	uM
4-cyano-N-[3-(1H-imidazol-5-ylmethylidene)-2-oxo-1H-indol-5-yl]benzamide	2062918: Inhibition of human TLK2 preincubated for 20 mins followed by 33P-ATP addition and measured after 120 mins by hotspot assay	ic50	0.0120	uM
N-[(3Z)-3-(1H-imidazol-5-ylmethylidene)-2-oxo-1H-indol-5-yl]thiophene-2-carboxamide	2062918: Inhibition of human TLK2 preincubated for 20 mins followed by 33P-ATP addition and measured after 120 mins by hotspot assay	ic50	0.0150	uM
N-[(3Z)-3-(1H-imidazol-5-ylmethylidene)-2-oxo-1H-indol-5-yl]-1,3-oxazole-2-carboxamide	2062918: Inhibition of human TLK2 preincubated for 20 mins followed by 33P-ATP addition and measured after 120 mins by hotspot assay	ic50	0.0150	uM
N-[(3Z)-3-[(5-methyl-1H-imidazol-4-yl)methylidene]-2-oxo-1H-indol-5-yl]benzamide	2062918: Inhibition of human TLK2 preincubated for 20 mins followed by 33P-ATP addition and measured after 120 mins by hotspot assay	ic50	0.0180	uM
3-[(3E)-3-[2-(1-methylpyrrolidin-2-yl)ethoxyimino]indol-2-yl]-1H-indol-2-ol	1887963: Binding affinity to full length FLAG/HA/Strep-tagged TLK2 (388 to 772 residues) (unknown origin) transfected in HEK293T cells by Alexa Fluor 647 staining based FRET assay	ic50	0.0186	uM
N-(2-oxo-1,3-dihydroindol-5-yl)thieno[3,2-b]thiophene-5-carboxamide	2062918: Inhibition of human TLK2 preincubated for 20 mins followed by 33P-ATP addition and measured after 120 mins by hotspot assay	ic50	0.0230	uM
(3Z)-3-(1H-imidazol-2-ylmethylidene)-2-oxo-1H-indole-5-carboxylic acid	2062918: Inhibition of human TLK2 preincubated for 20 mins followed by 33P-ATP addition and measured after 120 mins by hotspot assay	ic50	0.0260	uM
4-ethoxy-N-[3-(1H-imidazol-5-ylmethylidene)-2-oxo-1H-indol-5-yl]thiophene-2-carboxamide	2062918: Inhibition of human TLK2 preincubated for 20 mins followed by 33P-ATP addition and measured after 120 mins by hotspot assay	ic50	0.0270	uM
3-[(3E)-3-(1-methylpiperidin-4-yl)oxyiminoindol-2-yl]-1H-indol-2-ol	1887963: Binding affinity to full length FLAG/HA/Strep-tagged TLK2 (388 to 772 residues) (unknown origin) transfected in HEK293T cells by Alexa Fluor 647 staining based FRET assay	ic50	0.0331	uM
N-[3-(1H-imidazol-5-ylmethylidene)-2-oxo-1H-indol-5-yl]benzamide	2062918: Inhibition of human TLK2 preincubated for 20 mins followed by 33P-ATP addition and measured after 120 mins by hotspot assay	ic50	0.0340	uM
N-[3-(1H-imidazol-2-ylmethylidene)-2-oxo-1H-indol-5-yl]thiophene-2-carboxamide	2062918: Inhibition of human TLK2 preincubated for 20 mins followed by 33P-ATP addition and measured after 120 mins by hotspot assay	ic50	0.0360	uM
N-[3-(1H-imidazol-5-ylmethylidene)-2-oxo-1H-indol-5-yl]-1,2-thiazole-5-carboxamide	2062918: Inhibition of human TLK2 preincubated for 20 mins followed by 33P-ATP addition and measured after 120 mins by hotspot assay	ic50	0.0460	uM
N-[(3Z)-3-(1H-imidazol-5-ylmethylidene)-2-oxo-1H-indol-5-yl]thieno[3,2-b]thiophene-5-carboxamide	2062918: Inhibition of human TLK2 preincubated for 20 mins followed by 33P-ATP addition and measured after 120 mins by hotspot assay	ic50	0.0470	uM
3-cyano-N-[(3Z)-3-(1H-imidazol-2-ylmethylidene)-2-oxo-1H-indol-5-yl]benzamide	2062918: Inhibition of human TLK2 preincubated for 20 mins followed by 33P-ATP addition and measured after 120 mins by hotspot assay	ic50	0.0480	uM
(8Z)-8-(1H-imidazol-5-ylmethylidene)-6H-pyrrolo[2,3-g][1,3]benzothiazol-7-one	2062923: Inhibition of TLK2 (unknown origin)	ic50	0.0610	uM
(3Z)-2-oxo-3-(1H-pyrrol-2-ylmethylidene)-1H-indole-5-carboxylic acid	2062918: Inhibition of human TLK2 preincubated for 20 mins followed by 33P-ATP addition and measured after 120 mins by hotspot assay	ic50	0.0620	uM
(15S,16S,18R)-16-hydroxy-16-(hydroxymethyl)-15-methyl-28-oxa-4,14,19-triazaoctacyclo[12.11.2.115,18.02,6.07,27.08,13.019,26.020,25]octacosa-1,6,8,10,12,20,22,24,26-nonaen-3-one	508112: Binding affinity to TLK2	kd	0.0640	uM
N-[(3Z)-3-(1H-imidazol-2-ylmethylidene)-2-oxo-1H-indol-5-yl]-2-methoxybenzamide	2062918: Inhibition of human TLK2 preincubated for 20 mins followed by 33P-ATP addition and measured after 120 mins by hotspot assay	ic50	0.0670	uM
N-[(3Z)-3-(1H-imidazol-5-ylmethylidene)-2-oxo-1H-indol-5-yl]-4-methoxythiophene-2-carboxamide	2062918: Inhibition of human TLK2 preincubated for 20 mins followed by 33P-ATP addition and measured after 120 mins by hotspot assay	ic50	0.0770	uM
N-[(3Z)-3-(1H-imidazol-5-ylmethylidene)-2-oxo-1H-indol-5-yl]-4-methoxybenzamide	2062918: Inhibition of human TLK2 preincubated for 20 mins followed by 33P-ATP addition and measured after 120 mins by hotspot assay	ic50	0.0880	uM
3-cyano-N-[3-(1H-imidazol-5-ylmethylidene)-2-oxo-1H-indol-5-yl]benzamide	2062918: Inhibition of human TLK2 preincubated for 20 mins followed by 33P-ATP addition and measured after 120 mins by hotspot assay	ic50	0.0950	uM
(3Z)-5-(furan-2-carbonyl)-3-(1H-pyrrol-2-ylmethylidene)-1H-indol-2-one	2062918: Inhibition of human TLK2 preincubated for 20 mins followed by 33P-ATP addition and measured after 120 mins by hotspot assay	ic50	0.1000	uM
N-[(3Z)-3-(1H-imidazol-5-ylmethylidene)-2-oxo-1H-indol-5-yl]cyclohexanecarboxamide	2062918: Inhibition of human TLK2 preincubated for 20 mins followed by 33P-ATP addition and measured after 120 mins by hotspot assay	ic50	0.1000	uM
N-[(3Z)-3-(1H-imidazol-5-ylmethylidene)-2-oxo-1H-indol-5-yl]-3-methoxybenzamide	2062918: Inhibition of human TLK2 preincubated for 20 mins followed by 33P-ATP addition and measured after 120 mins by hotspot assay	ic50	0.1000	uM
N-[(3Z)-3-(1H-imidazol-2-ylmethylidene)-2-oxo-1H-indol-5-yl]benzamide	2062918: Inhibition of human TLK2 preincubated for 20 mins followed by 33P-ATP addition and measured after 120 mins by hotspot assay	ic50	0.1100	uM
N-[(3Z)-3-(1H-imidazol-2-ylmethylidene)-2-oxo-1H-indol-5-yl]-4-methoxybenzamide	2062918: Inhibition of human TLK2 preincubated for 20 mins followed by 33P-ATP addition and measured after 120 mins by hotspot assay	ic50	0.1100	uM
2-fluoro-N-[(3Z)-3-(1H-imidazol-2-ylmethylidene)-2-oxo-1H-indol-5-yl]benzamide	2062918: Inhibition of human TLK2 preincubated for 20 mins followed by 33P-ATP addition and measured after 120 mins by hotspot assay	ic50	0.1100	uM
N-[(3Z)-2-oxo-3-(1H-pyrrol-2-ylmethylidene)-1H-indol-5-yl]furan-2-carboxamide	2062918: Inhibition of human TLK2 preincubated for 20 mins followed by 33P-ATP addition and measured after 120 mins by hotspot assay	ic50	0.1200	uM
N-[(3Z)-3-(1H-imidazol-5-ylmethylidene)-2-oxo-1H-indol-5-yl]-1,3-thiazole-2-carboxamide	2062918: Inhibition of human TLK2 preincubated for 20 mins followed by 33P-ATP addition and measured after 120 mins by hotspot assay	ic50	0.1200	uM
N-[(3Z)-3-(1H-imidazol-2-ylmethylidene)-2-oxo-1H-indol-5-yl]cyclohexanecarboxamide	2062918: Inhibition of human TLK2 preincubated for 20 mins followed by 33P-ATP addition and measured after 120 mins by hotspot assay	ic50	0.1300	uM
N-[(3Z)-3-(1H-imidazol-2-ylmethylidene)-2-oxo-1H-indol-5-yl]furan-2-carboxamide	2062918: Inhibition of human TLK2 preincubated for 20 mins followed by 33P-ATP addition and measured after 120 mins by hotspot assay	ic50	0.1300	uM
3-(1H-imidazol-5-ylmethylidene)-2-oxo-1H-indole-5-carboxylic acid	2062918: Inhibition of human TLK2 preincubated for 20 mins followed by 33P-ATP addition and measured after 120 mins by hotspot assay	ic50	0.1400	uM
4-fluoro-N-[(3Z)-3-(1H-imidazol-2-ylmethylidene)-2-oxo-1H-indol-5-yl]benzamide	2062918: Inhibition of human TLK2 preincubated for 20 mins followed by 33P-ATP addition and measured after 120 mins by hotspot assay	ic50	0.1400	uM
N-[(3Z)-2-oxo-3-(1H-pyrrol-2-ylmethylidene)-1H-indol-5-yl]cyclohexanecarboxamide	2062918: Inhibition of human TLK2 preincubated for 20 mins followed by 33P-ATP addition and measured after 120 mins by hotspot assay	ic50	0.1500	uM
(3Z)-5-acetyl-3-(1H-pyrrol-2-ylmethylidene)-1H-indol-2-one	2062918: Inhibition of human TLK2 preincubated for 20 mins followed by 33P-ATP addition and measured after 120 mins by hotspot assay	ic50	0.1500	uM
(3Z)-3-(1H-imidazol-2-ylmethylidene)-5-propan-2-yloxy-1H-indol-2-one	2062918: Inhibition of human TLK2 preincubated for 20 mins followed by 33P-ATP addition and measured after 120 mins by hotspot assay	ic50	0.1600	uM
(3E)-3-[(3Z)-3-[2-(1-methylpiperidin-2-yl)ethoxyimino]-1H-inden-2-ylidene]-1H-indol-2-one	1887963: Binding affinity to full length FLAG/HA/Strep-tagged TLK2 (388 to 772 residues) (unknown origin) transfected in HEK293T cells by Alexa Fluor 647 staining based FRET assay	ic50	0.1634	uM
N-[(3Z)-2-oxo-3-(1H-pyrrol-2-ylmethylidene)-1H-indol-5-yl]butanamide	2062918: Inhibition of human TLK2 preincubated for 20 mins followed by 33P-ATP addition and measured after 120 mins by hotspot assay	ic50	0.1700	uM
4-fluoro-N-[(3Z)-3-(1H-imidazol-5-ylmethylidene)-2-oxo-1H-indol-5-yl]thiophene-2-carboxamide	2062918: Inhibition of human TLK2 preincubated for 20 mins followed by 33P-ATP addition and measured after 120 mins by hotspot assay	ic50	0.1800	uM
4-fluoro-N-[(3Z)-3-(1H-imidazol-5-ylmethylidene)-2-oxo-1H-indol-5-yl]benzamide	2062918: Inhibition of human TLK2 preincubated for 20 mins followed by 33P-ATP addition and measured after 120 mins by hotspot assay	ic50	0.1900	uM
N-[3-(1H-imidazol-2-ylmethylidene)-2-oxo-1H-indol-5-yl]-2-(trifluoromethyl)benzamide	2062918: Inhibition of human TLK2 preincubated for 20 mins followed by 33P-ATP addition and measured after 120 mins by hotspot assay	ic50	0.1900	uM
3-fluoro-N-[(3Z)-3-(1H-imidazol-5-ylmethylidene)-2-oxo-1H-indol-5-yl]benzamide	2062918: Inhibition of human TLK2 preincubated for 20 mins followed by 33P-ATP addition and measured after 120 mins by hotspot assay	ic50	0.2000	uM
(3Z)-5-butanoyl-3-(1H-pyrrol-2-ylmethylidene)-1H-indol-2-one	2062918: Inhibition of human TLK2 preincubated for 20 mins followed by 33P-ATP addition and measured after 120 mins by hotspot assay	ic50	0.2200	uM
(3Z)-5-butanoyl-3-(1H-imidazol-5-ylmethylidene)-1H-indol-2-one	2062918: Inhibition of human TLK2 preincubated for 20 mins followed by 33P-ATP addition and measured after 120 mins by hotspot assay	ic50	0.2300	uM
(3Z)-3-(1H-imidazol-5-ylmethylidene)-5-methoxy-1H-indol-2-one	2062918: Inhibition of human TLK2 preincubated for 20 mins followed by 33P-ATP addition and measured after 120 mins by hotspot assay	ic50	0.2400	uM
(3Z)-5-butanoyl-3-(1H-imidazol-2-ylmethylidene)-1H-indol-2-one	2062918: Inhibition of human TLK2 preincubated for 20 mins followed by 33P-ATP addition and measured after 120 mins by hotspot assay	ic50	0.2500	uM
N-[(3Z)-3-(1H-imidazol-5-ylmethylidene)-2-oxo-1H-indol-5-yl]-1,3-benzodioxole-4-carboxamide	2062918: Inhibition of human TLK2 preincubated for 20 mins followed by 33P-ATP addition and measured after 120 mins by hotspot assay	ic50	0.2600	uM
5-[(Z)-(5-fluoro-2-oxo-1H-indol-3-ylidene)methyl]-N-[(2S)-2-hydroxy-3-morpholin-4-ylpropyl]-2,4-dimethyl-1H-pyrrole-3-carboxamide	436054: Binding constant for TLK2 kinase domain	kd	0.2700	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, decreases methylation, affects cotreatment, decreases expression	7
trichostatin A	decreases expression, affects cotreatment	3
Phenylmercuric Acetate	affects cotreatment, decreases expression	2
Rotenone	decreases expression	2
7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide	decreases expression	2
aristolochic acid I	decreases expression	1
GSK-J4	increases expression	1
FR900359	affects phosphorylation	1
triphenyl phosphate	affects expression	1
pirinixic acid	affects binding, decreases expression, increases activity	1
tris(1,3-dichloro-2-propyl)phosphate	increases expression	1
aflatoxin B2	decreases methylation	1
coumarin	increases phosphorylation	1
di-n-butylphosphoric acid	affects expression	1
nickel acetate	affects expression	1
K 7174	increases expression	1
fenpyroximate	decreases expression	1
4-chloro-N-((4-(1,1-dimethylethyl)phenyl)methyl)-3-ethyl-1-methyl-1H-pyrazole-5-carboxamide	decreases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
pyrimidifen	decreases expression	1
abrine	increases expression	1
pyrachlostrobin	decreases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
picoxystrobin	decreases expression	1
4-(4-((5-(4,5-dimethyl-2-nitrophenyl)-2-furanyl)methylene)-4,5-dihydro-3-methyl-5-oxo-1H-pyrazol-1-yl)benzoic acid	decreases expression	1
Resveratrol	increases phosphorylation	1
Vorinostat	decreases expression	1
Leflunomide	increases expression	1
Antimycin A	decreases expression	1
Atrazine	decreases expression	1

ChEMBL screening assays

185 unique, capped per target: 185 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1059380	Binding	Inhibition of TLK2 assessed as enzyme activity at 1 uM relative to untreated control	Selective inhibitors of the mutant B-Raf pathway: discovery of a potent and orally bioavailable aminoisoquinoline. — J Med Chem

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT04586348	PHASE4	UNKNOWN	Prenatal Iodine Supplementation and Early Childhood Neurodevelopment
NCT04873115	PHASE4	UNKNOWN	Double-blind, Placebo-controlled, Randomized Clinical Trial Comparing the Efficacy and Safety of Sialanar Plus orAl rehabiLitation Against Placebo Plus Oral Rehabilitation for chIldren and Adolescents With seVere Sialorrhoea and Neurodisabilties,
NCT00169611	PHASE4	COMPLETED	NF1-Attention: Study of Children With Neurofibromatosis Type 1 Treated by Methylphenidate
NCT03975829	PHASE4	RECRUITING	Pediatric Long-Term Follow-up and Rollover Study
NCT02559102	PHASE3	COMPLETED	Dexmedetomidine Sedation Versus General Anaesthesia for Inguinal Hernia Surgery in Infants
NCT02757079	PHASE3	COMPLETED	Study of the Efficacy and Safety of NPC-15 for Sleep Disorders of Children With Neurodevelopmental Disorders
NCT06915480	PHASE3	RECRUITING	Reducing Missed Appointments
NCT07377032	PHASE3	RECRUITING	TAP-GRIN: Interventional Study on Patients With GRIN-related Neurodevelopmental Disorders
NCT02471339	PHASE3	COMPLETED	Acceptance and Commitment Training for Adolescents and Young Adults With Neurofibromatosis Type 1, Plexiform Neurofibromas, and Chronic Pain
NCT03871257	PHASE3	ACTIVE_NOT_RECRUITING	A Study of the Drugs Selumetinib Versus Carboplatin/Vincristine in Patients With Neurofibromatosis and Low-Grade Glioma
NCT04461886	PHASE3	TERMINATED	A Long-term Study of NPC-12G Gel in Neurofibromatosis Type I
NCT04924608	PHASE3	ACTIVE_NOT_RECRUITING	Efficacy and Safety of Selumetinib in Adults With NF1 Who Have Symptomatic, Inoperable Plexiform Neurofibromas
NCT05913037	PHASE3	ACTIVE_NOT_RECRUITING	FCN-159 in Adult Patients With Symptomatic, Inoperable Neurofibromatosis Type 1-Related Plexiform Neurofibromas
NCT02909959	PHASE2	COMPLETED	Sulforaphane for the Treatment of Young Men With Autism Spectrum Disorder
NCT06081348	PHASE2	RECRUITING	Sertraline vs. Placebo in the Treatment of Anxiety in Children and AdoLescents With NeurodevelopMental Disorders
NCT06352372	PHASE2	COMPLETED	Safety and Efficacy of tPBM for Epileptiform Activity in Autism
NCT00021541	PHASE2	COMPLETED	R115777 to Treat Children With Neurofibromatosis Type 1 and Progressive Plexiform Neurofibromas
NCT00030264	PHASE2	COMPLETED	Combination Chemotherapy in Treating Patients With Neurofibromatosis and Progressive Plexiform Neurofibromas
NCT00076102	PHASE2	COMPLETED	Pirfenidone in Children and Young Adults With Neurofibromatosis Type I and Progressive Plexiform Neurofibromas
NCT00304083	PHASE2	COMPLETED	Combination Chemotherapy in Treating Patients With Stage III or Stage IV Malignant Peripheral Nerve Sheath Tumors
NCT00326872	PHASE2	TERMINATED	AZD2171 in Treating Patients With Neurofibromatosis Type 1 and Plexiform Neurofibroma and/or Neurofibroma Near the Spine
NCT00589784	PHASE2	COMPLETED	Phase II Trial of Sunitinib (SU011248) in Patients With Recurrent or Inoperable Meningioma
NCT00634270	PHASE2	COMPLETED	A Phase II Study of the mTOR Inhibitor Sirolimus in Neurofibromatosis Type 1 Related Plexiform Neurofibromas
NCT00754780	PHASE2	COMPLETED	Clinical Trial of Pirfenidone in Adult Patients With Neurofibromatosis 1
NCT00846430	PHASE2	COMPLETED	Medical Treatment of High-Risk Neurofibromas
NCT00853580	PHASE2	COMPLETED	A Randomized Placebo-Controlled Study of Lovastatin in Children With Neurofibromatosis Type 1
NCT01125046	PHASE2	COMPLETED	Bevacizumab in Treating Patients With Recurrent or Progressive Meningiomas
NCT01402817	PHASE2	TERMINATED	Study of Sutent®/Sunitinib (SU11248) in Subjects With NF-1 Plexiform Neurofibromas
NCT01412892	PHASE2	COMPLETED	Use of RAD001 as Monotherapy in the Treatment of Neurofibromatosis 1 Related Internal Plexiform Neurofibromas
NCT01553149	PHASE2	COMPLETED	Low-Dose or High-Dose Lenalidomide in Treating Younger Patients With Recurrent, Refractory, or Progressive Pilocytic Astrocytoma or Optic Pathway Glioma
NCT01673009	PHASE2	COMPLETED	Phase II Study of Gleevec/Imatinib Mesylate (STI-571, NCS 716051) in Neurofibromatosis (NF1) Patients With Plexiform Neurofibromas
NCT01968590	PHASE2	TERMINATED	Vitamin D Supplementation for Adults With Neurofibromatosis Type 1 (NF1)
NCT02096471	PHASE2	COMPLETED	MEK Inhibitor PD-0325901 Trial in Adolescents and Adults With NF1
NCT02101736	PHASE2	COMPLETED	Cabozantinib for Plexiform Neurofibromas (PN) in Subjects With NF1 in Children and Adults
NCT02332902	PHASE2	COMPLETED	Everolimus for Treatment of Disfiguring Cutaneous Lesions in Neurofibromatosis1 CRAD001CUS232T
NCT02407405	PHASE2	ACTIVE_NOT_RECRUITING	MEK 1/2 Inhibitor Selumetinib (AZD6244 Hydrogen Sulfate) in Adults With Neurofibromatosis Type 1 (NF1) and Inoperable Plexiform Neurofibromas
NCT02728388	PHASE2	RECRUITING	Photodynamic Therapy for Benign Dermal Neurofibromas- Phase II
NCT02839720	PHASE2	COMPLETED	Selumetinib in Treating Patients With Neurofibromatosis Type 1 and Cutaneous Neurofibroma
NCT02964884	PHASE2	ACTIVE_NOT_RECRUITING	Interventions for Reading Disabilities in NF1
NCT03090971	PHASE2	COMPLETED	Use of Topical Liquid Diclofenac Following Laser Microporation of Cutaneous Neurofibromas in Patients With NF1