MARK2

Summary

MARK2 (microtubule affinity regulating kinase 2, HGNC:3332) is a protein-coding gene on chromosome 11q13.1, encoding Serine/threonine-protein kinase MARK2 (Q7KZI7). Serine/threonine-protein kinase. It is a selective cancer dependency (DepMap: 21.9% of cell lines).

This gene encodes a member of the Par-1 family of serine/threonine protein kinases. The protein is an important regulator of cell polarity in epithelial and neuronal cells, and also controls the stability of microtubules through phosphorylation and inactivation of several microtubule-associating proteins. The protein localizes to cell membranes. Multiple transcript variants encoding different isoforms have been found for this gene.

Source: NCBI Gene 2011 — RefSeq curated summary.

At a glance

• Gene–disease (curated): neurodevelopmental disorder (Strong, GenCC)
• GWAS associations: 2
• Clinical variants (ClinVar): 164 total — 19 pathogenic, 12 likely-pathogenic
• Phenotypes (HPO): 83
• Druggable target: yes — 45 molecules with ChEMBL bioactivity
• Cancer driver (intOGen): loss-of-function (tumor-suppressor-like) across 1 cancer types
• Cancer dependency (DepMap): dependent in 21.9% of screened cell lines
• MANE Select transcript: NM_001039469

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:3332
Approved symbol	MARK2
Name	microtubule affinity regulating kinase 2
Location	11q13.1
Locus type	gene with protein product
Status	Approved
Aliases	PAR-1, Par1b, PAR-1B
Ensembl gene	ENSG00000072518
Ensembl biotype	protein_coding
OMIM	600526
Entrez	2011

Gene structure

Transcript identifiers

Ensembl transcripts: 33 — 25 protein_coding, 6 retained_intron, 2 nonsense_mediated_decay

ENST00000350490, ENST00000361128, ENST00000377810, ENST00000402010, ENST00000408948, ENST00000425897, ENST00000502399, ENST00000508192, ENST00000509502, ENST00000512060, ENST00000513765, ENST00000535116, ENST00000540169, ENST00000543220, ENST00000543674, ENST00000676602, ENST00000677303, ENST00000677688, ENST00000678482, ENST00000678662, ENST00000679213, ENST00000679216, ENST00000679321, ENST00000707173, ENST00000906217, ENST00000906218, ENST00000906219, ENST00000906220, ENST00000911904, ENST00000911905, ENST00000911906, ENST00000911907, ENST00000911908

RefSeq mRNA: 5 — MANE Select: NM_001039469 NM_001039469, NM_001163296, NM_001163297, NM_004954, NM_017490

CCDS: CCDS41665, CCDS53649, CCDS53650, CCDS53651, CCDS8051

Canonical transcript exons

ENST00000402010 — 19 exons

Exon	Start	End
ENSE00001196424	63906088	63906114
ENSE00001196436	63902601	63902782
ENSE00001580534	63900957	63901069
ENSE00001582388	63903061	63903158
ENSE00001582516	63902198	63902330
ENSE00001583074	63903986	63904147
ENSE00001588083	63904786	63905043
ENSE00001588171	63900780	63900879
ENSE00001589587	63908260	63908304
ENSE00002080253	63908877	63911020
ENSE00002485667	63899874	63900110
ENSE00002495001	63899052	63899108
ENSE00002495785	63898763	63898833
ENSE00002499653	63898232	63898280
ENSE00002503318	63895580	63895633
ENSE00002525669	63900559	63900678
ENSE00002528194	63898608	63898673
ENSE00003576376	63895159	63895338
ENSE00003910365	63839110	63839560

Expression profiles

Bgee: expression breadth ubiquitous, 188 present calls, max score 95.07.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 24.9152 / max 312.3710, expressed in 1813 samples.

FANTOM5 promoters (6 alternative TSS)

Promoter ID	TPM avg	Samples expressed
114834	19.7863	1807
114838	2.2760	664
114832	2.1573	1050
114833	0.3498	172
114835	0.2569	109
114839	0.0889	31

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
lower esophagus mucosa	UBERON:0035834	95.07	gold quality
granulocyte	CL:0000094	92.77	gold quality
esophagus mucosa	UBERON:0002469	92.77	gold quality
skin of abdomen	UBERON:0001416	92.63	gold quality
mucosa of transverse colon	UBERON:0004991	92.59	gold quality
skin of leg	UBERON:0001511	92.52	gold quality
monocyte	CL:0000576	92.01	gold quality
leukocyte	CL:0000738	91.17	gold quality
mononuclear cell	CL:0000842	90.93	gold quality
rectum	UBERON:0001052	90.50	gold quality
minor salivary gland	UBERON:0001830	90.26	gold quality
transverse colon	UBERON:0001157	89.73	gold quality
esophagus	UBERON:0001043	89.66	gold quality
islet of Langerhans	UBERON:0000006	89.25	gold quality
right hemisphere of cerebellum	UBERON:0014890	88.95	gold quality
apex of heart	UBERON:0002098	88.82	gold quality
small intestine Peyer’s patch	UBERON:0003454	88.74	gold quality
colonic epithelium	UBERON:0000397	88.45	gold quality
right lobe of thyroid gland	UBERON:0001119	88.40	gold quality
body of pancreas	UBERON:0001150	88.40	gold quality
right uterine tube	UBERON:0001302	88.31	gold quality
zone of skin	UBERON:0000014	88.15	gold quality
cerebellar hemisphere	UBERON:0002245	88.11	gold quality
sural nerve	UBERON:0015488	88.11	gold quality
cerebellar cortex	UBERON:0002129	87.95	gold quality
mouth mucosa	UBERON:0003729	87.92	gold quality
adenohypophysis	UBERON:0002196	87.88	gold quality
right frontal lobe	UBERON:0002810	87.78	gold quality
cortical plate	UBERON:0005343	87.64	gold quality
blood	UBERON:0000178	87.63	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	8.50
E-ENAD-17	no	195.63

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

112 targeting MARK2, 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-3613-3P	100.00	76.36	7965
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-4533	100.00	69.48	2758
HSA-MIR-5196-5P	100.00	67.98	2761
HSA-MIR-4747-5P	100.00	67.90	2681
HSA-MIR-6127	100.00	66.76	2188
HSA-MIR-4510	100.00	66.60	2050
HSA-MIR-6129	100.00	66.46	2080
HSA-MIR-6130	100.00	66.69	2012
HSA-MIR-6133	100.00	66.48	2064
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-551B-5P	99.96	71.28	3493
HSA-MIR-4725-3P	99.96	69.53	2520
HSA-MIR-6780B-5P	99.96	69.60	2562
HSA-MIR-6825-5P	99.96	69.81	3431
HSA-MIR-6721-5P	99.93	68.92	2981
HSA-MIR-539-5P	99.93	70.30	2855
HSA-MIR-4753-3P	99.90	71.03	3786
HSA-MIR-4271	99.88	68.32	2244
HSA-MIR-4779	99.86	66.50	1583
HSA-MIR-3151-5P	99.86	63.83	1069
HSA-MIR-4728-5P	99.85	69.39	4718
HSA-MIR-4739	99.84	65.25	1832
HSA-MIR-1321	99.84	65.30	1811
HSA-MIR-4756-5P	99.84	64.98	1809
HSA-MIR-765	99.84	68.24	2442
HSA-MIR-6785-5P	99.82	68.68	4428
HSA-MIR-6794-5P	99.76	66.38	1048
HSA-MIR-3150A-3P	99.76	64.44	1640

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 21.9% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 40)

• Par1/Emk1 could have a role in the development of chronic allograft nephropathy in kidney allografts (PMID:15158914)
• Flot-2 binds to PAR-1, a known upstream mediator of major signal transduction pathways implicated in cell growth and metastasis, and may thereby influence tumor progression in melanoma. (PMID:15492257)
• GSK-3beta directly phosphorylates and activates MARK2/PAR-1 (PMID:16257959)
• The X-ray structure of the catalytic and ubiquitin-associated domains of human MARK2. (PMID:16472737)
• analysis of variations in the catalytic and ubiquitin-associated domains of microtubule-associated protein/microtubule affinity regulating kinase (MARK) 1 and MARK2 (PMID:16803889)
• Class IIa histone deacetylases (HDACs) are subjected to signal-independent nuclear export that relies on their constitutive phosphorylation. EMK and C-TAK1, are identified as regulators of this process. (PMID:16980613)
• Aberrant activation of PAR-1 may provide one of the molecular links in the pathogenic cascade of tauopathies. (PMID:17234589)
• We demonstrate that H. pylori causes the recruitment of MARK2 from the cytosol to the plasma membrane, where it colocalizes with the bacteria and interacts with CagA.[CagA in strain G27] (PMID:18005242)
• PAR-1 can be used with Breslow thickness and ulceration as a prognostic indicator for melanoma. (PMID:18315603)
• These results suggest that membrane accumulation of Par1b induced by Dvl is regulated by its phosphorylation status, which is important for Par1b to regulate the microtubule dynamics. (PMID:18760999)
• findings show protein kinase D phosphorylates Par-1b on S400 to positively regulate 14-3-3 binding and to negatively regulate membrane association (PMID:19011111)
• Par1b functions in the establishment of T cell polarity following engagement to an APC (PMID:19553522)
• the 8th and 9th spectrin-like repeats (R8 and R9) of utrophin cooperatively form a PAR-1b-interacting domain, and that Ser1258 within R9 is specifically phosphorylated by PAR-1b. (PMID:19945424)
• These results reveal that GAKIN/KIF13B is a key intermediate linking Par1b to the regulation of axon formation. (PMID:20194617)
• These data suggest that Par1b-phosphorylation regulates turnover of GEF-H1 localization by regulating its interaction with microtubules, which may contribute to cell polarization. (PMID:21513698)
• Polarity-regulating kinase partitioning-defective 1b (PAR1b) phosphorylates guanine nucleotide exchange factor H1 (GEF-H1) to regulate RhoA-dependent actin cytoskeletal reorganization. (PMID:22072711)
• The results identify MARK2 as an upstream regulator of PINK1 and DeltaN-PINK1 and provide insights into the regulation of mitochondrial trafficking in neurons and neurodegeneration in PD. (PMID:22238344)
• automated image analysis of MT assembly dynamics identified MARK2 as a target regulated downstream of Rac1 that promotes oriented MT growth in the leading edge to mediate directed cell migration. (PMID:22848487)
• The scaffolding adaptor GAB1 interacts with two polarity proteins, PAR1 and PAR3. (PMID:22883624)
• Hepatocyte Par1b defines lumen position in concert with the position of the astral microtubule anchoring complex LGN-NuMA to yield the distinct epithelial division phenotypes. (PMID:24165937)
• The MARK2 binds to the N-terminal tail of Tau and selectively phosphorylates three major and five minor serine residues in the repeat domain and C-terminal tail. (PMID:24251416)
• Phosphorylation of RNF41 by Par-1b regulates basolateral membrane targeting of laminin-111 receptors. (PMID:24259665)
• Perturbation of PAR1b and SHP2 by CagA underlies the oncogenic potential of CagA. (PMID:24354359)
• induces asymmetric inheritance of plasma membrane domains via LGN-dependent mitotic spindle orientation in proliferating hepatocytes (PMID:24358023)
• MARK2 plays a role in promoting malignant phenotypes of lung cancer. (PMID:25907283)
• In this study, through quantitative analysis of the complex formation between CagA and PAR1b, the authors found that several CagA species have acquired elevated PAR1b-binding activity via duplication of the CagA multimerization motifs, while others have lost their PAR1b-binding activity. (PMID:27445265)
• In cell-based assays, Mark2 depletion indeed reduces Dvl gene expression and interrupts neural stem cell (NSCs) growth and differentiation, which are likely to be mediated through a decrease in class IIa HDAC phosphorylation and reduced H3K4ac and H3K27ac occupancies at the Dvl1/2 promoters. (PMID:27714636)
• In conclusion, baicalin and DDP were synergistic at inhibiting proliferation and invasion of human lung cancer cells at appropriate dosages and incubation time in the presence or absence of DDP resistance. The attenuation of DDP resistance was associated with downregulation of MARK2 and p-Akt. (PMID:27878245)
• Low expression of Mark2 is associated with uterine cervical neoplasms. (PMID:28560405)
• In the modeled structure of inactive MARK2, activation segment occludes the enzyme active site and assumes a relatively stable position. (PMID:28711359)
• HIV-1 did not stimulate widespread FEZ1 phosphorylation but, instead, bound microtubule (MT) affinity-regulating kinase 2 (MARK2) to stimulate FEZ1 phosphorylation on viral cores. (PMID:28930676)
• The authors uncovered a novel role for MARK2 in maintaining the mitotic spindle at the cell’s geometric center. (PMID:29941476)
• Par1b-inhibition by CagA contributes to DNA Double Strand Breaks in H. pylori infected human primary gastric epithelial cells. (PMID:30580666)
• Clustering of the CD44 extracellular domain by high-molecular-weight hyaluronan leads to recruitment of the polarity-regulating kinase PAR1b by the CD44 intracellular domain, which results in disruption of the Hippo signaling-inhibitory PAR1b-MST complex. (PMID:31080060)
• Study shows that MARK2 is required to recentre spindles that are off-centred following actin disassembly, showing the close functional relationship between MARK2 and the actin network. These results suggest that, during both interphase and mitosis, MARK2 localizes at specialized membrane subdomains and coordinates actin and microtubule cytoskeletal changes, thus enabling normal cell division. (PMID:31238822)
• The cell polarity kinase Par1b/MARK2 activation selects specific NF-kB transcripts via phosphorylation of core mediator Med17/TRAP80. (PMID:33596087)
• MARK2 phosphorylates eIF2alpha in response to proteotoxic stress. (PMID:33705388)
• Long non-coding RNA ABHD11-AS1 facilitates the progression of cervical cancer by competitively binding to miR-330-5p and upregulating MARK2. (PMID:34793775)
• MARK2 potentiate aerobic glycolysis-mediated cell growth in breast cancer through regulating mTOR/HIF-1alpha and p53 pathways. (PMID:35048405)
• MARK2/4 promotes Warburg effect and cell growth in non-small cell lung carcinoma through the AMPKalpha1/mTOR/HIF-1alpha signaling pathway. (PMID:35192892)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	mark2b	ENSDARG00000032458
danio_rerio	mark2a	ENSDARG00000079905
mus_musculus	Mark2	ENSMUSG00000024969
rattus_norvegicus	Mark2	ENSRNOG00000021184

Paralogs (3): MARK4 (ENSG00000007047), MARK3 (ENSG00000075413), MARK1 (ENSG00000116141)

Protein

Protein identifiers

Serine/threonine-protein kinase MARK2 — Q7KZI7 (reviewed: Q7KZI7)

Alternative names: ELKL motif kinase 1, MAP/microtubule affinity-regulating kinase 2, PAR1 homolog, PAR1 homolog b

All UniProt accessions (13): Q7KZI7, A0A0A0MRU9, A0A140VJP1, A0A1B0GXH6, A0A7I2V3R3, A0A7I2YQF3, A0A7I2YQR3, A0AA34QVG3, E7ETY4, E9PC69, F5H4F6, F5H4J8, F5H6N2

UniProt curated annotations — full annotation on UniProt →

Function. Serine/threonine-protein kinase. Involved in cell polarity and microtubule dynamics regulation. Phosphorylates CRTC2/TORC2, DCX, HDAC7, KIF13B, MAP2, MAP4 and RAB11FIP2. Phosphorylates the microtubule-associated protein MAPT/TAU. Plays a key role in cell polarity by phosphorylating the microtubule-associated proteins MAP2, MAP4 and MAPT/TAU at KXGS motifs, causing detachment from microtubules, and their disassembly. Regulates epithelial cell polarity by phosphorylating RAB11FIP2. Involved in the regulation of neuronal migration through its dual activities in regulating cellular polarity and microtubule dynamics, possibly by phosphorylating and regulating DCX. Regulates axogenesis by phosphorylating KIF13B, promoting interaction between KIF13B and 14-3-3 and inhibiting microtubule-dependent accumulation of KIF13B. Also required for neurite outgrowth and establishment of neuronal polarity. Regulates localization and activity of some histone deacetylases by mediating phosphorylation of HDAC7, promoting subsequent interaction between HDAC7 and 14-3-3 and export from the nucleus. Also acts as a positive regulator of the Wnt signaling pathway, probably by mediating phosphorylation of dishevelled proteins (DVL1, DVL2 and/or DVL3). Modulates the developmental decision to build a columnar versus a hepatic epithelial cell apparently by promoting a switch from a direct to a transcytotic mode of apical protein delivery. Essential for the asymmetric development of membrane domains of polarized epithelial cells.

Subunit / interactions. Homodimer. Interacts with PAK5; leading to inhibit the protein kinase activity. Interacts with MAPT/TAU. Interacts with MTCL1 isoform 1; the interaction is direct and increases MARK2 microtubule-binding ability. Interacts (when phosphorylated at Thr-596) with YWHAZ. Interacts with YWHAB, YWHAG and YWHAQ. (Microbial infection) In case of infection, interacts with H.pylori CagA, leading to inhibit kinase activity and junctional and polarity defects.

Subcellular location. Cell membrane. Cytoplasm. Lateral cell membrane. Cytoskeleton. Cell projection. Dendrite.

Tissue specificity. High levels of expression in heart, brain, skeletal muscle and pancreas, lower levels observed in lung, liver and kidney.

Post-translational modifications. Autophosphorylated. Phosphorylated at Thr-208 by STK11/LKB1 in complex with STE20-related adapter-alpha (STRADA) pseudo kinase and CAB39. Phosphorylation at Thr-208 by TAOK1 activates the kinase activity, leading to phosphorylation and detachment of MAPT/TAU from microtubules. Phosphorylation at Ser-212 by GSK3-beta (GSK3B) inhibits the kinase activity. Phosphorylation by CaMK1 promotes activity and is required to promote neurite outgrowth. Phosphorylation at Thr-596 by PRKCZ/aPKC in polarized epithelial cells inhibits the kinase activity and promotes binding to 14-3-3 protein YWHAZ, leading to relocation from cell membrane to cytoplasm.

Disease relevance. Intellectual developmental disorder, autosomal dominant 76 (MRD76) [MIM:621285] An autosomal dominant disorder characterized by developmental delay, impaired intellectual development, speech and language deficits, and autism. More variable features include seizures, motor delay, behavior problems, eye abnormalities, and distinctive facial features. The disease is caused by variants affecting the gene represented in this entry.

Activity regulation. Inhibited by PAK5; inhibition is independent of the kinase activity of PAK5. Activated by phosphorylation on Thr-208. Inhibited by phosphorylation at Ser-212 and Thr-596. Inhibited by hymenialdisine. Specifically inhibited by the H.pylori CagA peptide FPLKRHDKVDDLSK that mimics host substrates and binds to the kinase substrate-binding site.

Domain organisation. The UBA domain does not seem to bind ubiquitin and ubiquitin-like and might play a role in regulating the enzyme conformation and localization. Activation of the kinase activity following phosphorylation at Thr-208 is accompanied by a conformational change that alters the orientation of the UBA domain with respect to the catalytic domain. The KA1 domain mediates binding to phospholipids and targeting to membranes.

Miscellaneous. Produced by alternative promoter usage. Produced by alternative splicing of isoform 6. Produced by alternative splicing of isoform 6. Produced by alternative splicing of isoform 1. Produced by alternative splicing of isoform 1. Produced by alternative promoter usage. Produced by alternative splicing of isoform 6. Produced by alternative splicing of isoform 1. Produced by alternative splicing of isoform 1. Produced by alternative splicing of isoform 6. Produced by alternative splicing of isoform 1. Produced by alternative splicing of isoform 6. Produced by alternative splicing of isoform 6. Produced by alternative splicing of isoform 6. Produced by alternative splicing of isoform 1. Produced by alternative splicing of isoform 1.

Similarity. Belongs to the protein kinase superfamily. CAMK Ser/Thr protein kinase family. SNF1 subfamily.

Isoforms (16)

UniProt ID	Names	Canonical?
Q7KZI7-1	1, Alpha	yes
Q7KZI7-2	2
Q7KZI7-3	3
Q7KZI7-4	4, Par-1Balpha
Q7KZI7-5	5
Q7KZI7-6	6, Beta
Q7KZI7-7	7
Q7KZI7-8	8
Q7KZI7-9	9
Q7KZI7-10	10
Q7KZI7-11	11
Q7KZI7-12	12
Q7KZI7-13	13
Q7KZI7-14	14
Q7KZI7-15	15
Q7KZI7-16	16

RefSeq proteins (5): NP_001034558, NP_001156768, NP_001156769, NP_004945, NP_059672 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000719	Prot_kinase_dom	Domain
IPR001772	KA1_dom	Domain
IPR008271	Ser/Thr_kinase_AS	Active_site
IPR011009	Kinase-like_dom_sf	Homologous_superfamily
IPR015940	UBA	Domain
IPR017441	Protein_kinase_ATP_BS	Binding_site
IPR028375	KA1/Ssp2_C	Homologous_superfamily
IPR049508	MARK1-4_cat	Domain

Pfam: PF00069, PF00627, PF02149

Catalyzed reactions (Rhea), 4 shown:

• L-seryl-[tau protein] + ATP = O-phospho-L-seryl-[tau protein] + ADP + H(+) (RHEA:12801)
• 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)
• L-threonyl-[tau protein] + ATP = O-phospho-L-threonyl-[tau protein] + ADP + H(+) (RHEA:53904)

UniProt features (88 total): modified residue 25, helix 16, sequence variant 12, strand 8, compositionally biased region 6, splice variant 6, domain 3, sequence conflict 3, binding site 2, region of interest 2, mutagenesis site 2, chain 1, active site 1, turn 1

Structure

Experimental structures (PDB)

5 structures.

PDB	Method	Resolution (Å)
8TXY	X-RAY DIFFRACTION	2.1
3IEC	X-RAY DIFFRACTION	2.2
5EAK	X-RAY DIFFRACTION	2.8
5KZ7	X-RAY DIFFRACTION	3.2
5KZ8	X-RAY DIFFRACTION	3.21

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q7KZI7-F1	68.21	0.41

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): 175 (proton acceptor)

Ligand- & substrate-binding residues (2): 59–67; 82

Post-translational modifications (25): 40, 58, 91, 92, 93, 208, 212, 274, 275, 294, 409, 456, 467, 486, 493, 569, 571, 592, 596, 619 …

Mutagenesis-validated functional residues (2):

Position	Phenotype
208	prevents phosphorylation and activation by stk11/lkb1 complex.
596	loss of membrane dissociation and binding to ywhaz.

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 221 (showing top): GGTGTGT_MIR329, GOBP_REGULATION_OF_CELL_MORPHOGENESIS, GOBP_ESTABLISHMENT_OR_MAINTENANCE_OF_CELL_POLARITY, GOBP_REGULATION_OF_MICROTUBULE_BASED_PROCESS, BROWNE_HCMV_INFECTION_8HR_UP, THEILGAARD_NEUTROPHIL_AT_SKIN_WOUND_DN, GOBP_NEUROGENESIS, GOBP_REGULATION_OF_CELLULAR_COMPONENT_BIOGENESIS, GGGTGGRR_PAX4_03, chr11q13, CAGCTG_AP4_Q5, COUP_01, GOMF_KINASE_ACTIVATOR_ACTIVITY, GOBP_ESTABLISHMENT_OF_CELL_POLARITY, GOBP_REGULATION_OF_CELL_PROJECTION_ORGANIZATION

GO Biological Process (18): microtubule cytoskeleton organization (GO:0000226), autophagy of mitochondrion (GO:0000422), neuron migration (GO:0001764), protein phosphorylation (GO:0006468), positive regulation of neuron projection development (GO:0010976), Wnt signaling pathway (GO:0016055), establishment of cell polarity (GO:0030010), intracellular signal transduction (GO:0035556), establishment or maintenance of epithelial cell apical/basal polarity (GO:0045197), protein autophosphorylation (GO:0046777), regulation of axonogenesis (GO:0050770), regulation of cytoskeleton organization (GO:0051493), mitochondrion localization (GO:0051646), axon development (GO:0061564), regulation of microtubule cytoskeleton organization (GO:0070507), establishment or maintenance of cell polarity regulating cell shape (GO:0071963), regulation of neurofibrillary tangle assembly (GO:1902996), cell differentiation (GO:0030154)

GO Molecular Function (16): magnesium ion binding (GO:0000287), RNA binding (GO:0003723), protein serine/threonine kinase activity (GO:0004674), ATP binding (GO:0005524), lipid binding (GO:0008289), protein kinase activator activity (GO:0030295), cadherin binding (GO:0045296), tau protein binding (GO:0048156), tau-protein kinase activity (GO:0050321), 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), metal ion binding (GO:0046872)

GO Cellular Component (12): nucleoplasm (GO:0005654), cytoplasm (GO:0005737), mitochondrion (GO:0005739), actin filament (GO:0005884), plasma membrane (GO:0005886), membrane (GO:0016020), lateral plasma membrane (GO:0016328), dendrite (GO:0030425), microtubule bundle (GO:0097427), cytoskeleton (GO:0005856), endomembrane system (GO:0012505), cell projection (GO:0042995)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	7
protein kinase activity	3
cytoskeleton organization	2
regulation of neuron projection development	2
neuron projection development	2
establishment or maintenance of cell polarity	2
intracellular anatomical structure	2
binding	2
plasma membrane	2
microtubule-based process	1
autophagy	1
cell migration	1
generation of neurons	1
phosphorylation	1
protein modification process	1
positive regulation of cell projection organization	1
cell surface receptor signaling pathway	1
signal transduction	1
establishment or maintenance of apical/basal cell polarity	1
protein phosphorylation	1
axonogenesis	1
regulation of anatomical structure morphogenesis	1
regulation of organelle organization	1
organelle localization	1
microtubule cytoskeleton organization	1
regulation of microtubule-based process	1
regulation of cytoskeleton organization	1
regulation of cell shape	1
regulation of inclusion body assembly	1
neurofibrillary tangle assembly	1
cellular developmental process	1
metal ion binding	1
nucleic acid binding	1
adenyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1
kinase activator activity	1
protein kinase regulator activity	1
cell adhesion molecule binding	1
cytoskeletal protein binding	1
protein serine/threonine kinase activity	1

Protein interactions and networks

STRING

1796 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
MARK2	PYGM	P11217	778
MARK2	FOSL1	P15407	775
MARK2	FKBP2	P26885	769
MARK2	COX8A	P10176	767
MARK2	SF1	Q15637	765
MARK2	PLCB3	Q01970	765
MARK2	FTH1	P02794	764
MARK2	AHNAK	Q09666	764
MARK2	ROM1	Q03395	763
MARK2	SCGB1A1	P11684	762
MARK2	CHRM1	P11229	762
MARK2	CAPN1	P07384	762
MARK2	RNF41	Q9H4P4	681
MARK2	RELA	Q04206	669
MARK2	MEN1	O00255	647

IntAct

186 interactions, top by confidence:

A	B	Type	Score
YWHAZ	MARK2	psi-mi:“MI:0915”(physical association)	0.930
YWHAZ	MARK2	psi-mi:“MI:0407”(direct interaction)	0.930
YWHAH	MARK2	psi-mi:“MI:0915”(physical association)	0.920
YWHAH	MARK2	psi-mi:“MI:0914”(association)	0.920
YWHAB	MARK2	psi-mi:“MI:0915”(physical association)	0.890
MARK2	YWHAB	psi-mi:“MI:0915”(physical association)	0.890
YWHAG	MARK2	psi-mi:“MI:0915”(physical association)	0.860
YWHAH	TSC2	psi-mi:“MI:0914”(association)	0.850
YWHAQ	WDR62	psi-mi:“MI:0914”(association)	0.830
YWHAH	ABLIM1	psi-mi:“MI:0914”(association)	0.800
YWHAB	PIK3C2A	psi-mi:“MI:0914”(association)	0.800
MARK2	YWHAE	psi-mi:“MI:0914”(association)	0.730
PARD6G	PRKCI	psi-mi:“MI:0914”(association)	0.720
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
	TOMM70	psi-mi:“MI:0914”(association)	0.690
MARK2	MAPT	psi-mi:“MI:2364”(proximity)	0.680
MARK2	cagA	psi-mi:“MI:0915”(physical association)	0.650
MARK2	cagA	psi-mi:“MI:0407”(direct interaction)	0.650
YWHAG	BLTP3B	psi-mi:“MI:0914”(association)	0.640
PPP2R2B	MYO9A	psi-mi:“MI:0914”(association)	0.640

BioGRID (479): Crtc2 (Biochemical Activity), MTCL1 (Affinity Capture-MS), MTCL1 (Affinity Capture-Western), MARK2 (Affinity Capture-Western), MARK2 (Reconstituted Complex), MARK2 (Affinity Capture-MS), MARK2 (Affinity Capture-MS), MARK2 (Affinity Capture-MS), MARK2 (Affinity Capture-MS), MARK2 (Affinity Capture-MS), ARHGEF2 (Affinity Capture-Western), MARK2 (Affinity Capture-Western), MARK2 (Reconstituted Complex), MARK2 (Proximity Label-MS), MARK2 (Proximity Label-MS)

ESM2 similar proteins: A0A194VNL2, A4QXX4, B0WAU8, B0XPE4, G4N6Z6, G4N7X0, G5EFU0, G5EGQ3, H2L099, O24527, O42626, O96013, P0C198, P0CP70, P0CP71, P0CS76, P0CS77, P0DP15, P11837, P32490, P32491, P38679, P48479, Q0UY20, Q16W24, Q17850, Q19469, Q23356, Q2GYV9, Q2ULU3, Q2VWQ3, Q4P5N0, Q4WHP3, Q4WJJ0, Q501Q9, Q5B4Z3, Q5BBL3, Q5U4C9, Q754N7, Q75DK7

Diamond homologs: A0AUV4, A1A5Q6, A2KF29, A2XFF4, A8WYE4, B2DD29, B7XHR6, B8BBT7, C0HKC8, C0HKC9, F1QGZ6, O08678, O08679, O22932, O22971, O65554, O74536, O94168, P27448, P52497, P54645, P54646, P57059, P92958, Q00372, Q02723, Q03141, Q05512, Q09137, Q0D4B2, Q0JI49, Q13131, Q19469, Q28948, Q2QY53, Q2RAX3, Q2V452, Q38997, Q54DF2, Q54TA3

SIGNOR signaling

26 interactions.

A	Effect	B	Mechanism
STK11	up-regulates	MARK2	phosphorylation
PRKCZ	down-regulates	MARK2	phosphorylation
MARK2	up-regulates	RAB11FIP2	phosphorylation
MARK2	down-regulates	HDAC7	phosphorylation
MARK2	up-regulates	UTRN	phosphorylation
MARK2	down-regulates	ARHGEF2	phosphorylation
MARK2	up-regulates	PARD3	phosphorylation
MARK2	“down-regulates activity”	TNK1	phosphorylation
PRKACA	“down-regulates activity”	MARK2	phosphorylation
MARK2	“down-regulates activity”	BAIAP2	phosphorylation
MARK2	“up-regulates activity”	PINK1	phosphorylation
MARK2	“down-regulates activity”	KSR1	phosphorylation
GSK3B	“up-regulates activity”	MARK2	phosphorylation
MARK2	“down-regulates quantity”	MAPT	phosphorylation
MARK2	“down-regulates activity”	KIF13B	phosphorylation
MARK2	“up-regulates quantity”	RAB11FIP1	phosphorylation
MARK2	“down-regulates activity”	MAPT	phosphorylation
GSK3B	“down-regulates activity”	MARK2	phosphorylation
TAOK1	“up-regulates activity”	MARK2	phosphorylation
STK11	“up-regulates activity”	MARK2	phosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 166 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	8	48.4×	9e-10
Activation of BAD and translocation to mitochondria	7	48.0×	9e-09
SARS-CoV-1 targets host intracellular signalling and regulatory pathways	7	42.4×	2e-08
Activation of BH3-only proteins	7	31.3×	1e-07
RHO GTPases activate PKNs	7	20.0×	2e-06
Intrinsic Pathway for Apoptosis	7	18.5×	3e-06
RAF activation	6	18.2×	3e-05
Signaling by high-kinase activity BRAF mutants	6	17.1×	3e-05

GO biological processes:

GO term	Partners	Fold	FDR
mitotic spindle organization	7	12.9×	7e-04
protein targeting	5	12.5×	7e-03
positive regulation of autophagy	6	8.5×	9e-03
MAPK cascade	8	8.3×	2e-03
chromosome segregation	7	8.3×	4e-03
protein autophosphorylation	8	7.9×	2e-03
intracellular protein localization	11	7.8×	2e-04
protein phosphorylation	11	5.1×	3e-03

Disease & clinical

Cancer significance

From intOGen — cancer-driver classification: loss-of-function (tumor-suppressor-like) across 1 cancer types — PAAD.

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	19
Likely pathogenic	12
Uncertain significance	89
Likely benign	7
Benign	4

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
3253624	NM_001039469.3(MARK2):c.211C>T (p.Arg71Ter)	Pathogenic
3253625	NM_001039469.3(MARK2):c.812del (p.Phe271fs)	Pathogenic
3253627	NM_001039469.3(MARK2):c.989-1G>A	Pathogenic
3253628	NM_001039469.3(MARK2):c.1101+1G>A	Pathogenic
3253629	NM_001039469.3(MARK2):c.1181dup (p.Val395fs)	Pathogenic
3253632	NM_001039469.3(MARK2):c.1750C>T (p.Arg584Ter)	Pathogenic
3253634	NM_001039469.3(MARK2):c.1769del (p.Gly590fs)	Pathogenic
3253639	NM_001039469.3(MARK2):c.2168_2169del (p.Cys723fs)	Pathogenic
3253640	NM_001039469.3(MARK2):c.2239C>T (p.Gln747Ter)	Pathogenic
3253645	NM_001039469.3(MARK2):c.288dup (p.Leu97fs)	Pathogenic
3253646	NM_001039469.3(MARK2):c.337+1G>T	Pathogenic
3253648	NM_001039469.3(MARK2):c.757C>T (p.Gln253Ter)	Pathogenic
4071509	c.1514+2G-T	Pathogenic
4071510	MARK2, EX2-19DEL	Pathogenic
4071964	NM_001039469.3(MARK2):c.664del (p.Gln222fs)	Pathogenic
4075487	NM_001039469.3(MARK2):c.1780C>T (p.Arg594Ter)	Pathogenic
4730447	NM_001039469.3(MARK2):c.1053C>G (p.Tyr351Ter)	Pathogenic
4819133	NM_001039469.3(MARK2):c.1737_1738dup (p.Gly580fs)	Pathogenic
4845390	NM_001039469.3(MARK2):c.800dup (p.Tyr267Ter)	Pathogenic
3253630	NM_001039469.3(MARK2):c.1514+2T>G	Likely pathogenic
3253631	NM_001039469.3(MARK2):c.1516dup (p.Leu506fs)	Likely pathogenic
3253633	NM_001039469.3(MARK2):c.235-2A>G	Likely pathogenic
3253636	NM_001039469.3(MARK2):c.1934+1G>A	Likely pathogenic
3253637	NM_001039469.3(MARK2):c.1939_1940del (p.Leu647fs)	Likely pathogenic
3253638	NM_001039469.3(MARK2):c.1990C>T (p.Arg664Ter)	Likely pathogenic
3253641	NM_001039469.3(MARK2):c.2255T>C (p.Val752Ala)	Likely pathogenic
3253642	NM_001039469.3(MARK2):c.2291G>C (p.Arg764Pro)	Likely pathogenic
3253644	NM_001039469.3(MARK2):c.258_259dup (p.Thr87fs)	Likely pathogenic
3253647	NM_001039469.3(MARK2):c.403G>A (p.Gly135Arg)	Likely pathogenic
4532117	NM_001039469.3(MARK2):c.2309G>A (p.Gly770Asp)	Likely pathogenic

SpliceAI

3768 predictions. Top by Δscore:

Variant	Effect	Δscore
11:63895150:A:AG	acceptor_gain	1.0000
11:63895150:ACCCC:A	acceptor_gain	1.0000
11:63895151:C:G	acceptor_gain	1.0000
11:63895154:C:CA	acceptor_gain	1.0000
11:63895154:CGCA:C	acceptor_loss	1.0000
11:63895157:A:AC	acceptor_loss	1.0000
11:63895157:A:AG	acceptor_gain	1.0000
11:63895158:G:GA	acceptor_gain	1.0000
11:63895158:GC:G	acceptor_gain	1.0000
11:63895158:GCC:G	acceptor_gain	1.0000
11:63895158:GCCC:G	acceptor_gain	1.0000
11:63895158:GCCCA:G	acceptor_gain	1.0000
11:63895335:AGAG:A	donor_loss	1.0000
11:63895336:GAG:G	donor_gain	1.0000
11:63895337:AG:A	donor_loss	1.0000
11:63895338:GGTGA:G	donor_loss	1.0000
11:63895339:G:C	donor_loss	1.0000
11:63895630:GAAA:G	donor_gain	1.0000
11:63895634:G:GG	donor_gain	1.0000
11:63898403:G:GT	donor_gain	1.0000
11:63898603:TGTA:T	acceptor_loss	1.0000
11:63898606:A:AG	acceptor_gain	1.0000
11:63898606:A:T	acceptor_loss	1.0000
11:63898607:G:GA	acceptor_gain	1.0000
11:63898607:GT:G	acceptor_gain	1.0000
11:63898607:GTT:G	acceptor_gain	1.0000
11:63898607:GTTA:G	acceptor_gain	1.0000
11:63898607:GTTAA:G	acceptor_gain	1.0000
11:63898761:A:AG	acceptor_gain	1.0000
11:63898762:G:GA	acceptor_gain	1.0000

AlphaMissense

5186 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
11:63895261:T:C	Y53H	1.000
11:63895261:T:G	Y53D	1.000
11:63895280:T:A	I59N	1.000
11:63895282:G:C	G60R	1.000
11:63895282:G:T	G60C	1.000
11:63895283:G:A	G60D	1.000
11:63895283:G:T	G60V	1.000
11:63895288:G:A	G62S	1.000
11:63895288:G:C	G62R	1.000
11:63895288:G:T	G62C	1.000
11:63895289:G:A	G62D	1.000
11:63895289:G:C	G62A	1.000
11:63895289:G:T	G62V	1.000
11:63895293:T:A	N63K	1.000
11:63895293:T:G	N63K	1.000
11:63895294:T:A	F64I	1.000
11:63895294:T:C	F64L	1.000
11:63895294:T:G	F64V	1.000
11:63895295:T:C	F64S	1.000
11:63895295:T:G	F64C	1.000
11:63895296:T:A	F64L	1.000
11:63895296:T:G	F64L	1.000
11:63895297:G:C	A65P	1.000
11:63895298:C:A	A65D	1.000
11:63895298:C:T	A65V	1.000
11:63895303:G:A	V67M	1.000
11:63895304:T:A	V67E	1.000
11:63895304:T:C	V67A	1.000
11:63895306:A:G	K68E	1.000
11:63895308:G:C	K68N	1.000

dbSNP variants (sampled 300 via entrez): RS1000025447 (11:63869725 T>G), RS1000033263 (11:63875808 G>T), RS1000079057 (11:63869932 C>T), RS1000166145 (11:63851813 C>G), RS1000187336 (11:63869275 C>G), RS1000273488 (11:63845554 C>T), RS1000284369 (11:63846080 G>A), RS1000328967 (11:63857653 A>G), RS1000363805 (11:63863240 G>C), RS1000377035 (11:63897889 G>A), RS1000454749 (11:63900202 T>C), RS1000504235 (11:63893872 G>A), RS1000542323 (11:63850261 G>A), RS1000612578 (11:63846805 G>A), RS1000613538 (11:63887430 C>T)

Disease associations

OMIM: gene MIM:600526 | disease phenotypes: MIM:607834, MIM:621285, MIM:209850

GenCC curated gene-disease

Disease	Classification	Inheritance
neurodevelopmental disorder	Strong	Autosomal dominant

Mondo (8): dyslexia (MONDO:0005489), attention deficit-hyperactivity disorder (MONDO:0007743), anxiety (MONDO:0011918), autism spectrum disorder (MONDO:0005258), intellectual developmental disorder, autosomal dominant 76 (MONDO:0979575), intellectual disability (MONDO:0001071), autism (MONDO:0005260), neurodevelopmental disorder (MONDO:0700092)

Orphanet (2): NON RARE IN EUROPE: Autism (Orphanet:106), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658)

HPO phenotypes

83 total (30 of 83 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000047	Hypospadias
HP:0000252	Microcephaly
HP:0000256	Macrocephaly
HP:0000275	Narrow face
HP:0000286	Epicanthus
HP:0000289	Broad philtrum
HP:0000316	Hypertelorism
HP:0000322	Short philtrum
HP:0000337	Broad forehead
HP:0000343	Long philtrum
HP:0000348	High forehead
HP:0000358	Posteriorly rotated ears
HP:0000365	Hearing impairment
HP:0000369	Low-set ears
HP:0000391	Thickened helices
HP:0000396	Overfolded helix
HP:0000400	Macrotia
HP:0000411	Protruding ear
HP:0000414	Bulbous nose
HP:0000417	Slender nose
HP:0000421	Epistaxis
HP:0000431	Wide nasal bridge
HP:0000448	Prominent nose
HP:0000463	Anteverted nares
HP:0000483	Astigmatism
HP:0000486	Strabismus
HP:0000490	Deeply set eye
HP:0000494	Downslanted palpebral fissures
HP:0000506	Telecanthus

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST000903_3	Response to methylphenidate treatment in attention-deficit/hyperactivity disorder (blood pressure)	5.000000e-06
GCST009600_98	Anorexia nervosa, attention-deficit/hyperactivity disorder, autism spectrum disorder, bipolar disorder, major depression, obsessive-compulsive disorder, schizophrenia, or Tourette syndrome (pleiotropy)	8.000000e-09

MeSH disease descriptors (5)

Descriptor	Name	Tree numbers
D001007	Anxiety	F01.470.132
D001321	Autistic Disorder	F03.625.164.113.500
D004410	Dyslexia	C10.597.606.150.500.300; C10.597.606.150.550.700.500; C23.888.592.604.150.500.300; C23.888.592.604.150.550.700.500; F03.625.374.188.700.500; F03.625.562.700.500
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539
D065886	Neurodevelopmental Disorders	F03.625

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL3831 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

45 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 152,396 (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
CHEMBL1078178	MOMELOTINIB	4	3,481
CHEMBL1287853	FEDRATINIB	4	3,554
CHEMBL1789941	RUXOLITINIB	4	11,547
CHEMBL2105759	BARICITINIB	4	6,741
CHEMBL221959	TOFACITINIB	4	10,408
CHEMBL3545311	BRIGATINIB	4	5,634
CHEMBL502835	NINTEDANIB	4	8,545
CHEMBL535	SUNITINIB	4	79,020
CHEMBL608533	MIDOSTAURIN	4	7,259
CHEMBL2105728	CRENOLANIB	3	2,167
CHEMBL223360	LINIFANIB	3	3,925
CHEMBL3137331	DEFACTINIB	3	1,229
CHEMBL3426621	RIPASUDIL	3	870
CHEMBL522892	DOVITINIB	3	4,944
CHEMBL603469	LESTAURTINIB	3
CHEMBL91829	RUBOXISTAURIN	3	77
CHEMBL103667	DORAMAPIMOD	2	1,681
CHEMBL1230165	SILMITASERTIB	2	593
CHEMBL1721885	SU-014813	2	363
CHEMBL1967878	CENISERTIB	2	358
CHEMBL1980297	ILORASERTIB	2
CHEMBL253969	OSI-632	2
CHEMBL3039513	DECERNOTINIB	2
CHEMBL3115681	NARAZACICLIB	2
CHEMBL3137336	UPROSERTIB	2
CHEMBL3545396	BMS-690514	2
CHEMBL402548	DANUSERTIB	2
CHEMBL4116008	CERDULATINIB	2
CHEMBL475251	R-406	2
CHEMBL495727	AT-9283	2

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

GtoPdb / IUPHAR curated pharmacology

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

Target class: enzyme — MARK subfamily

Most potent curated ligand interactions (1 total), top 1:

Ligand	Action	Affinity	Parameter
PCC0105003	Inhibition	8.7	pIC50

Binding affinities (BindingDB)

18 measured of 18 human assays (18 total across all organisms); most potent 18 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
Staurosporine	KD	1.7 nM
PKC-412	KD	190 nM
(3Z)-4-amino-5-fluoro-3-[5-(4-methylpiperazino)-1,3-dihydrobenzimidazol-2-ylidene]carbostyril	KD	520 nM
N-[4-({4-[(3-methyl-1H-pyrazol-5-yl)amino]-6-(4-methylpiperazin-1-yl)pyrimidin-2-yl}sulfanyl)phenyl]cyclopropanecarboxamide	KD	1100 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-((1R,3aS,6S, 7R,7aS)-5,5- difluoro-7- ((E)-2-(5-(3- fluorophenyl) pyridin-2- yl)vinyl)-1,6- dimethyl-3- oxo-octahydro- isobenzofuran- 3a-yl)azetidine- 3-carboxamide	IC50	3000 nM	US-9701669: Preparation and use of 7a-amide substituted- 6,6-difluoro bicyclic himbacine derivatives as PAR-1 receptor antagonists
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
(1R,3aR, 6S,7R,7aS)- 5,5-difluoro- 7-((E)-2-(5- (3-fluoro-2- methylphenyl) pyridin-2- yl)vinyl)-1,6- dimethyl-3- oxooctahydro- isobenzofuran- 3a- carboxamide	IC50	12000 nM	US-9701669: Preparation and use of 7a-amide substituted- 6,6-difluoro bicyclic himbacine derivatives as PAR-1 receptor antagonists
(1R,3aR,6S,7R, 7aS)-5,5-difluoro- 7-((E)-2-(5- (2-fluoro-3- methylphenyl) pyridin-2- yl)vinyl)-1,6- dimethyl-3- oxooctahydro- isobenzofuran- 3a- carboxamide	IC50	13000 nM	US-9701669: Preparation and use of 7a-amide substituted- 6,6-difluoro bicyclic himbacine derivatives as PAR-1 receptor antagonists
2-((1R,3aR, 6S,7R,7aS)-5,5- difluoro-7- ((E)-2-(5-(3- fluorophenyl) pyridin-2- yl)vinyl)-1,6- dimethyl-3- oxooctahydro- isobenzofuran- 3a-yl)acetamide	IC50	20400 nM	US-9701669: Preparation and use of 7a-amide substituted- 6,6-difluoro bicyclic himbacine derivatives as PAR-1 receptor antagonists
2-((1R,3aR,6S, 7R,7aS)-7-((E)- 2- (2’-cyano-[3,3’- bipyridin]-6- yl)vinyl)-5,5- difluoro-1,6- dimethyl-3- oxooctahydro- isobenzofuran- 3a- yl)acetamide	IC50	21900 nM	US-9701669: Preparation and use of 7a-amide substituted- 6,6-difluoro bicyclic himbacine derivatives as PAR-1 receptor antagonists
2-((1R,3aR,6S, 7R,7aS)-5,5- difluoro-7- ((E)-2-(2’- methoxy-[3,3’- bipyridin]-6- yl)vinyl)-1,6- dimethyl-3- oxooctahydro- isobenzofuran- 3a-yl)acetamide	IC50	25900 nM	US-9701669: Preparation and use of 7a-amide substituted- 6,6-difluoro bicyclic himbacine derivatives as PAR-1 receptor antagonists
2-((1R,3aR, 6S,7R,7aS)-7- ((E)-2-(5-(2- cyanophenyl) pyridin-2- yl)vinyl)-5,5- difluoro- 1,6-dimethyl-3- oxooctahydro- isobenzofuran- 3a- yl)propanamide	IC50	26300 nM	US-9701669: Preparation and use of 7a-amide substituted- 6,6-difluoro bicyclic himbacine derivatives as PAR-1 receptor antagonists
(1R,3aR,6S,7R, 7aS)-7-((E)-2-(5- (2-cyanophenyl)- 6- methylpyridin-2- yl)vinyl)-5,5- difluoro-1,6- dimethyl-3- oxooctahydro- isobenzofuran- 3a- carboxamide	IC50	60000 nM	US-9701669: Preparation and use of 7a-amide substituted- 6,6-difluoro bicyclic himbacine derivatives as PAR-1 receptor antagonists
1R,3aR,6S, 7R,7aS)-7-((E)-2- (2’-cyano-[3,3’- bipyridin]-6- yl)vinyl)-5,5- difluoro-1,6- dimethyl-3- oxooctahydro- isobenzofuran- 3a-carboxamide	IC50	60000 nM	US-9701669: Preparation and use of 7a-amide substituted- 6,6-difluoro bicyclic himbacine derivatives as PAR-1 receptor antagonists
3-((1R,3aR,6S, 7R,7aS)-7 -((E)- 2- (2’-cyano-[3,3’- bipyridin]-6- yl)vinyl)-5,5- difluoro-1,6- dimethyl-3- oxooctahydro- isobenzofuran- 3a- yl)propanamide	IC50	60000 nM	US-9701669: Preparation and use of 7a-amide substituted- 6,6-difluoro bicyclic himbacine derivatives as PAR-1 receptor antagonists
(S and R)-2- ((1R,3aR,6S, 7R,7aS)-7- ((E)-2-(5-(2- cyanophenyl) pyridin-2- yl)vinyl)- 5,5-difluoro- 1,6-dimethyl-3- oxooctahydro- isobenzofuran- 3a-yl)-2- hydroxyacetamide	IC50	60000 nM	US-9701669: Preparation and use of 7a-amide substituted- 6,6-difluoro bicyclic himbacine derivatives as PAR-1 receptor antagonists

ChEMBL bioactivities

369 potent at pChembl≥5 of 375 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
10.00	Kd	0.1	nM	STAUROSPORINE
9.88	IC50	0.133	nM	STAUROSPORINE
9.86	IC50	0.139	nM	STAUROSPORINE
9.83	IC50	0.148	nM	STAUROSPORINE
9.15	Kd	0.7	nM	STAUROSPORINE
8.86	IC50	1.37	nM	CHEMBL6037827
8.70	IC50	2	nM	CHEMBL5305160
8.58	IC50	2.62	nM	CHEMBL5741564
8.52	Kd	3	nM	CHEMBL4576489
8.42	IC50	3.8	nM	CHEMBL5923194
8.40	IC50	4	nM	CERDULATINIB
8.39	IC50	4.07	nM	CHEMBL5945844
8.36	IC50	4.41	nM	CHEMBL5905066
8.35	IC50	4.43	nM	CHEMBL5945844
8.22	Kd	6	nM	CHEMBL4465866
8.20	IC50	6.34	nM	CHEMBL5768285
8.16	IC50	6.92	nM	CHEMBL5949816
8.10	Ki	7.943	nM	CHEMBL1980995
8.01	IC50	9.68	nM	CHEMBL5909304
7.95	IC50	11.3	nM	CHEMBL5945844
7.89	Kd	13	nM	UCN-01
7.86	IC50	13.9	nM	CHEMBL5768755
7.85	Kd	14	nM	LESTAURTINIB
7.81	Kd	15.43	nM	CHEMBL3752910
7.80	Ki	15.85	nM	CHEMBL1984162
7.80	Ki	15.85	nM	CHEMBL1241473
7.80	Ki	15.85	nM	CHEMBL1971029
7.69	ED50	20.48	nM	CHEMBL3752910
7.68	Kd	20.83	nM	CHEMBL5653589
7.67	IC50	21.2	nM	CHEMBL5885431
7.60	Ki	25.12	nM	GO-6976
7.56	ED50	27.65	nM	CHEMBL5653589
7.40	Ki	39.81	nM	CHEMBL1970317
7.40	Ki	39.81	nM	CHEMBL1987034
7.36	Kd	44	nM	TAE-684
7.30	Ki	50.12	nM	CHEMBL592030
7.30	Ki	50.12	nM	CHEMBL1998121
7.30	Ki	50.12	nM	CHEMBL1987054
7.28	IC50	52	nM	CHEMBL3605057
7.20	Ki	63.1	nM	CHEMBL1973540
7.20	Ki	63.1	nM	CHEMBL1999931
7.20	Ki	63.1	nM	CHEMBL1981047
7.10	Ki	79.43	nM	CHEMBL1998159
7.10	Ki	79.43	nM	CHEMBL1970104
7.10	Ki	79.43	nM	CHEMBL1982957
7.10	Ki	79.43	nM	CHEMBL590109
7.10	Ki	79.43	nM	CHEMBL2001751
7.10	Ki	79.43	nM	CHEMBL2000393
7.10	Ki	79.43	nM	CHEMBL2005886
7.10	Ki	79.43	nM	CHEMBL1990583

PubChem BioAssay actives

84 with measured affinity, of 1093 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	1531759: Inhibition of human MARK2 using KKKVSRSGLYRSPSMPENLNRPR as substrate by [gamma-33P]-ATP assay	ic50	0.0001	uM
7-[(1S)-4-hydroxy-2,3-dihydro-1H-inden-1-yl]-5,5-dimethyl-2-[3-(pyrrolidin-1-ylmethyl)anilino]pyrrolo[2,3-d]pyrimidin-6-one	1992918: Inhibition of MARK2 (unknown origin)	ic50	0.0020	uM
3-(2,2-difluoro-10,12-dimethyl-1-aza-3-azonia-2-boranuidatricyclo[7.3.0.03,7]dodeca-3,5,7,9,11-pentaen-4-yl)-N-[2-[2-[2-[2-[[(2S,3R,4R,6R)-3-methoxy-2-methyl-16-oxo-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-4-yl]-methylamino]ethoxy]ethoxy]ethoxy]ethyl]propanamide	1526305: Binding affinity to recombinant full-length N-terminal His-FLAG-GST-tagged MARK2 (unknown origin) expressed in baculovirus infected Sf9 insect cells incubated for 1 hr by TR-FRET assay	kd	0.0030	uM
4-(cyclopropylamino)-2-[4-(4-ethylsulfonylpiperazin-1-yl)anilino]pyrimidine-5-carboxamide	1993897: Inhibition of PAR1B-a (unknown origin)	ic50	0.0040	uM
3-(2,2-difluoro-10,12-dimethyl-1-aza-3-azonia-2-boranuidatricyclo[7.3.0.03,7]dodeca-3,5,7,9,11-pentaen-4-yl)-N-[2-[2-[2-[2-[[(2S,3R,4R,6R)-3-methoxy-2-methyl-16-oxo-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-4-yl]amino]ethoxy]ethoxy]ethoxy]ethyl]propanamide	1526305: Binding affinity to recombinant full-length N-terminal His-FLAG-GST-tagged MARK2 (unknown origin) expressed in baculovirus infected Sf9 insect cells incubated for 1 hr by TR-FRET assay	kd	0.0060	uM
(2S,3R,4R,6R,18S)-18-hydroxy-3-methoxy-2-methyl-4-(methylamino)-29-oxa-1,7,17-triazaoctacyclo[12.12.2.12,6.07,28.08,13.015,19.020,27.021,26]nonacosa-8,10,12,14,19,21,23,25,27-nonaen-16-one	1425068: 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	0.0130	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	507608: Binding affinity to MARK2	kd	0.0140	uM
4-methyl-3-[(1-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2148718: Binding affinity to human MARK2 incubated for 45 mins by Kinobead based pull down assay	kd	0.0154	uM
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2148718: Binding affinity to human MARK2 incubated for 45 mins by Kinobead based pull down assay	kd	0.0208	uM
5-chloro-2-N-[2-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl]-4-N-(2-propan-2-ylsulfonylphenyl)pyrimidine-2,4-diamine	625106: Binding constant for MARK2 kinase domain	kd	0.0440	uM
N-[3-[[5-cyclopropyl-2-[3-(morpholin-4-ylmethyl)anilino]pyrimidin-4-yl]amino]propyl]cyclobutanecarboxamide	1992918: Inhibition of MARK2 (unknown origin)	ic50	0.0520	uM
Brigatinib	2182827: Inhibition of human Par-1Balpha using KKKVSRSGLYRSPSMPENLNRPR as substrate in presence of [gamma33P]-ATP by HotSpot assay	ic50	0.0930	uM
Midostaurin	435296: Binding constant for MARK2 kinase domain	kd	0.1000	uM
N-[(1S)-2-(dimethylamino)-1-phenylethyl]-6,6-dimethyl-3-[(2-methylthieno[3,2-d]pyrimidin-4-yl)amino]-1,4-dihydropyrrolo[3,4-d]pyrazole-5-carboxamide	1425068: 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	0.1140	uM
Baricitinib	1425068: 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	0.1250	uM
4-N-(5-cyclopropyl-1H-pyrazol-3-yl)-6-(4-methylpiperazin-1-yl)-2-N-[(3-propan-2-yl-1,2-oxazol-5-yl)methyl]pyrimidine-2,4-diamine	1425068: 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	0.1960	uM
6-[[5-fluoro-2-(3,4,5-trimethoxyanilino)pyrimidin-4-yl]amino]-2,2-dimethyl-4H-pyrido[3,2-b][1,4]oxazin-3-one	625106: Binding constant for MARK2 kinase domain	kd	0.2800	uM
1-[2-[5-[(3-methyloxetan-3-yl)methoxy]benzimidazol-1-yl]quinolin-8-yl]piperidin-4-amine	1425068: 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	0.3000	uM
4-(cyclopropylamino)-2-[4-(4-ethylsulfonylpiperazin-1-yl)anilino]pyrimidine-5-carboxamide;hydrochloride	1425068: 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	0.3020	uM
Sunitinib	435296: Binding constant for MARK2 kinase domain	kd	0.3100	uM
4-[2-(4-amino-1,2,5-oxadiazol-3-yl)-1-ethyl-7-[[(3S)-piperidin-3-yl]methoxy]imidazo[4,5-c]pyridin-4-yl]-2-methylbut-3-yn-2-ol	1425068: 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	0.3510	uM
N-[5-[(2R)-2-methoxy-2-phenylacetyl]-4,6-dihydro-1H-pyrrolo[3,4-d]pyrazol-3-yl]-4-(4-methylpiperazin-1-yl)benzamide	1425068: 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	0.3650	uM
N-[(2S,3R,4R,6R,18S)-18-hydroxy-3-methoxy-2-methyl-16-oxo-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-4-yl]-N-methylbenzamide	507608: Binding affinity to MARK2	kd	0.4000	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	435296: Binding constant for MARK2 kinase domain	kd	0.4400	uM
[4-[(E)-2-(1H-indazol-3-yl)ethenyl]phenyl]-piperazin-1-ylmethanone	625106: Binding constant for MARK2 kinase domain	kd	0.4400	uM
3-(carbamoylamino)-5-(3-fluorophenyl)-N-[(3S)-piperidin-3-yl]thiophene-2-carboxamide	1425068: 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	0.4420	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	1425068: 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	0.4910	uM
N-[2-[4-[[4-(cyclobutylamino)-5-(trifluoromethyl)pyrimidin-2-yl]amino]-11-azatricyclo[6.2.1.02,7]undeca-2(7),3,5-trien-11-yl]-2-oxoethyl]acetamide	1425068: 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	0.5800	uM
Momelotinib	1425068: 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	0.6140	uM
Ruxolitinib	625106: Binding constant for MARK2 kinase domain	kd	0.6600	uM
methyl (15S,16R,18R)-16-hydroxy-15-methyl-3-oxo-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-nonaene-16-carboxylate	1425068: 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	0.7040	uM
4-[[5-amino-1-(2,6-difluorobenzoyl)-1,2,4-triazol-3-yl]amino]benzenesulfonamide	435296: Binding constant for MARK2 kinase domain	kd	1.2000	uM
1-cyclopropyl-3-[5-[6-(morpholin-4-ylmethyl)-1H-benzimidazol-2-yl]-1H-pyrazol-4-yl]urea	1425068: 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	1.3640	uM
methyl 2-hydroxy-3-[N-[4-[methyl-[2-(4-methylpiperazin-1-yl)acetyl]amino]phenyl]-C-phenylcarbonimidoyl]-1H-indole-6-carboxylate	625106: Binding constant for MARK2 kinase domain	kd	1.4000	uM
N-[4-[4-(4-methylpiperazin-1-yl)-6-[(5-methyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl]sulfanylphenyl]cyclopropanecarboxamide	435296: Binding constant for MARK2 kinase domain	kd	1.4000	uM
4-amino-5-fluoro-3-[6-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl]-1H-quinolin-2-one	435296: Binding constant for MARK2 kinase domain	kd	1.5000	uM
14,15-diazatetracyclo[7.6.1.02,7.013,16]hexadeca-1(15),2,4,6,9(16),10,12-heptaen-8-one	256608: Average Binding Constant for MARK2; NA=Not Active at 10 uM	kd	1.8000	uM
N-[(2S)-1-amino-3-(3,4-difluorophenyl)propan-2-yl]-5-chloro-4-(4-chloro-1-methylpyrazol-5-yl)furan-2-carboxamide	1425068: 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	2.0750	uM
(3R,4R)-4-amino-1-[[4-(3-methoxyanilino)pyrrolo[2,1-f][1,2,4]triazin-5-yl]methyl]piperidin-3-ol	1425068: 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	2.1740	uM
N-methyl-N-[3-[[[2-[(2-oxo-1,3-dihydroindol-5-yl)amino]-5-(trifluoromethyl)pyrimidin-4-yl]amino]methyl]-2-pyridinyl]methanesulfonamide	1425068: 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	2.2900	uM
(18S)-18-[(dimethylamino)methyl]-17-oxa-4,14,21-triazahexacyclo[19.6.1.17,14.02,6.08,13.022,27]nonacosa-1(28),2(6),7(29),8,10,12,22,24,26-nonaene-3,5-dione	256608: Average Binding Constant for MARK2; NA=Not Active at 10 uM	kd	2.3000	uM
5-cyano-N-[2-(cyclohexen-1-yl)-4-[1-[2-(dimethylamino)acetyl]piperidin-4-yl]phenyl]-1H-imidazole-2-carboxamide;hydrochloride	625106: Binding constant for MARK2 kinase domain	kd	2.3000	uM
(2R)-2-methyl-2-[[2-(1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl]amino]-N-(2,2,2-trifluoroethyl)butanamide	1425068: 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	2.3100	uM
5-(3-ethylsulfonylphenyl)-3,8-dimethyl-N-(1-methylpiperidin-4-yl)-9H-pyrido[2,3-b]indole-7-carboxamide	1425068: 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	2.3320	uM
N,1,4,4-tetramethyl-8-[4-(4-methylpiperazin-1-yl)anilino]-5H-pyrazolo[4,5-h]quinazoline-3-carboxamide	1425068: 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	2.3650	uM
N-methyl-4-[[4-[[3-[methyl(methylsulfonyl)amino]pyrazin-2-yl]methylamino]-5-(trifluoromethyl)pyrimidin-2-yl]amino]benzamide	1425068: 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	2.6010	uM
Fedratinib	625106: Binding constant for MARK2 kinase domain	kd	3.1000	uM
4-methyl-5-[2-(4-morpholin-4-ylanilino)pyrimidin-4-yl]-1,3-thiazol-2-amine	1425068: 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	3.1470	uM
5-(3-chloroanilino)benzo[c][2,6]naphthyridine-8-carboxylic acid	1425068: 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	3.1840	uM
N-[4-[2-(4-morpholin-4-ylanilino)pyrimidin-4-yl]phenyl]pyrrolidine-2-carboxamide	1425068: 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	3.2000	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
bisphenol A	decreases expression	2
Aflatoxin B1	increases methylation	2
Cadmium Chloride	decreases expression, increases expression	2
FR900359	affects phosphorylation	1
dicrotophos	increases expression	1
2,4,6-tribromophenol	decreases expression	1
triphenyl phosphate	affects expression	1
pirinixic acid	affects binding, decreases expression, increases activity	1
lead acetate	affects cotreatment, increases expression	1
pyrogallol 1,3-dimethyl ether	affects cotreatment, affects localization, decreases expression	1
beta-lapachone	increases expression	1
zinc protoporphyrin	affects cotreatment, increases expression	1
tetrabromobisphenol A	decreases expression	1
coumarin	decreases phosphorylation	1
CGP 52608	affects binding, increases reaction	1
abrine	increases expression	1
2,2’,4,4’-tetrabromodiphenyl ether	decreases expression	1
pentabrominated diphenyl ether 100	decreases expression	1
hexabrominated diphenyl ether 153	decreases expression	1
Bortezomib	decreases expression	1
Resveratrol	increases expression	1
Sunitinib	increases expression	1
Air Pollutants	increases abundance, affects expression	1
Air Pollutants, Occupational	decreases expression	1
Arsenic	affects methylation	1
Vehicle Emissions	increases methylation	1
Benzo(a)pyrene	decreases methylation	1
Caffeine	affects phosphorylation	1
Cisplatin	decreases expression	1
Dibutyl Phthalate	decreases expression, affects cotreatment	1

ChEMBL screening assays

356 unique, capped per target: 355 binding, 1 functional

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1040682	Binding	Residual activity of MARK2 at 0.1 uM by microplate scintillation counting	Substituted 2-arylbenzothiazoles as kinase inhibitors: hit-to-lead optimization. — Bioorg Med Chem
CHEMBL1963834	Functional	PUBCHEM_BIOASSAY: Navigating the Kinome. (Class of assay: other) Panel member name: MARK2	PubChem BioAssay data set

Cellosaurus cell lines

4 cell lines: 4 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_D1XJ	Abcam A-549 MARK2 KO	Cancer cell line	Male
CVCL_D2BU	Abcam HCT 116 MARK2 KO	Cancer cell line	Male
CVCL_SX13	HAP1 MARK2 (-) 1	Cancer cell line	Male
CVCL_SX14	HAP1 MARK2 (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

498 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,
NCT00111371	PHASE4	UNKNOWN	Dopaminergic Enhancement of Learning and Memory in Healthy Adults and Patients With Dyslexia
NCT00607919	PHASE4	COMPLETED	Treatment of ADHD With Atomoxetine in Children & Adolescents With ADHD & Comorbid Dyslexia
NCT00716274	PHASE4	COMPLETED	Effects of Atomoxetine on Brain Activation During Attention & Reading Tasks in Participants With ADHD & Comorbid Dyslexia
NCT00152750	PHASE4	UNKNOWN	Study of Clonidine on Sleep Architecture in Children With Tourette’s Syndrome (TS) and Comorbid ADHD
NCT00181571	PHASE4	COMPLETED	A Double-Blind Comparison of Concerta and Placebo in Adults With Attention Deficit Hyperactivity Disorder
NCT00181675	PHASE4	COMPLETED	A Double-Blind Comparison of Galantamine HBr and Placebo in Adults With Attention Deficit Hyperactivity Disorder
NCT00181714	PHASE4	COMPLETED	Prevention of Cigarette Smoking in Attention Deficit Hyperactivity Disorder (ADHD) Youth With Concerta
NCT00181948	PHASE4	COMPLETED	Strattera Treatment in Children With ADHD Who Have Poor Response to Stimulant Therapy
NCT00181987	PHASE4	COMPLETED	Concerta in the Treatment of ADHD in Youth and Adults With Bipolar Disorder
NCT00190736	PHASE4	COMPLETED	Efficacy and Safety of Once-Daily Atomoxetine Hydrochloride in Adults With ADHD Over an Extended Period of Time (6 Months)
NCT00190775	PHASE4	COMPLETED	A Randomized, Double-Blind Comparison of Placebo and Atomoxetine Hydrochloride Given Once a Day in Adults With Attention-Deficit/Hyperactivity Disorder (ADHD)
NCT00190879	PHASE4	COMPLETED	Placebo-Controlled Study of Atomoxetine Hydrochloride in the Treatment of Adults With ADHD and Comorbid Social Anxiety Disorder
NCT00190957	PHASE4	COMPLETED	Atomoxetine Treatment of Adults With ADHD and Comorbid Alcohol Abuse
NCT00191035	PHASE4	COMPLETED	Maintenance of Benefit With Atomoxetine Hydrochloride in Adolescents With ADHD
NCT00191048	PHASE4	COMPLETED	Treatment With Atomoxetine Hydrochloride in Children and Adolescents With ADHD
NCT00191633	PHASE4	COMPLETED	Study of Atomoxetine in Children With ADHD to Assess Symptomatic and Functional Outcomes
NCT00191906	PHASE4	COMPLETED	Comparison of Atomoxetine and Placebo in Children With Attention-Deficit/Hyperactivity Disorder (ADHD) and/or Reading Disorder (RD)
NCT00216918	PHASE4	COMPLETED	Neuropsychological Functioning in Children With Attention-Deficit/Hyperactivity Disorder.
NCT00221962	PHASE4	COMPLETED	Study of Aripiprazole (Abilify) in Children With ADHD (Attention Deficit Hyperactivity Disorder)
NCT00223561	PHASE4	COMPLETED	Methylphenidate and Driving Ability in Adult Patients With Attention-Deficit Hyperactivity Disorder
NCT00299234	PHASE4	TERMINATED	Atomoxetine for Children With Acquired Attentional Disorders Following Completion of Chemotherapy for ALL
NCT00302406	PHASE4	COMPLETED	Naturalistic Substitution of Concerta in Adult Subject With ADHD Receiving Immediate Release Methylphenidate
NCT00305370	PHASE4	COMPLETED	Aripiprazole Associated With Methylphenidate in Children and Adolescents With Bipolar Disorder and ADHD
NCT00381758	PHASE4	COMPLETED	The COMACS Study: A Comparison of Methylphenidates in an Analog Classroom Setting
NCT00406354	PHASE4	COMPLETED	Comparison of Atomoxetine Versus Placebo in Children and Adolescents With ADHD and Comorbid ODD in Germany
NCT00434213	PHASE4	COMPLETED	Characterization of Dermal Reactions in Pediatric Patients With ADHD Using DAYTRANA
NCT00468143	PHASE4	COMPLETED	A Within-Subject Cross-Over Comparison Between Immediate Release and Extended Release Adderall
NCT00471354	PHASE4	COMPLETED	A Study for Patients With Attention-Deficit/Hyperactivity Disorder Treated With Atomoxetine
NCT00483106	PHASE4	COMPLETED	Clinical and Pharmacogenetic Study of Attention Deficit With Hyperactivity Disorder (ADHD)
NCT00485849	PHASE4	COMPLETED	A Study of Atomoxetine for Attention Deficit and Hyperactive/Impulsive Behaviour Problems in Children With ASD
NCT00485875	PHASE4	COMPLETED	Safety and Efficacy of Switching From a Stimulant Medication to Atomoxetine in Children and Adolescents With ADHD
NCT00486122	PHASE4	COMPLETED	Evaluation of Continuous Symptom Treatment of ADHD
NCT00500071	PHASE4	COMPLETED	Dose-Optimization Study Evaluating the Efficacy, Safety and Tolerability of Vyvanse (Lisdexamfetamine Dimesylate) in Children Aged 6-12 Diagnosed With ADHD
NCT00506727	PHASE4	COMPLETED	Analog Classroom Study Comparison of ADDERALL XR With STRATTERA in Children Aged 6-12 With ADHD
NCT00510276	PHASE4	COMPLETED	Treatment of Attention-Deficit/Hyperactivity Disorder (ADHD) With Atomoxetine in Young Adults and Its Effects on Functional Outcomes
NCT00517504	PHASE4	COMPLETED	Methylphenidate Study in Young Children With Developmental Disorders
NCT00517647	PHASE4	COMPLETED	Atomoxetine Pilot Study in Preschool Children With ADHD
NCT00518232	PHASE4	COMPLETED	A Study to Determine Effective and Tolerable Titration Scheme for OROS-Methylphenidate in Children With Attention-deficit Hyperactivity Disorder