MAP4K1

Summary

MAP4K1 (mitogen-activated protein kinase kinase kinase kinase 1, HGNC:6863) is a protein-coding gene on chromosome 19q13.2, encoding Mitogen-activated protein kinase kinase kinase kinase 1 (Q92918). Serine/threonine-protein kinase, which plays a role in the response to environmental stress.

Enables ATP binding activity and MAP kinase kinase kinase kinase activity. Involved in several processes, including JNK cascade; cellular response to phorbol 13-acetate 12-myristate; and protein phosphorylation. Located in membrane.

Source: NCBI Gene 11184 — RefSeq curated summary.

At a glance

• GWAS associations: 1
• Clinical variants (ClinVar): 102 total
• Druggable target: yes — 42 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_001042600

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:6863
Approved symbol	MAP4K1
Name	mitogen-activated protein kinase kinase kinase kinase 1
Location	19q13.2
Locus type	gene with protein product
Status	Approved
Aliases	HPK1
Ensembl gene	ENSG00000104814
Ensembl biotype	protein_coding
OMIM	601983
Entrez	11184

Gene structure

Transcript identifiers

Ensembl transcripts: 19 — 9 protein_coding, 7 retained_intron, 2 protein_coding_CDS_not_defined, 1 nonsense_mediated_decay

ENST00000396857, ENST00000585583, ENST00000586296, ENST00000587300, ENST00000588083, ENST00000588938, ENST00000589002, ENST00000589130, ENST00000591210, ENST00000591517, ENST00000591707, ENST00000591921, ENST00000592225, ENST00000592888, ENST00000593196, ENST00000864510, ENST00000864511, ENST00000929927, ENST00000929928

RefSeq mRNA: 2 — MANE Select: NM_001042600 NM_001042600, NM_007181

CCDS: CCDS42564, CCDS59385

Canonical transcript exons

ENST00000396857 — 31 exons

Exon	Start	End
ENSE00000704443	38599925	38599985
ENSE00002225029	38597326	38597384
ENSE00002230080	38617797	38617953
ENSE00002269600	38611051	38611132
ENSE00002275181	38597034	38597137
ENSE00002275239	38595640	38595729
ENSE00002276141	38597486	38597594
ENSE00002764596	38587641	38587817
ENSE00003464382	38611243	38611305
ENSE00003474979	38606173	38606215
ENSE00003494801	38595939	38596001
ENSE00003519661	38607990	38608033
ENSE00003534919	38595485	38595555
ENSE00003540611	38609909	38610025
ENSE00003544858	38596312	38596486
ENSE00003546078	38614245	38614292
ENSE00003561997	38593282	38593337
ENSE00003562992	38617354	38617444
ENSE00003576411	38614043	38614085
ENSE00003577078	38605568	38605730
ENSE00003583770	38614390	38614445
ENSE00003609156	38607864	38607911
ENSE00003614088	38608112	38608170
ENSE00003633067	38612611	38612742
ENSE00003637378	38616195	38616259
ENSE00003639750	38601441	38601525
ENSE00003642063	38617568	38617625
ENSE00003660921	38613880	38613952
ENSE00003671092	38600077	38600153
ENSE00003673566	38605409	38605491
ENSE00003680214	38609596	38609674

Expression profiles

Bgee: expression breadth ubiquitous, 134 present calls, max score 98.11.

FANTOM5 (CAGE): breadth broad, TPM avg 6.4220 / max 242.3305, expressed in 656 samples.

FANTOM5 promoters (8 alternative TSS)

Promoter ID	TPM avg	Samples expressed
180790	4.7815	369
180791	0.5295	180
180793	0.4006	195
180783	0.3144	117
180789	0.2297	117
180785	0.1153	62
180786	0.0348	12
180792	0.0162	10

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
granulocyte	CL:0000094	98.11	gold quality
lymph node	UBERON:0000029	98.01	gold quality
spleen	UBERON:0002106	96.83	gold quality
vermiform appendix	UBERON:0001154	95.76	gold quality
bone marrow cell	CL:0002092	94.04	gold quality
blood	UBERON:0000178	93.49	gold quality
bone marrow	UBERON:0002371	92.63	gold quality
leukocyte	CL:0000738	90.95	gold quality
monocyte	CL:0000576	90.45	gold quality
small intestine Peyer’s patch	UBERON:0003454	87.94	gold quality
small intestine	UBERON:0002108	86.90	gold quality
tonsil	UBERON:0002372	86.42	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	84.44	gold quality
sural nerve	UBERON:0015488	84.15	gold quality
skeletal muscle tissue	UBERON:0001134	83.64	gold quality
gastrocnemius	UBERON:0001388	82.78	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	82.54	gold quality
muscle of leg	UBERON:0001383	82.45	gold quality
colonic epithelium	UBERON:0000397	82.35	gold quality
rectum	UBERON:0001052	82.30	gold quality
muscle tissue	UBERON:0002385	82.29	gold quality
gall bladder	UBERON:0002110	81.94	gold quality
duodenum	UBERON:0002114	81.38	gold quality
mucosa of transverse colon	UBERON:0004991	80.51	gold quality
upper lobe of left lung	UBERON:0008952	80.16	gold quality
hindlimb stylopod muscle	UBERON:0004252	79.14	gold quality
lung	UBERON:0002048	78.55	gold quality
placenta	UBERON:0001987	78.09	gold quality
right lung	UBERON:0002167	77.30	gold quality
intestine	UBERON:0000160	77.25	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	13.42
E-MTAB-9388	yes	11.58

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): MYC

miRNA regulators (miRDB)

14 targeting MAP4K1, 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-6870-5P	99.99	68.55	2115
HSA-MIR-4723-5P	99.97	68.70	2034
HSA-MIR-5698	99.97	68.49	2029
HSA-MIR-7111-5P	99.97	68.48	2062
HSA-MIR-5004-5P	99.68	66.63	1294
HSA-MIR-3975	99.62	65.97	697
HSA-MIR-887-5P	98.82	65.90	1347
HSA-MIR-4664-5P	98.17	65.07	1020
HSA-MIR-4659A-5P	98.03	66.42	819
HSA-MIR-4659B-5P	98.03	66.84	979
HSA-MIR-30C-1-3P	97.80	66.36	1499
HSA-MIR-30C-2-3P	97.80	66.45	1499
HSA-MIR-6788-5P	97.80	66.41	1532
HSA-MIR-342-5P	97.25	64.10	817

Literature-anchored findings (GeneRIF, showing 29)

• The catalytic activity of a hematopoietic cell-restricted, Ste20-related S/TPK, HPK1, is positively regulated by exposure to physiological concentrations of PGE2. HPK1 is a negative regulator of PGE2-induced FOS gene transcription. (PMID:12522005)
• PP4 is a positive regulator for HPK1 and the HPK1-JNK signaling pathway (PMID:15364934)
• Full activation of HPK1 is dependent on autophosphorylation of threonine 165 and phosphorylation of serine 171, which is a target site for protein kinase D (PKD) in vitro. (PMID:15743830)
• suppression or activation of NFkappaB by HPK1 determines sensitivity to activation-induced cell death (PMID:16341093)
• Pdcd4 suppresses tumor progression in colon carcinoma cells by the novel mechanism of down-regulating MAP4K1 transcription, with consequent inhibition of c-Jun activation and AP-1-dependent transcription. (PMID:16449643)
• Our work explains growth factor-independent survival during monocytic differentiation by caspase-mediated processing of HPK1 towards HPK1-N. (PMID:17024227)
• A novel negative feedback loop involves HPK-1-dependent serine phosphorylation of SLP-76 and 14-3-3 protein recruitment, which tunes T cell activation. (PMID:17353368)
• HPK1-C as a suppressor of antiapoptotic Bcl-2 proteins and provide a molecular basis for our understanding of CD95L-independent activation-induced cell death of lymphocytes. (PMID:17712048)
• Prostaglandin E2 activates HPK1 kinase activity via a PKA-dependent pathway (PMID:17895239)
• Restoring wild-type HPK1 protein in pancreatic cancer cells led to the increase in p21 and p27 protein expression and cell cycle arrest. HPK1 may function as a novel tumor suppressor and its loss plays a critical role in pancreatic cancer. (PMID:19141650)
• Results suggest HPK1-mediated phosphorylation of CARMA1 as an additional regulatory mechanism tuning the NF-kappaB response upon TCR stimulation. (PMID:19706536)
• The purpose of the study was to investigate the potential contribution of HPK1, MEKK1, TAK1, p-MKK4 to the development of extramammary Paget disease (PMID:21915030)
• HPK1 negatively regulates T cell activation by reducing the persistence of signaling microclusters. (PMID:22105350)
• results indicate that uncleaved HPK1 is a positive regulator of vitamin D-induced differentiation in acute myeloid leukemia cells, but the cleaved HPK1 fragment inhibits differentiation (PMID:22421156)
• QVD and 1,25D-induced differentiation was accompanied by increased signaling by Hematopoietic Progenitor Kinase 1(HPK1), and the expression of transcription factors known to be involved in monocytic differentiation was increased. (PMID:22541691)
• Pdcd4 knockdown up-regulates MAP kinase kinase kinase kinase 1 (MAP4K1) expression and increases phosphorylation of c-Jun. (PMID:22801218)
• HPK1 is critically involved in LFA-1-mediated polymorphonuclear neutrophils trafficking during acute inflammation. (PMID:23460610)
• CUL7/Fbxw8 ubiquitin ligase-mediated HPK1 degradation revealed a direct link and novel role of CUL7/Fbxw8 ubiquitin ligase in the MAPK pathway, which plays a critical role in cell proliferation and differentiation. (PMID:24362026)
• HPK1 protein expression, which is expressed at significantly higher levels in NATs compared with paired IDC-NOS tissues, is significantly negatively associated with ER positivity and is positively associated with OS duration, suggesting that HPK1 may exhibit anticancer activities. (PMID:28765906)
• Interactions between HPK1 and its adaptor proteins related to immunity has been discussed (Review). (PMID:28901492)
• Hematopoietic progenitor kinase 1 down-regulates the oncogenic receptor tyrosine kinase AXL in pancreatic cancer. (PMID:31959629)
• MAP4K Interactome Reveals STRN4 as a Key STRIPAK Complex Component in Hippo Pathway Regulation. (PMID:32640226)
• Hematopoietic Progenitor Kinase1 (HPK1) Mediates T Cell Dysfunction and Is a Druggable Target for T Cell-Based Immunotherapies. (PMID:32860752)
• Using yeast surface display to engineer a soluble and crystallizable construct of hematopoietic progenitor kinase 1 (HPK1). (PMID:33439152)
• MAP4K1 functions as a tumor promotor and drug mediator for AML via modulation of DNA damage/repair system and MAPK pathway. (PMID:34166980)
• The Kinase MAP4K1 Inhibits Cytosolic RNA-Induced Antiviral Signaling by Promoting Proteasomal Degradation of TBK1/IKKepsilon. (PMID:34908452)
• Decoding the signaling profile of hematopoietic progenitor kinase 1 (HPK1) in innate immunity: A proteomic approach. (PMID:35099066)
• Glioblastoma cellular MAP4K1 facilitates tumor growth and disrupts T effector cell infiltration. (PMID:37734869)
• HPK1 Dysregulation-Associated NK Cell Dysfunction and Defective Expansion Promotes Metastatic Melanoma Progression. (PMID:38828677)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio		ENSDARG00000114026
mus_musculus	Map4k1	ENSMUSG00000037337
rattus_norvegicus	Map4k1	ENSRNOG00000020505

Paralogs (35): MAP3K14 (ENSG00000006062), MAP4K3 (ENSG00000011566), MAP4K5 (ENSG00000012983), MAP2K3 (ENSG00000034152), SLK (ENSG00000065613), MAP4K4 (ENSG00000071054), STK10 (ENSG00000072786), PAK3 (ENSG00000077264), STRADB (ENSG00000082146), MAP3K1 (ENSG00000095015), STK4 (ENSG00000101109), PAK5 (ENSG00000101349), STK24 (ENSG00000102572), STK3 (ENSG00000104375), MAP3K8 (ENSG00000107968), MAP2K6 (ENSG00000108984), NEK4 (ENSG00000114904), STK25 (ENSG00000115694), NRK (ENSG00000123572), PAK4 (ENSG00000130669), STK26 (ENSG00000134602), TAOK3 (ENSG00000135090), PAK6 (ENSG00000137843), MINK1 (ENSG00000141503), PAK1 (ENSG00000149269), TAOK2 (ENSG00000149930), TNIK (ENSG00000154310), TAOK1 (ENSG00000160551), MAP4K2 (ENSG00000168067), OXSR1 (ENSG00000172939), MAP3K19 (ENSG00000176601), PAK2 (ENSG00000180370), SBK2 (ENSG00000187550), STK39 (ENSG00000198648), STRADA (ENSG00000266173)

Protein

Protein identifiers

Mitogen-activated protein kinase kinase kinase kinase 1 — Q92918 (reviewed: Q92918)

Alternative names: Hematopoietic progenitor kinase, MAPK/ERK kinase kinase kinase 1

All UniProt accessions (5): Q92918, K7EJS6, K7EKT6, K7ER95, K7ERT2

UniProt curated annotations — full annotation on UniProt →

Function. Serine/threonine-protein kinase, which plays a role in the response to environmental stress. Appears to act upstream of the JUN N-terminal pathway. Activator of the Hippo signaling pathway which plays a pivotal role in organ size control and tumor suppression by restricting proliferation and promoting apoptosis. MAP4Ks act in parallel to and are partially redundant with STK3/MST2 and STK4/MST2 in the phosphorylation and activation of LATS1/2, and establish MAP4Ks as components of the expanded Hippo pathway. May play a role in hematopoietic lineage decisions and growth regulation. Together with CLNK, it enhances CD3-triggered activation of T-cells and subsequent IL2 production.

Subunit / interactions. Interacts with MAP3K1. Interacts with FBXW8. Interacts with CLNK (via its SH2 domain).

Tissue specificity. Expressed primarily in hematopoietic organs, including bone marrow, spleen and thymus. Also expressed at very low levels in lung, kidney, mammary glands and small intestine.

Post-translational modifications. Autophosphorylates: phosphorylation promotes ubiquitination by the Cul7-RING(FBXW8) ubiquitin-protein ligase complex, leading to its degradation by the proteasome. Tyrosine-phosphorylated after activation of hemopoietic cells. Ubiquitinated by the Cul7-RING(FBXW8) ubiquitin-protein ligase complex following autophosphorylation, leading to its degradation by the proteasome.

Similarity. Belongs to the protein kinase superfamily. STE Ser/Thr protein kinase family. STE20 subfamily.

Isoforms (2)

UniProt ID	Names	Canonical?
Q92918-1	1	yes
Q92918-2	2

RefSeq proteins (2): NP_001036065, NP_009112 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000719	Prot_kinase_dom	Domain
IPR001180	CNH_dom	Domain
IPR011009	Kinase-like_dom_sf	Homologous_superfamily
IPR017441	Protein_kinase_ATP_BS	Binding_site
IPR021160	MAPKKKK	Family
IPR050629	STE20/SPS1-PAK	Family

Pfam: PF00069, PF00780

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 (89 total): strand 37, helix 17, modified residue 11, turn 6, sequence variant 5, compositionally biased region 4, domain 2, binding site 2, chain 1, splice variant 1, mutagenesis site 1, region of interest 1, active site 1

Structure

Experimental structures (PDB)

45 structures, top 30 by resolution.

PDB	Method	Resolution (Å)
9H8F	X-RAY DIFFRACTION	1.39
9NAC	X-RAY DIFFRACTION	1.45
9CZX	X-RAY DIFFRACTION	1.46
7R9N	X-RAY DIFFRACTION	1.5
9NC2	X-RAY DIFFRACTION	1.5
9CZW	X-RAY DIFFRACTION	1.59
9H8E	X-RAY DIFFRACTION	1.63
9H8D	X-RAY DIFFRACTION	1.64
9CZT	X-RAY DIFFRACTION	1.69
9QT6	X-RAY DIFFRACTION	1.76
7SIU	X-RAY DIFFRACTION	1.79
9NBS	X-RAY DIFFRACTION	1.8
8FH4	X-RAY DIFFRACTION	1.83
7KAC	X-RAY DIFFRACTION	1.85
7L25	X-RAY DIFFRACTION	1.85
9CZU	X-RAY DIFFRACTION	1.85
6CQE	X-RAY DIFFRACTION	1.89
8FJZ	X-RAY DIFFRACTION	1.9
7M0M	X-RAY DIFFRACTION	1.93
8CDW	X-RAY DIFFRACTION	1.94
9D00	X-RAY DIFFRACTION	1.95
7R9T	X-RAY DIFFRACTION	2
8PAR	X-RAY DIFFRACTION	2
7M0K	X-RAY DIFFRACTION	2.01
6NG0	X-RAY DIFFRACTION	2.05
8FKO	X-RAY DIFFRACTION	2.1
6CQD	X-RAY DIFFRACTION	2.12
9N7R	X-RAY DIFFRACTION	2.13
6NFY	X-RAY DIFFRACTION	2.17
9BJ1	X-RAY DIFFRACTION	2.18

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q92918-F1	68.83	0.27

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): 137 (proton acceptor)

Ligand- & substrate-binding residues (2): 46; 23–31

Post-translational modifications (11): 165, 171, 175, 355, 374, 376, 405, 407, 413, 421, 586

Mutagenesis-validated functional residues (1):

Position	Phenotype
355	retains kinase activity. not degraded by the cul7-ring ubiquitin-protein ligase complex containing fbxw8.

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 270 (showing top): PID_BCR_5PATHWAY, GSE18804_SPLEEN_MACROPHAGE_VS_COLON_TUMORAL_MACROPHAGE_UP, E2F_Q4_01, WALLACE_PROSTATE_CANCER_RACE_UP, TGCGCANK_UNKNOWN, GOBP_CELLULAR_RESPONSE_TO_LIPID, KEGG_MAPK_SIGNALING_PATHWAY, MODULE_45, GOBP_PEPTIDYL_SERINE_MODIFICATION, MATTIOLI_MGUS_VS_PCL, GOBP_POSITIVE_REGULATION_OF_MAPK_CASCADE, GOBP_CELLULAR_RESPONSE_TO_OXYGEN_CONTAINING_COMPOUND, FINETTI_BREAST_CANCER_KINOME_GREEN, GOBP_RESPONSE_TO_KETONE, GGAANCGGAANY_UNKNOWN

GO Biological Process (9): protein phosphorylation (GO:0006468), JNK cascade (GO:0007254), cell population proliferation (GO:0008283), peptidyl-serine phosphorylation (GO:0018105), intracellular signal transduction (GO:0035556), positive regulation of MAPK cascade (GO:0043410), protein autophosphorylation (GO:0046777), cellular response to phorbol 13-acetate 12-myristate (GO:1904628), MAPK cascade (GO:0000165)

GO Molecular Function (9): protein serine/threonine kinase activity (GO:0004674), ATP binding (GO:0005524), MAP kinase kinase kinase kinase activity (GO:0008349), 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 (2): cytoplasm (GO:0005737), membrane (GO:0016020)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
MAPK cascade	3
protein phosphorylation	2
intracellular anatomical structure	2
protein kinase activity	2
cellular anatomical structure	2
phosphorylation	1
protein modification process	1
cellular process	1
peptidyl-serine modification	1
signal transduction	1
regulation of MAPK cascade	1
positive regulation of intracellular signal transduction	1
cellular response to lipid	1
cellular response to alcohol	1
cellular response to ketone	1
response to phorbol 13-acetate 12-myristate	1
intracellular signaling cassette	1
adenyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1
protein serine/threonine kinase activity	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

Protein interactions and networks

STRING

1198 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
MAP4K1	DBNL	P84070	942
MAP4K1	LCP2	Q13094	900
MAP4K1	GRB2	P29354	757
MAP4K1	GRAP2	O75791	678
MAP4K1	DBN1	Q16643	668
MAP4K1	PLCG1	P19174	636
MAP4K1	GRAP	Q13588	621
MAP4K1	FYB1	O15117	601
MAP4K1	SKAP1	Q86WV1	593
MAP4K1	CRKL	P46109	583
MAP4K1	UBASH3A	P57075	580
MAP4K1	CRK	P46108	577
MAP4K1	PDIA6	Q15084	552
MAP4K1	BCKDK	O14874	532
MAP4K1	DAPP1	Q9UN19	520

IntAct

67 interactions, top by confidence:

A	B	Type	Score
SLAMF1	SH2D1A	psi-mi:“MI:0914”(association)	0.940
GRB2	MAP4K1	psi-mi:“MI:0915”(physical association)	0.780
MAP4K1	GRB2	psi-mi:“MI:0915”(physical association)	0.780
MAP4K1	HSP90AB1	psi-mi:“MI:0914”(association)	0.670
HSP90AB1	MAP4K1	psi-mi:“MI:0915”(physical association)	0.670
PLCG1	MAP4K1	psi-mi:“MI:0915”(physical association)	0.660
MAP4K1	PLCG1	psi-mi:“MI:0407”(direct interaction)	0.660
MAP4K1	PLCG1	psi-mi:“MI:0915”(physical association)	0.660
MAP4K1	NCK1	psi-mi:“MI:0915”(physical association)	0.650
MAP4K1	CRK	psi-mi:“MI:0915”(physical association)	0.590
CRK	MAP4K1	psi-mi:“MI:0915”(physical association)	0.590
MAP4K1	SLAMF1	psi-mi:“MI:0915”(physical association)	0.580
MAP4K1	ABL1	psi-mi:“MI:0915”(physical association)	0.570
EGFR	MAP4K1	psi-mi:“MI:0915”(physical association)	0.550

BioGRID (170): MAP4K1 (Two-hybrid), MAP4K1 (PCA), HIST1H2AB (Biochemical Activity), MAP4K1 (Affinity Capture-MS), MAP4K1 (Affinity Capture-MS), MAP4K1 (Affinity Capture-MS), MAP4K1 (Affinity Capture-MS), MAP4K1 (Affinity Capture-Western), CARD11 (Biochemical Activity), MAP4K1 (Biochemical Activity), SPHK1 (Negative Genetic), RPS6KA4 (Negative Genetic), UCK2 (Positive Genetic), MAP4K1 (Positive Genetic), MAP4K1 (Affinity Capture-MS)

ESM2 similar proteins: A0A1D5PJB7, A0A1L8HX76, A6QR40, O08764, O60294, O95382, P10938, P70218, P97452, Q12851, Q14137, Q15334, Q16586, Q28686, Q32P44, Q3TJ91, Q499N3, Q499U2, Q4KLI9, Q561R2, Q562C2, Q5RBH8, Q5RCX2, Q61161, Q6AY79, Q6F5E8, Q6P1M3, Q6V7V2, Q7SZE3, Q7TMC8, Q80Y17, Q8BYZ7, Q8C3I8, Q8C6B2, Q8CHW4, Q8K4K5, Q8MKF0, Q8N0W3, Q8VC03, Q91WI7

Diamond homologs: A0A096LPI5, A6NIU2, A6NJG6, F2Z398, P0DTE4, P51957, Q09FC8, Q5H9K5, Q5T7P6, Q68CZ1, Q6B4Z3, Q6UX73, Q86U02, Q8IV13, Q8N7M2, Q8N9N2, Q8NDZ0, Q8NEM8, Q8TDM0, Q92918, Q96J02, Q96MD7, Q9BUA6, Q9NXG0, A0A078CGE6, A2AQW0, A2QHV0, A2YMV6, A9RVK2, A9SY39, C4YRB7, D4A280, M9PGC5, O14305, O24527, O75914, O81472, O88643, P0CY23, P0CY24

SIGNOR signaling

19 interactions.

A	Effect	B	Mechanism
MAP4K1	up-regulates	MAP4K1	phosphorylation
MAP4K1	up-regulates	LCP2	phosphorylation
SYK	“up-regulates activity”	MAP4K1	phosphorylation
ABL1	“up-regulates activity”	MAP4K1	phosphorylation
MAP4K1	“down-regulates activity”	LCP2	phosphorylation
MAP4K1	down-regulates	T_cell_activation
MAP4K1	“down-regulates activity”	GRAP2	phosphorylation
MAP4K1	up-regulates	MAP3K1	phosphorylation
MAP4K1	up-regulates	MAPK8
CRK	up-regulates	MAP4K1	binding
CRKL	up-regulates	MAP4K1	binding
GRB2	up-regulates	MAP4K1	binding
MAP4K1	up-regulates	MAP3K7
MAP4K1	up-regulates	MAP3K11	phosphorylation
LYN	“up-regulates activity”	MAP4K1	phosphorylation
MAP4K1	“up-regulates activity”	PSMD2	phosphorylation
MAP4K1	“up-regulates activity”	CARD11	phosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 38 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
Constitutive Signaling by EGFRvIII	5	142.8×	3e-08
Signaling by ERBB2 ECD mutants	5	134.3×	3e-08
Constitutive Signaling by Ligand-Responsive EGFR Cancer Variants	5	114.2×	6e-08
Downstream signal transduction	7	106.6×	9e-11
Regulation of signaling by CBL	5	99.3×	1e-07
Signaling by ERBB2 KD Mutants	5	84.6×	2e-07
FCGR3A-mediated phagocytosis	6	44.9×	2e-07
Regulation of actin dynamics for phagocytic cup formation	6	44.2×	2e-07

GO biological processes:

GO term	Partners	Fold	FDR
ephrin receptor signaling pathway	5	57.3×	1e-05
epidermal growth factor receptor signaling pathway	5	41.3×	3e-05
neuron migration	5	22.3×	3e-04
positive regulation of ERK1 and ERK2 cascade	5	14.2×	1e-03
negative regulation of apoptotic process	6	7.0×	4e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	70
Likely benign	8
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

4518 predictions. Top by Δscore:

Variant	Effect	Δscore
19:38595628:C:A	donor_gain	1.0000
19:38597133:CTCCG:C	acceptor_gain	1.0000
19:38597135:CCG:C	acceptor_gain	1.0000
19:38597136:CGC:C	acceptor_gain	1.0000
19:38597138:C:CC	acceptor_gain	1.0000
19:38597144:C:CT	acceptor_gain	1.0000
19:38597145:A:AC	acceptor_gain	1.0000
19:38597606:G:C	acceptor_gain	1.0000
19:38597606:G:GC	acceptor_gain	1.0000
19:38597610:A:AC	acceptor_gain	1.0000
19:38597610:A:C	acceptor_gain	1.0000
19:38600071:CCTCA:C	donor_loss	1.0000
19:38600072:CTCAC:C	donor_loss	1.0000
19:38600073:TCAC:T	donor_loss	1.0000
19:38600074:CACCA:C	donor_loss	1.0000
19:38600075:A:AC	donor_gain	1.0000
19:38600075:A:C	donor_loss	1.0000
19:38600076:C:CC	donor_gain	1.0000
19:38605258:CA:C	acceptor_gain	1.0000
19:38605259:A:C	acceptor_gain	1.0000
19:38605488:GGTTC:G	acceptor_loss	1.0000
19:38605491:TC:T	acceptor_loss	1.0000
19:38605492:C:CC	acceptor_gain	1.0000
19:38605492:CTGAG:C	acceptor_loss	1.0000
19:38607858:A:AC	donor_gain	1.0000
19:38607859:C:CC	donor_gain	1.0000
19:38607862:A:AC	donor_gain	1.0000
19:38607863:C:CC	donor_gain	1.0000
19:38609903:TCTCA:T	donor_loss	1.0000
19:38609904:CTCA:C	donor_loss	1.0000

AlphaMissense

5317 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
19:38612681:A:G	W199R	1.000
19:38612681:A:T	W199R	1.000
19:38612740:A:G	M179T	1.000
19:38613881:A:G	W178R	1.000
19:38613881:A:T	W178R	1.000
19:38613897:G:C	F172L	1.000
19:38613897:G:T	F172L	1.000
19:38613899:A:G	F172L	1.000
19:38613949:T:A	D155V	1.000
19:38614252:T:G	D137A	1.000
19:38617587:C:A	K46N	1.000
19:38617587:C:G	K46N	1.000
19:38600124:C:G	G521R	0.999
19:38612653:A:G	L208P	0.999
19:38612671:C:T	G202D	0.999
19:38612672:C:G	G202R	0.999
19:38612686:T:A	D197V	0.999
19:38612686:T:G	D197A	0.999
19:38612687:C:G	D197H	0.999
19:38612740:A:C	M179R	0.999
19:38612742:C:A	W178C	0.999
19:38612742:C:G	W178C	0.999
19:38613892:C:T	G174E	0.999
19:38613893:C:A	G174W	0.999
19:38613893:C:G	G174R	0.999
19:38613893:C:T	G174R	0.999
19:38613898:A:G	F172S	0.999
19:38613901:G:A	S171F	0.999
19:38613908:G:T	R169S	0.999
19:38613948:G:C	D155E	0.999

dbSNP variants (sampled 300 via entrez): RS1000063226 (19:38598179 C>G,T), RS1000176379 (19:38613224 T>G), RS1000248709 (19:38596573 C>T), RS1000351892 (19:38608672 C>T), RS1000383046 (19:38608821 A>C), RS1000501098 (19:38618233 C>A), RS1000524902 (19:38602347 T>A), RS1000699909 (19:38615401 A>G), RS1000856442 (19:38606109 C>A), RS1000887807 (19:38605910 C>T), RS1000896711 (19:38589866 C>T), RS1001014316 (19:38599256 G>A), RS1001139731 (19:38593201 C>A,G), RS1001264669 (19:38603369 T>C), RS1001300019 (19:38616731 G>A)

Disease associations

OMIM: gene MIM:601983 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST002875_93	Diisocyanate-induced asthma	5.000000e-06

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0006995	response to diisocyanate

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (2): CHEMBL5169088 (PROTEIN-PROTEIN INTERACTION), CHEMBL5749 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

42 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 359,938 (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
CHEMBL1171837	PONATINIB	4	8,955
CHEMBL1287853	FEDRATINIB	4	3,554
CHEMBL1289926	AXITINIB	4	15,732
CHEMBL1336	SORAFENIB	4	86,060
CHEMBL180022	NERATINIB	4	9,404
CHEMBL2035187	PACRITINIB	4	3,345
CHEMBL24828	VANDETANIB	4	42,230
CHEMBL255863	NILOTINIB	4	38,627
CHEMBL288441	BOSUTINIB	4	12,255
CHEMBL3301622	GILTERITINIB	4	2,395
CHEMBL477772	PAZOPANIB	4	15,540
CHEMBL502835	NINTEDANIB	4	8,545
CHEMBL535	SUNITINIB	4	79,020
CHEMBL5416410	DASATINIB	4	655
CHEMBL601719	CRIZOTINIB	4	14,403
CHEMBL608533	MIDOSTAURIN	4	7,259
CHEMBL223360	LINIFANIB	3	3,925
CHEMBL274654	ORANTINIB	3	3,596
CHEMBL300138	ENZASTAURIN	3	3,209
CHEMBL3137331	DEFACTINIB	3	1,229
CHEMBL428690	ALVOCIDIB	3
CHEMBL491473	CEDIRANIB	3
CHEMBL522892	DOVITINIB	3
CHEMBL572881	MOTESANIB	3
CHEMBL603469	LESTAURTINIB	3
CHEMBL91829	RUBOXISTAURIN	3
CHEMBL1230609	FORETINIB	2
CHEMBL1721885	SU-014813	2
CHEMBL1738757	REBASTINIB	2
CHEMBL402548	DANUSERTIB	2

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

GtoPdb / IUPHAR curated pharmacology

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

Target class: enzyme — KHS subfamily

Most potent curated ligand interactions (3 total), top 3:

Ligand	Action	Affinity	Parameter
compound 5i [PMID: 36542759]	Inhibition	9.1	pIC50
AZ3246	Inhibition	8.52	pIC50
fimsosertib	Inhibition	8.0	pIC50

Binding affinities (BindingDB)

888 measured of 2000 human assays (2000 total across all organisms); most potent 50 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
2-[[6-(5-amino-4-methyl-3-pyridyl)-7-fluoro-3- isoquinolyl]amino]-6-methyl-spiro[5,8- dihydropyrazolo[1,5-d][1,4]diazepine-4,1’- cyclopropane]-7-one	KI	0.01 nM	US-12378249: Isoquinoline compounds and uses thereof
tert-butyl 7-[7-fluoro-3-[(6-methyl-7-oxo-5,8- dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-2- yl)amino]-6-isoquinolyl]-8-methyl-2,3- dihydropyrido[2,3-b][1,4]oxazine-1- carboxylate	KI	0.01 nM	US-12378249: Isoquinoline compounds and uses thereof
2-((7,8-difluoro-6-(8-methyl-2,3-dihydro-1H- pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3- yl)amino)-6-methyl-5,6-dihydro-4H- pyrazolo[1,5-d][1,4]diazepin-7(8H)-one	KI	0.013 nM	US-12378249: Isoquinoline compounds and uses thereof
N-(7-fluoro-6-(8-methyl-2,3-dihydro-1H- pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3- yl)-5,6-dihydro-11H-imidazo[1,2- a]pyrazolo[1,5-d][1,4]diazepin-8-amine	KI	0.013 nM	US-12378249: Isoquinoline compounds and uses thereof
2-((7-fluoro-6-(8-methyl-2,3-dihydro-1H- pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3- yl)amino)-6-(2-hydroxyethyl)-5,6-dihydro-4H- pyrazolo[1,5-d][1,4]diazepin-7(8H)-one	KI	0.013 nM	US-12378249: Isoquinoline compounds and uses thereof
1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-	KI	0.013 nM	US-12378249: Isoquinoline compounds and uses thereof
(S)-2-((7-fluoro-6-(8-methyl-2,3-dihydro-1H-	KI	0.013 nM	US-12378249: Isoquinoline compounds and uses thereof
pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-	KI	0.013 nM	US-12378249: Isoquinoline compounds and uses thereof
N-(7-fluoro-6-(8-methyl-2,3-dihydro-1H- pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3- yl)-5,6-dihydro-11H-pyrazolo[1,5- d][1,2,4]triazolo[4,3-a][1,4]diazepin-8-amine	KI	0.013 nM	US-12378249: Isoquinoline compounds and uses thereof
2-((7-fluoro-6-(8-methyl-2,3-dihydro-1H- pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3- yl)amino)-6-(2-methoxyethyl)-5,6-dihydro-4H- pyrazolo[1,5-d][1,4]diazepin-7(8H)-one	KI	0.013 nM	US-12378249: Isoquinoline compounds and uses thereof
2-((7-fluoro-6-(8-methyl-2,3-dihydro-1H- pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3- yl)amino)-5,6-dihydro-4H-pyrazolo[1,5- d][1,4]diazepin-7(8H)-one	KI	0.013 nM	US-12378249: Isoquinoline compounds and uses thereof
N-(6-(5-amino-4-methylpyridin-3-yl)-7- fluoroisoquinolin-3-yl)-3-methyl-5,6-dihydro- 11H-imidazo[1,2-a]pyrazolo[1,5- d][1,4]diazepin-8-amine	KI	0.013 nM	US-12378249: Isoquinoline compounds and uses thereof
2-((6-(5-amino-4-methylpyridin-3-yl)-7- fluoroisoquinolin-3-yl)amino)-6-(2-(3- fluoroazetidin-1-yl)ethyl)-5,6-dihydro-4H- pyrazolo[1,5-d][1,4]diazepin-7(8H)-one	KI	0.013 nM	US-12378249: Isoquinoline compounds and uses thereof
2-((6-(5-amino-4-methylpyridin-3-yl)-7- fluoroisoquinolin-3-yl)amino)-6-(2-(3- hydroxyazetidin-1-yl)ethyl)-5,6-dihydro-4H- pyrazolo[1,5-d][1,4]diazepin-7(8H)-one	KI	0.013 nM	US-12378249: Isoquinoline compounds and uses thereof
fluoroisoquinolin-3-yl)amino)-6-(tert-butyl)-4-	KI	0.013 nM	US-12378249: Isoquinoline compounds and uses thereof
N-(7-fluoro-6-(9-methyl-1,2,3,4- tetrahydropyrido[2,3-b][1,4]oxazepin-8- yl)isoquinolin-3-yl)-5,6-dihydro-11H- imidazo[1,2-a]pyrazolo[1,5-d][1,4]diazepin-8- amine	KI	0.013 nM	US-12378249: Isoquinoline compounds and uses thereof
(R)-2’-((7-fluoro-6-(8-hydroxy-4-methyl-	KI	0.013 nM	US-12378249: Isoquinoline compounds and uses thereof
5,6,7,8-tetrahydro-1,5-naphthyridin-3-	KI	0.013 nM	US-12378249: Isoquinoline compounds and uses thereof
2’-((6-(5-amino-4-methylpyridin-3-yl)-7- fluoroisoquinolin-3-yl)amino)-5’,6’- dihydrospiro[cyclopropane-1,4’-pyrazolo[1,5- d][1,4]diazepin]-7’(8’H)-one	KI	0.013 nM	US-12378249: Isoquinoline compounds and uses thereof
2’-((6-(5-amino-4-methylpyridin-3-yl)-8- fluoroisoquinolin-3-yl)amino)-5’,6’- dihydrospiro[cyclopropane-1,4’-pyrazolo[1,5- d][1,4]diazepin]-7’(8’H)-one	KI	0.013 nM	US-12378249: Isoquinoline compounds and uses thereof
(S)-7-(3-((5,6-dihydro-11H-imidazo[1,2-	KI	0.013 nM	US-12378249: Isoquinoline compounds and uses thereof
2-((7-fluoro-6-(8-methyl-2,3-dihydro-1H-	KI	0.013 nM	US-12378249: Isoquinoline compounds and uses thereof
2-((7-fluoro-6-(8-methyl-2,3-dihydro-1H- pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3- yl)amino)-6-isopropyl-5,6-dihydro-4H- pyrazolo[1,5-d][1,4]diazepin-7(8H)-one	KI	0.014 nM	US-12378249: Isoquinoline compounds and uses thereof
(S)-2-(2-((7-fluoro-6-(8-methyl-2,3-dihydro-	KI	0.014 nM	US-12378249: Isoquinoline compounds and uses thereof
(S)-2-(2-((6-(5-amino-4-methylpyridin-3-yl)-7-	KI	0.014 nM	US-12378249: Isoquinoline compounds and uses thereof
N-(6-(5-amino-4-methylpyridin-3-yl)-7,8- difluoroisoquinolin-3-yl)-5,6-dihydro-11H- imidazo[1,2-a]pyrazolo[1,5-d][1,4]diazepin-8- amine	KI	0.014 nM	US-12378249: Isoquinoline compounds and uses thereof
N-(7,8-difluoro-6-(8-methyl-2,3-dihydro-1H- pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3- yl)-5,6-dihydro-11H-imidazo[1,2- a]pyrazolo[1,5-d][1,4]diazepin-8-amine	KI	0.014 nM	US-12378249: Isoquinoline compounds and uses thereof
2-((7-fluoro-6-(4,7,7-trimethyl-8-oxo-5,6,7,8- tetrahydro-1,5-naphthyridin-3-yl)isoquinolin-3- yl)amino)-6-methyl-5,6-dihydro-4H- pyrazolo[1,5-d][1,4]diazepin-7(8H)-one	KI	0.014 nM	US-12378249: Isoquinoline compounds and uses thereof
2-((6-(5-amino-4-methylpyridin-3-yl)-7- fluoroisoquinolin-3-yl)amino)-6-(2- hydroxyethyl)-5,6-dihydro-4H-pyrazolo[1,5- d][1,4]diazepin-7(8H)-one	KI	0.015 nM	US-12378249: Isoquinoline compounds and uses thereof
5,6,7,8-tetrahydro-1,5-naphthyridin-3-	KI	0.016 nM	US-12378249: Isoquinoline compounds and uses thereof
2-((6-(5-amino-4-methylpyridin-3-yl)-7- fluoroisoquinolin-3-yl)amino)-6-(2- methoxyethyl)-5,6-dihydro-4H-pyrazolo[1,5- d][1,4]diazepin-7(8H)-one	KI	0.017 nM	US-12378249: Isoquinoline compounds and uses thereof
pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-	KI	0.018 nM	US-12378249: Isoquinoline compounds and uses thereof
2-((6-(3,8-dimethyl-2,3-dihydro-1H- pyrido[2,3-b][1,4]oxazin-7-yl)-7- fluoroisoquinolin-3-yl)amino)-5,6-dihydro-4H- pyrazolo[1,5-d][1,4]diazepin-7(8H)-one	KI	0.018 nM	US-12378249: Isoquinoline compounds and uses thereof
2-((7-fluoro-6-(4-methyl-5,6,7,8-tetrahydro- 1,5-naphthyridin-3-yl)isoquinolin-3-yl)amino)- 5,6-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin- 7(8H)-one	KI	0.018 nM	US-12378249: Isoquinoline compounds and uses thereof
fluoroisoquinolin-3-yl)amino)-6-(1-	KI	0.019 nM	US-12378249: Isoquinoline compounds and uses thereof
2-[[7-fluoro-6-(8-methyl-2,3-dihydro-1H- pyrido[2,3-b][1,4]oxazin-7-yl)-3- isoquinolyl]amino]-6-(2-morpholinoethyl)-5,8- dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7-one	KI	0.02 nM	US-12378249: Isoquinoline compounds and uses thereof
2-((6-(8,8-difluoro-4-methyl-5,6,7,8- tetrahydro-1,5-naphthyridin-3-yl)-7- fluoroisoquinolin-3-yl)amino)-6-methyl-5,6- dihydro-4H-pyrazolo[1,5-d][1,4]diazepin- 7(8H)-one	KI	0.02 nM	US-12378249: Isoquinoline compounds and uses thereof
alpyrazolo[1,5-d][1,4]diazepin-8-yl)amino)-7-	KI	0.02 nM	US-12378249: Isoquinoline compounds and uses thereof
12-[[7-(1-methylpyrrolo[2,3-b]pyridin-4-yl)-3-oxo-1,2-dihydroisoindol-4-yl]amino]-4-oxa-8,11-diazatricyclo[8.4.0.02,6]tetradeca-1(10),11,13-trien-7-one	IC50	0.02 nM	US-20250282798: HETEROARYL-SUBSTITUTED BICYCLIC COMPOUND AND USE THEREOF
2-((6-(5-amino-4-methylpyridin-3-yl)-7- fluoroisoquinolin-3-yl)amino)-6-(2-hydroxy-2- methylpropyl)-5,6-dihydro-4H-pyrazolo[1,5- d][1,4]diazepin-7(8H)-one	KI	0.023 nM	US-12378249: Isoquinoline compounds and uses thereof
2-((5-fluoro-6-(8-methyl-2,3-dihydro-1H- pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3- yl)amino)-6-methyl-5,6-dihydro-4H- pyrazolo[1,5-d][1,4]diazepin-7(8H)-one	KI	0.026 nM	US-12378249: Isoquinoline compounds and uses thereof
2-((7-fluoro-6-(4-methyl-5- (methylamino)pyridin-3-yl)isoquinolin-3- yl)amino)-5,6-dihydro-4H-pyrazolo[1,5- d][1,4]diazepin-7(8H)-one	KI	0.026 nM	US-12378249: Isoquinoline compounds and uses thereof
2-((6-(5-amino-4-methylpyridin-3-yl)-7- fluoroisoquinolin-3-yl)amino)-6-(2- morpholinoethyl)-5,6-dihydro-4H- pyrazolo[1,5-d][1,4]diazepin-7(8H)-one	KI	0.028 nM	US-12378249: Isoquinoline compounds and uses thereof
2-((6-(5-amino-4-methylpyridin-3-yl)-5- chloroisoquinolin-3-yl)amino)-6-isopropyl-5,6- dihydro-4H-pyrazolo[1,5-d][1,4]diazepin- 7(8H)-one	KI	0.028 nM	US-12378249: Isoquinoline compounds and uses thereof
N-(6-(5-amino-4-methylpyridin-3-yl)-8- fluoroisoquinolin-3-yl)-5,6-dihydro-11H- imidazo[1,2-a]pyrazolo[1,5-d][1,4]diazepin-8- amine	KI	0.028 nM	US-12378249: Isoquinoline compounds and uses thereof
N-(6-(5-amino-4-methylpyridin-3-yl)-7- fluoroisoquinolin-3-yl)-5,6-dihydro-11H- imidazo[1,2-a]pyrazolo[1,5-d][1,4]diazepin-8- amine	KI	0.03 nM	US-12378249: Isoquinoline compounds and uses thereof
fluoroisoquinolin-3-yl)amino)-7-oxo-4,5,7,8-	KI	0.032 nM	US-12378249: Isoquinoline compounds and uses thereof
(R)-2-((7-fluoro-6-(8-methyl-2,3-dihydro-1H-	KI	0.033 nM	US-12378249: Isoquinoline compounds and uses thereof
2-((5-fluoro-6-(8-methyl-2,3-dihydro-1H- pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3- yl)amino)-6-(2-hydroxyethyl)-5,6-dihydro-4H- pyrazolo[1,5-d][1,4]diazepin-7(8H)-one	KI	0.034 nM	US-12378249: Isoquinoline compounds and uses thereof
8-((6-(5-amino-4-methylpyridin-3-yl)-7,8- difluoroisoquinolin-3-yl)amino)-5,6-dihydro- 11H-imidazo[1,2-a]pyrazolo[1,5- d][1,4]diazepin-6-ol	KI	0.035 nM	US-12378249: Isoquinoline compounds and uses thereof

ChEMBL bioactivities

4033 potent at pChembl≥5 of 4079 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
11.00	IC50	0.01	nM	CHEMBL4859451
11.00	IC50	0.01	nM	CHEMBL5739649
10.89	Ki	0.013	nM	CHEMBL5203557
10.89	Ki	0.013	nM	CHEMBL5876217
10.89	Ki	0.013	nM	CHEMBL6051016
10.89	Ki	0.013	nM	CHEMBL5767547
10.89	Ki	0.013	nM	CHEMBL5945736
10.89	Ki	0.013	nM	CHEMBL5930429
10.89	Ki	0.013	nM	CHEMBL6055934
10.89	Ki	0.013	nM	CHEMBL5826866
10.89	Ki	0.013	nM	CHEMBL6007786
10.89	Ki	0.013	nM	CHEMBL5926866
10.89	Ki	0.013	nM	CHEMBL5972125
10.89	Ki	0.013	nM	CHEMBL5950739
10.89	Ki	0.013	nM	CHEMBL5847266
10.89	Ki	0.013	nM	CHEMBL6007576
10.89	Ki	0.013	nM	CHEMBL6003532
10.85	Ki	0.014	nM	CHEMBL6025519
10.85	Ki	0.014	nM	CHEMBL6054020
10.85	Ki	0.014	nM	CHEMBL5870448
10.85	Ki	0.014	nM	CHEMBL6017903
10.85	Ki	0.014	nM	CHEMBL5768364
10.85	Ki	0.014	nM	CHEMBL5878545
10.85	Ki	0.014	nM	CHEMBL5768173
10.85	Ki	0.014	nM	CHEMBL5823802
10.85	Ki	0.014	nM	CHEMBL6064596
10.82	Ki	0.015	nM	CHEMBL6010272
10.82	Ki	0.015	nM	CHEMBL5911872
10.82	Ki	0.015	nM	CHEMBL5968822
10.82	Ki	0.015	nM	CHEMBL5884183
10.82	Ki	0.015	nM	CHEMBL5784442
10.82	Ki	0.015	nM	CHEMBL5784550
10.82	Ki	0.015	nM	CHEMBL5978013
10.82	Ki	0.015	nM	CHEMBL5851737
10.82	Ki	0.015	nM	CHEMBL5902455
10.82	Ki	0.015	nM	CHEMBL5744503
10.82	Ki	0.015	nM	CHEMBL5929303
10.82	Ki	0.015	nM	CHEMBL5971796
10.80	Ki	0.016	nM	CHEMBL5787502
10.80	Ki	0.016	nM	CHEMBL5991019
10.80	Ki	0.016	nM	CHEMBL5848911
10.80	Ki	0.016	nM	CHEMBL5917182
10.80	Ki	0.016	nM	CHEMBL5872109
10.80	Ki	0.016	nM	CHEMBL6030505
10.80	Ki	0.016	nM	CHEMBL5769111
10.80	Ki	0.016	nM	CHEMBL5975801
10.77	Ki	0.017	nM	CHEMBL5921660
10.77	Ki	0.017	nM	CHEMBL5947889
10.77	Ki	0.017	nM	CHEMBL5866824
10.77	Ki	0.017	nM	CHEMBL5767936

PubChem BioAssay actives

814 with measured affinity, of 1512 total; 50 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
2-[[8-amino-6-(5-amino-4-methyl-3-pyridinyl)-7-fluoroisoquinolin-3-yl]amino]-6-propan-2-yl-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7-one	1884756: Inhibition of full-length HPK1 (unknown origin) assessed as inhibition constant in presence of ATP by HTRF assay	ki	<0.0001	uM
4-(aminomethyl)-6-[(2R)-2-methylpyrrolidin-1-yl]-2-[6-(4-propan-2-yl-1,2,4-triazol-3-yl)-2-pyridinyl]-3H-pyrrolo[3,4-c]pyridin-1-one	1884775: Inhibition of HPK1 (unknown origin) assessed as inhibition constant in presence of ATP	ki	<0.0001	uM
N-[8-amino-6-(4-methyl-3-pyridinyl)-2,7-naphthyridin-3-yl]-2-(3-cyanocyclobutylidene)acetamide	1884764: Inhibition of HPK1 (unknown origin) by ADP-Glo kinase assay	ic50	<0.0001	uM
4-[2-[(1R)-1-methoxyethyl]anilino]-2-[(6-methoxy-2-methyl-3,4-dihydro-1H-isoquinolin-7-yl)amino]pyrimidine-5-carboxamide	2010033: Inhibition of human HPK1 catalytic domain (1 to 346 residues) using His-tagged SLP76 as substrate assessed as reduction in substrate phosphorylation preincubated for 30 mins followed by substrate and ATP addition and measured after 60 mins by TR-FRET assay	ic50	<0.0001	uM
4-[2-[(1S)-1-methoxyethyl]anilino]-2-[(6-methoxy-2-methyl-3,4-dihydro-1H-isoquinolin-7-yl)amino]pyrimidine-5-carboxamide	1759753: Inhibition of HPK1 (unknown origin) using SLP76 as substrate incubated for 1 hr by TR-FRET assay	ic50	<0.0001	uM
4-(2-ethoxyanilino)-2-[(6-methoxy-2-methyl-3,4-dihydro-1H-isoquinolin-7-yl)amino]pyrimidine-5-carboxamide	2010033: Inhibition of human HPK1 catalytic domain (1 to 346 residues) using His-tagged SLP76 as substrate assessed as reduction in substrate phosphorylation preincubated for 30 mins followed by substrate and ATP addition and measured after 60 mins by TR-FRET assay	ic50	<0.0001	uM
4-[2-(1,1-difluoroethyl)anilino]-2-[(6-methoxy-2-methyl-3,4-dihydro-1H-isoquinolin-7-yl)amino]pyrimidine-5-carboxamide	1759753: Inhibition of HPK1 (unknown origin) using SLP76 as substrate incubated for 1 hr by TR-FRET assay	ic50	<0.0001	uM
4-(2-methoxyanilino)-2-[(6-methoxy-2-methyl-3,4-dihydro-1H-isoquinolin-7-yl)amino]pyrimidine-5-carboxamide	1759753: Inhibition of HPK1 (unknown origin) using SLP76 as substrate incubated for 1 hr by TR-FRET assay	ic50	<0.0001	uM
4-(2,3-dihydro-1-benzofuran-7-ylamino)-2-[(6-methoxy-2-methyl-3,4-dihydro-1H-isoquinolin-7-yl)amino]pyrimidine-5-carboxamide	2010033: Inhibition of human HPK1 catalytic domain (1 to 346 residues) using His-tagged SLP76 as substrate assessed as reduction in substrate phosphorylation preincubated for 30 mins followed by substrate and ATP addition and measured after 60 mins by TR-FRET assay	ic50	<0.0001	uM
4-[2-(methoxymethyl)anilino]-2-[(6-methoxy-2-methyl-3,4-dihydro-1H-isoquinolin-7-yl)amino]pyrimidine-5-carboxamide	1759753: Inhibition of HPK1 (unknown origin) using SLP76 as substrate incubated for 1 hr by TR-FRET assay	ic50	<0.0001	uM
N-[2-[(2S,4S)-4-amino-2-(hydroxymethyl)pyrrolidin-1-yl]-4-(4-cyano-3-pyridinyl)phenyl]-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide	1922865: Inhibition of HPK1 in human Jurkat cells assessed as inhibition constant incubated for 1 hr by HTRF assay	ki	0.0001	uM
N-[8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl]cyclopropanecarboxamide	1969083: Inhibition of N-terminal DYKDDDDK tagged HPK1 CD (1 to 346 residues) (unknown origin) incubated for 1 hr in presence of ATP by TR-FRET assay	ic50	0.0001	uM
2-[[6-(5-amino-4-methyl-3-pyridinyl)-7-fluoroisoquinolin-3-yl]amino]-6-propan-2-yl-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7-one	1884756: Inhibition of full-length HPK1 (unknown origin) assessed as inhibition constant in presence of ATP by HTRF assay	ki	0.0001	uM
(3Z)-3-(1H-indol-2-ylmethylidene)-5-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)-1H-indol-2-one	1733679: Inhibition of recombinant human HPK1 expressed in baculovirus infected insect cells using SRKS1 peptide as substrate incubated for 15 mins followed by substrate addition and measured after 3 hrs by TR-FRET assay	ic50	0.0001	uM
(3Z)-5-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)-3-(1H-pyrrolo[3,2-c]pyridin-2-ylmethylidene)-1H-indol-2-one	1733679: Inhibition of recombinant human HPK1 expressed in baculovirus infected insect cells using SRKS1 peptide as substrate incubated for 15 mins followed by substrate addition and measured after 3 hrs by TR-FRET assay	ic50	0.0001	uM
(3Z)-5-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)-3-[(5-methyl-1H-pyrrol-2-yl)methylidene]-1H-indol-2-one	1733679: Inhibition of recombinant human HPK1 expressed in baculovirus infected insect cells using SRKS1 peptide as substrate incubated for 15 mins followed by substrate addition and measured after 3 hrs by TR-FRET assay	ic50	0.0001	uM
(3Z)-6-fluoro-5-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)-3-(1H-pyrrolo[3,2-b]pyridin-2-ylmethylidene)-1H-indol-2-one	1733679: Inhibition of recombinant human HPK1 expressed in baculovirus infected insect cells using SRKS1 peptide as substrate incubated for 15 mins followed by substrate addition and measured after 3 hrs by TR-FRET assay	ic50	0.0001	uM
5-[(Z)-[5-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)-2-oxo-1H-indol-3-ylidene]methyl]-1H-pyrrole-3-carbonitrile	1733679: Inhibition of recombinant human HPK1 expressed in baculovirus infected insect cells using SRKS1 peptide as substrate incubated for 15 mins followed by substrate addition and measured after 3 hrs by TR-FRET assay	ic50	0.0001	uM
N-[2-(diethylamino)ethyl]-5-[(Z)-[6-fluoro-5-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)-2-oxo-1H-indol-3-ylidene]methyl]-2,4-dimethyl-1H-pyrrole-3-carboxamide	1884772: Inhibition of HPK1 (unknown origin) in presence of ATP by ADP-Glo kinase assay	ic50	0.0001	uM
4-(2-bromoanilino)-2-[(6-methoxy-2-methyl-3,4-dihydro-1H-isoquinolin-7-yl)amino]pyrimidine-5-carboxamide	1759753: Inhibition of HPK1 (unknown origin) using SLP76 as substrate incubated for 1 hr by TR-FRET assay	ic50	0.0001	uM
4-[2-(hydroxymethyl)anilino]-2-[(6-methoxy-2-methyl-3,4-dihydro-1H-isoquinolin-7-yl)amino]pyrimidine-5-carboxamide	1759753: Inhibition of HPK1 (unknown origin) using SLP76 as substrate incubated for 1 hr by TR-FRET assay	ic50	0.0001	uM
(3Z)-3-[(5-cyclopropyl-1H-pyrrol-2-yl)methylidene]-7-fluoro-5-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)-1H-indol-2-one	1733679: Inhibition of recombinant human HPK1 expressed in baculovirus infected insect cells using SRKS1 peptide as substrate incubated for 15 mins followed by substrate addition and measured after 3 hrs by TR-FRET assay	ic50	0.0001	uM
4-[2-(1-methoxyethyl)anilino]-2-[(6-methoxy-2-methyl-3,4-dihydro-1H-isoquinolin-7-yl)amino]pyrimidine-5-carboxamide	1759753: Inhibition of HPK1 (unknown origin) using SLP76 as substrate incubated for 1 hr by TR-FRET assay	ic50	0.0001	uM
2-[(6-methoxy-2-methyl-3,4-dihydro-1H-isoquinolin-7-yl)amino]-4-[2-(trifluoromethyl)anilino]pyrimidine-5-carboxamide	1759753: Inhibition of HPK1 (unknown origin) using SLP76 as substrate incubated for 1 hr by TR-FRET assay	ic50	0.0001	uM
2-[(6-methoxy-2-methyl-3,4-dihydro-1H-isoquinolin-7-yl)amino]-4-(2-sulfamoylanilino)pyrimidine-5-carboxamide	1759753: Inhibition of HPK1 (unknown origin) using SLP76 as substrate incubated for 1 hr by TR-FRET assay	ic50	0.0001	uM
4-(2-chloroanilino)-2-[(6-methoxy-2-methyl-3,4-dihydro-1H-isoquinolin-7-yl)amino]pyrimidine-5-carboxamide	1759753: Inhibition of HPK1 (unknown origin) using SLP76 as substrate incubated for 1 hr by TR-FRET assay	ic50	0.0001	uM
(3S)-6-[[5-[(1R)-1-amino-1-cyclopropylethyl]-8-cyclopropyloxy-2,7-naphthyridin-3-yl]amino]-3-methylspiro[2,3-dihydronaphthalene-4,1’-cyclopropane]-1-one	1884761: Inhibition of HPK1 (unknown origin) in presence of ATP	ic50	0.0001	uM
5-amino-2-[(6-methoxy-2-methyl-3,4-dihydro-1H-isoquinolin-7-yl)amino]-8-[[2-(trifluoromethyl)phenyl]methyl]pyrido[2,3-d]pyrimidin-7-one	2062029: Inhibition of HPK1 (unknown origin) by ADP-Glo assay	ic50	0.0001	uM
7-(2-fluoro-4-methoxy-3-pyridinyl)-N-[4-(1-methylpiperidin-4-yl)phenyl]quinazolin-2-amine	1975896: Inhibition of human HPK1 in human Jurkat cells assessed as reduction in SLP76 phosphorylation at Ser376 residue preincubated for 60 mins followed by alphaCD3/alphaCD28 DynabeadsTM stimulation for 15 mins by AlphaLISA assay	ic50	0.0001	uM
3-[4-[(3R,5S)-3-amino-5-methylpiperidin-1-yl]-6-chloro-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-2-fluorobenzonitrile	2029397: Inhibition of full length human recombinant HPK1 expressed in baculovirus-infected insect cells using 5-FAM-KRRALSSLRA-COOH peptide as substrate preincubated with enzyme and ATP for 20 mins followed by substrate addition and measured after 1 hrs by microfluidic mobility shift assay	ki	0.0001	uM
7-(5-cyclopropyl-1-methylpyrazol-4-yl)-N-[4-(1-methylpiperidin-4-yl)phenyl]quinazolin-2-amine	1975895: Inhibition of full-length human GST-tagged HPK1 expressed in baculovirus infected Sf21 insect cells using MBP and ATP as substrate preincubated for 15 mins followed by substrate addition and measured after 120 mins by ADP-Glo reagent based assay	ic50	0.0001	uM
4-[(1R)-1,2-diaminoethyl]-2-[6-[(5S)-5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl]-2-pyridinyl]-6-[(2R)-2-methylpyrrolidin-1-yl]-3H-pyrrolo[3,4-c]pyridin-1-one	2023088: Inhibition of HPK1 (unknown origin)	ki	0.0001	uM
4-[(1R)-1-aminopropyl]-2-[6-[(5S)-5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl]-2-pyridinyl]-6-[(2R)-2-methylpyrrolidin-1-yl]-3H-isoindol-1-one	2062048: Inhibition of HPK1 (unknown origin)	ki	0.0001	uM
N-[8-amino-7-cyano-6-(4-methyl-3-pyridinyl)isoquinolin-3-yl]cyclopropanecarboxamide	1884768: Inhibition of HPK1 (1 to 346 residues) (unknown origin) assessed as inhibition constant by Lanthascreen binding assay	ki	0.0002	uM
5-[[4-[[(1S)-2-hydroxy-1-phenylethyl]amino]-5-[3-(1-methylpiperidin-4-yl)-1,2,4-oxadiazol-5-yl]pyrimidin-2-yl]amino]-3,3-dimethyl-2-benzofuran-1-one	1694480: Inhibition of recombinant human N-terminal GST-tagged HPK1 (1 to 346 residues) expressed in baculovirus infected Sf9 cells using NH2-fluorescein-RFARKGSLRQKNV-COOH as substrate incubated for 3 hrs in presence of ATP by by capillary electrophoresis method	ic50	0.0002	uM
7-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)-N-[4-(methylsulfonylmethyl)phenyl]quinazolin-2-amine	1975895: Inhibition of full-length human GST-tagged HPK1 expressed in baculovirus infected Sf21 insect cells using MBP and ATP as substrate preincubated for 15 mins followed by substrate addition and measured after 120 mins by ADP-Glo reagent based assay	ic50	0.0002	uM
4-(2,6-difluoroanilino)-2-[(6-methoxy-2-methyl-3,4-dihydro-1H-isoquinolin-7-yl)amino]pyrimidine-5-carboxamide	1759753: Inhibition of HPK1 (unknown origin) using SLP76 as substrate incubated for 1 hr by TR-FRET assay	ic50	0.0002	uM
2-[(6-methoxy-2-methyl-3,4-dihydro-1H-isoquinolin-7-yl)amino]-4-[2-(oxolan-2-yl)anilino]pyrimidine-5-carboxamide	1759753: Inhibition of HPK1 (unknown origin) using SLP76 as substrate incubated for 1 hr by TR-FRET assay	ic50	0.0002	uM
2-[(6-methoxy-2-methyl-3,4-dihydro-1H-isoquinolin-7-yl)amino]-4-[2-(2-oxo-1,3-oxazolidin-3-yl)anilino]pyrimidine-5-carboxamide	1759753: Inhibition of HPK1 (unknown origin) using SLP76 as substrate incubated for 1 hr by TR-FRET assay	ic50	0.0002	uM
2-[(6-methoxy-2-methyl-3,4-dihydro-1H-isoquinolin-7-yl)amino]-4-(2-methylanilino)pyrimidine-5-carboxamide	1759753: Inhibition of HPK1 (unknown origin) using SLP76 as substrate incubated for 1 hr by TR-FRET assay	ic50	0.0002	uM
2-[6-[4-[(1S)-1-cyclopropylethyl]-1,2,4-triazol-3-yl]-2-pyridinyl]-6-methoxy-4-(methylaminomethyl)-3H-isoindol-1-one;hydrochloride	1808200: Inhibition of human full length recombinant HPK1 using 5FAM-AKRRRLSSLRACOOH as substrate preincubated for 20 mins and measured for 60 mins by microfluidic mobility shift assay	ki	0.0002	uM
2-(azetidin-1-yl)-N-[2-methyl-4-[[7-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)quinazolin-2-yl]amino]phenyl]acetamide	1975895: Inhibition of full-length human GST-tagged HPK1 expressed in baculovirus infected Sf21 insect cells using MBP and ATP as substrate preincubated for 15 mins followed by substrate addition and measured after 120 mins by ADP-Glo reagent based assay	ic50	0.0002	uM
N-[2-methyl-4-[[7-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)quinazolin-2-yl]amino]phenyl]acetamide	1975895: Inhibition of full-length human GST-tagged HPK1 expressed in baculovirus infected Sf21 insect cells using MBP and ATP as substrate preincubated for 15 mins followed by substrate addition and measured after 120 mins by ADP-Glo reagent based assay	ic50	0.0002	uM
(9S)-6-[1-[2-(dimethylamino)ethyl]pyrazol-4-yl]-9-(hydroxymethyl)-16-oxa-2,4,8,26-tetrazatetracyclo[19.3.1.13,7.010,15]hexacosa-1(25),3,5,7(26),10,12,14,21,23-nonaene-22-carbonitrile	1964747: Inhibition of HPK1 (unknown origin) using MBP protein as substrate in presence of ATP preincubated for 15 mins followed by substrate addition and measured after 90 mins by ADP-Glo assay	ic50	0.0002	uM
2-(dimethylamino)-N-[2-methyl-4-[[7-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)quinazolin-2-yl]amino]phenyl]acetamide	1975895: Inhibition of full-length human GST-tagged HPK1 expressed in baculovirus infected Sf21 insect cells using MBP and ATP as substrate preincubated for 15 mins followed by substrate addition and measured after 120 mins by ADP-Glo reagent based assay	ic50	0.0002	uM
5-chloro-4-N-(2-dimethylphosphorylphenyl)-2-N-(6-methoxy-2-methyl-3,4-dihydro-1H-isoquinolin-7-yl)pyrimidine-2,4-diamine	1884762: Inhibition of N-terminal DYKDDDDK-tagged human HPK1 (1 to 346 residues) expressed in baculovirus expression system using SLP76 as substrate incubated for 1 hr in presence of ATP by TR-FRET assay	ic50	0.0003	uM
2-[[8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl]amino]-6-propan-2-yl-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7-one	1975895: Inhibition of full-length human GST-tagged HPK1 expressed in baculovirus infected Sf21 insect cells using MBP and ATP as substrate preincubated for 15 mins followed by substrate addition and measured after 120 mins by ADP-Glo reagent based assay	ic50	0.0003	uM
5-[[5-[3-(1-azabicyclo[2.2.2]octan-4-yl)-1,2,4-oxadiazol-5-yl]-4-[[(1S)-2-hydroxy-1-phenylethyl]amino]pyrimidin-2-yl]amino]-3,3-dimethyl-2-benzofuran-1-one	1694480: Inhibition of recombinant human N-terminal GST-tagged HPK1 (1 to 346 residues) expressed in baculovirus infected Sf9 cells using NH2-fluorescein-RFARKGSLRQKNV-COOH as substrate incubated for 3 hrs in presence of ATP by by capillary electrophoresis method	ic50	0.0003	uM
4-[2-fluoro-6-(trifluoromethyl)anilino]-2-[(6-methoxy-2-methyl-3,4-dihydro-1H-isoquinolin-7-yl)amino]pyrimidine-5-carboxamide	1759753: Inhibition of HPK1 (unknown origin) using SLP76 as substrate incubated for 1 hr by TR-FRET assay	ic50	0.0003	uM
4-(2-tert-butylanilino)-2-[(6-methoxy-2-methyl-3,4-dihydro-1H-isoquinolin-7-yl)amino]pyrimidine-5-carboxamide	1759753: Inhibition of HPK1 (unknown origin) using SLP76 as substrate incubated for 1 hr by TR-FRET assay	ic50	0.0003	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	increases methylation, affects expression, increases expression	3
(+)-JQ1 compound	decreases expression	2
Benzo(a)pyrene	affects methylation, increases methylation	2
Cisplatin	affects expression, affects cotreatment, increases expression	2
Phenylmercuric Acetate	affects cotreatment, decreases expression	2
Aflatoxin B1	increases methylation	2
sotorasib	increases expression, affects cotreatment	1
methylmercuric chloride	decreases expression	1
perfluorooctanoic acid	decreases expression	1
aflatoxin B2	increases methylation	1
tamibarotene	increases expression	1
di-n-butylphosphoric acid	affects expression	1
Am 580	decreases expression	1
perfluorooctane sulfonic acid	decreases expression	1
CGP 52608	affects binding, increases reaction	1
perfluoro-n-nonanoic acid	decreases expression	1
2-palmitoylglycerol	increases expression	1
entinostat	increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
jinfukang	affects cotreatment, increases expression	1
trametinib	affects cotreatment, increases expression	1
NVP-BKM120	affects cotreatment, increases expression	1
Rosiglitazone	decreases expression	1
Decitabine	affects expression	1
Sunitinib	increases expression	1
Cacodylic Acid	decreases expression	1
Carbamazepine	affects expression	1
Estradiol	affects cotreatment, increases expression	1
Lead	decreases expression	1

ChEMBL screening assays

379 unique, capped per target: 379 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5140659	Binding	PROTAC activity at CRBN/HPK1 (unknown origin) assessed as degradation of HPK1 at 10 nM incubated for 12 hrs by cell based assay relative to control	Hematopoietic Progenitor Kinase 1 in Tumor Immunology: A Medicinal Chemistry Perspective. — J Med Chem

Cellosaurus cell lines

4 cell lines: 4 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_D1NN	Abcam K-562 MAP4K1 KO	Cancer cell line	Female
CVCL_D2K9	Abcam Raji MAP4K1 KO	Cancer cell line	Male
CVCL_E8IW	Jurkat-NFAT-Luc2-HPK1-KO-2B1	Cancer cell line	Male
CVCL_UQ90	Abcam Jurkat MAP4K1 KO	Cancer cell line	Male

Clinical trials (associated diseases)

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