PIKFYVE

Summary

PIKFYVE (phosphoinositide kinase, FYVE-type zinc finger containing, HGNC:23785) is a protein-coding gene on chromosome 2q34, encoding 1-phosphatidylinositol 3-phosphate 5-kinase (Q9Y2I7). Dual specificity kinase implicated in myriad essential cellular processes such as maintenance of endomembrane homeostasis, and endocytic-vacuolar pathway, lysosomal trafficking, nuclear transport, stress- or hormone-induced signaling and cell cycle progression.

Phosphorylated derivatives of phosphatidylinositol (PtdIns) regulate cytoskeletal functions, membrane trafficking, and receptor signaling by recruiting protein complexes to cell- and endosomal-membranes. Humans have multiple PtdIns proteins that differ by the degree and position of phosphorylation of the inositol ring. This gene encodes an enzyme (PIKfyve; also known as phosphatidylinositol-3-phosphate 5-kinase type III or PIPKIII) that phosphorylates the D-5 position in PtdIns and phosphatidylinositol-3-phosphate (PtdIns3P) to make PtdIns5P and PtdIns(3,5)biphosphate. The D-5 position also can be phosphorylated by type I PtdIns4P-5-kinases (PIP5Ks) that are encoded by distinct genes and preferentially phosphorylate D-4 phosphorylated PtdIns. In contrast, PIKfyve preferentially phosphorylates D-3 phosphorylated PtdIns. In addition to being a lipid kinase, PIKfyve also has protein kinase activity. PIKfyve regulates endomembrane homeostasis and plays a role in the biogenesis of endosome carrier vesicles from early endosomes. The protein plays a key role in cell entry of ebola virus and SARS-CoV-2 by endocytosis Mutations in this gene cause corneal fleck dystrophy (CFD); an autosomal dominant disorder characterized by numerous small white flecks present in all layers of the corneal stroma. Histologically, these flecks appear to be keratocytes distended with lipid and mucopolysaccharide filled intracytoplasmic vacuoles.

Source: NCBI Gene 200576 — RefSeq curated summary.

At a glance

• Gene–disease (curated): fleck corneal dystrophy (Definitive, GenCC)
• GWAS associations: 2
• Clinical variants (ClinVar): 511 total — 11 pathogenic, 13 likely-pathogenic
• Phenotypes (HPO): 3
• Druggable target: yes — 1 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_015040

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:23785
Approved symbol	PIKFYVE
Name	phosphoinositide kinase, FYVE-type zinc finger containing
Location	2q34
Locus type	gene with protein product
Status	Approved
Aliases	MGC40423, KIAA0981, PIP5K, p235, ZFYVE29, FAB1
Ensembl gene	ENSG00000115020
Ensembl biotype	protein_coding
OMIM	609414
Entrez	200576

Gene structure

Transcript identifiers

Ensembl transcripts: 21 — 18 protein_coding, 1 nonsense_mediated_decay, 1 protein_coding_CDS_not_defined, 1 retained_intron

ENST00000264380, ENST00000308862, ENST00000392202, ENST00000407449, ENST00000422495, ENST00000443896, ENST00000452564, ENST00000474721, ENST00000477200, ENST00000909798, ENST00000923110, ENST00000923111, ENST00000923112, ENST00000923113, ENST00000923114, ENST00000923115, ENST00000923116, ENST00000923117, ENST00000960156, ENST00000960157, ENST00000960158

RefSeq mRNA: 3 — MANE Select: NM_015040 NM_001178000, NM_015040, NM_152671

CCDS: CCDS2382, CCDS33368, CCDS54431

Canonical transcript exons

ENST00000264380 — 42 exons

Exon	Start	End
ENSE00002209204	208330523	208330694
ENSE00002214083	208328180	208328280
ENSE00002291645	208325270	208326429
ENSE00002311595	208329842	208329913
ENSE00002320241	208333315	208333493
ENSE00002433954	208346050	208346147
ENSE00002448086	208350771	208350947
ENSE00002458369	208351352	208351455
ENSE00002463870	208347859	208348023
ENSE00002464059	208354571	208354645
ENSE00002468316	208338508	208338568
ENSE00002468671	208342554	208342649
ENSE00002471891	208340011	208340131
ENSE00002477289	208339418	208339555
ENSE00002487432	208352654	208352782
ENSE00002491359	208336838	208336928
ENSE00002497151	208276712	208276830
ENSE00002500877	208355190	208358746
ENSE00002516508	208350024	208350083
ENSE00002517931	208273584	208273733
ENSE00002521668	208353898	208354159
ENSE00002528164	208277537	208277708
ENSE00002533454	208345111	208345194
ENSE00002703248	208271511	208271691
ENSE00003488165	208335306	208335419
ENSE00003489495	208288729	208288818
ENSE00003513715	208320252	208320359
ENSE00003523401	208324911	208325037
ENSE00003523491	208312236	208312295
ENSE00003563613	208285726	208285933
ENSE00003564646	208300937	208301094
ENSE00003592941	208314294	208314423
ENSE00003609006	208317867	208317941
ENSE00003613025	208315193	208315373
ENSE00003624546	208304171	208304318
ENSE00003633232	208324142	208324282
ENSE00003644097	208336046	208336200
ENSE00003654095	208298641	208298779
ENSE00003654475	208335793	208335901
ENSE00003683206	208304846	208305013
ENSE00003693133	208302242	208302353
ENSE00003846258	208266255	208266415

Expression profiles

Bgee: expression breadth ubiquitous, 292 present calls, max score 94.81.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 38.6779 / max 407.9332, expressed in 1819 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter ID	TPM avg	Samples expressed
24905	37.5520	1819
24904	0.6149	311
24906	0.3688	205
24903	0.1052	20
24915	0.0371	11

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
secondary oocyte	CL:0000655	94.81	gold quality
choroid plexus epithelium	UBERON:0003911	94.14	gold quality
seminal vesicle	UBERON:0000998	93.22	gold quality
oocyte	CL:0000023	92.64	gold quality
corpus epididymis	UBERON:0004359	92.22	gold quality
cartilage tissue	UBERON:0002418	92.13	gold quality
tibia	UBERON:0000979	91.37	gold quality
calcaneal tendon	UBERON:0003701	91.35	gold quality
cauda epididymis	UBERON:0004360	91.17	gold quality
jejunal mucosa	UBERON:0000399	90.58	gold quality
bone marrow	UBERON:0002371	90.52	gold quality
superficial temporal artery	UBERON:0001614	90.18	gold quality
Brodmann (1909) area 46	UBERON:0006483	90.09	gold quality
adrenal tissue	UBERON:0018303	90.00	gold quality
bone marrow cell	CL:0002092	89.83	gold quality
caput epididymis	UBERON:0004358	89.69	gold quality
palpebral conjunctiva	UBERON:0001812	89.61	gold quality
epithelium of nasopharynx	UBERON:0001951	89.30	gold quality
paraflocculus	UBERON:0005351	89.28	gold quality
eye	UBERON:0000970	89.18	gold quality
corpus callosum	UBERON:0002336	89.07	gold quality
visceral pleura	UBERON:0002401	89.02	gold quality
parietal pleura	UBERON:0002400	88.95	gold quality
tonsil	UBERON:0002372	88.63	gold quality
dorsal motor nucleus of vagus nerve	UBERON:0002870	88.57	gold quality
pleura	UBERON:0000977	88.48	gold quality
postcentral gyrus	UBERON:0002581	88.33	gold quality
pigmented layer of retina	UBERON:0001782	87.90	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	87.87	gold quality
trabecular bone tissue	UBERON:0002483	87.78	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-CURD-122	yes	21.94
E-ANND-3	yes	9.11

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

216 targeting PIKFYVE, 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-3163	100.00	77.23	8605
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-200B-3P	100.00	73.31	2693
HSA-MIR-200C-3P	100.00	73.35	2685
HSA-MIR-429	100.00	73.44	2698
HSA-LET-7A-3P	100.00	74.03	3932
HSA-LET-7B-3P	100.00	74.08	3913
HSA-LET-7F-1-3P	100.00	74.02	3928
HSA-MIR-98-3P	100.00	74.08	3907
HSA-MIR-4682	100.00	68.89	1258
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-1252-5P	100.00	69.80	2774
HSA-MIR-3064-3P	100.00	70.09	1254
HSA-MIR-4668-3P	100.00	68.74	2635
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-32-5P	99.98	75.21	1964
HSA-MIR-363-3P	99.98	74.72	1821
HSA-MIR-367-3P	99.98	74.83	1819
HSA-MIR-92A-3P	99.98	75.21	1960
HSA-MIR-92B-3P	99.98	75.25	1955
HSA-MIR-25-3P	99.98	74.60	1817
HSA-MIR-19A-3P	99.98	75.33	2762
HSA-MIR-19B-3P	99.98	75.44	2754
HSA-MIR-27A-3P	99.98	72.13	2955
HSA-MIR-27B-3P	99.98	72.13	2955

Literature-anchored findings (GeneRIF, showing 40)

• p40 interaction with PIKfyve p40 os demonstrated; PIKfyve interaction and the subsequent PIKfyve-catalyzed p40 phosphorylation anchor p40 to discrete membranes facilitating late endosome-to-TGN transport. (PMID:14530284)
• PIKfyve selectively regulates the sorting and traffic of peripheral endosomes containing lysosomaly directed fluid phase cargo through controlling the morphogenesis and function of multivesicular bodies (PMID:14551253)
• the PIKfyve-associated hVac14 protein has a major role in activating PIKfyve and thereby regulating PtdIns(3,5)P(2) synthesis and endomembrane homeostasis in mammalian cells (PMID:15542851)
• Linkage analysis localized CFD to a 24-cM (18-Mb) interval of chromosome 2q35 flanked by D2S2289 and D2S126 and containing PIP5K3. (PMID:15902656)
• PIKfyve is distributed in microdomains that are distinct from those occupied by EEA1 and Hrs (PMID:16448788)
• The first multicellular model for PIKFYVE loss, pointing to a role in lysosome maturation (PMID:16801682)
• PIKfyve regulates endosome-to-TGN retrograde transport. (PMID:16954148)
• results suggest that the local production of PtdIns(3)P implicates the fusion of macropinosomes via EEA1 as well as conventional early endosomes (PMID:17146146)
• The observations disclose that PIKfyve participates in the SGK1-dependent regulation of SLC5A1. (PMID:17570343)
• REVIEW : PIKFYVE and other phosphoinositides regulatory proteins are implicated in human genetic diseases (PMID:18429927)
• These data suggest for the first time a role of PtdIns5P and PIKfyve in oncogenesis, potentially linking intracellular trafficking to cancer. (PMID:18501703)
• A phylogenetic study revealing co-evolution of phosphoinositides kinases and phosphatases ; PIKFYVE is absent from several organisms and co-evolved with VAC14 and FIG4 (PMID:18774718)
• The authors data indicate that the PAS complex is organized to provide optimal PIKfyve functionality and is maintained via ArPIKfyve homomeric and heteromeric interactions. (PMID:18950639)
• Kinesin adapter JLP links PIKfyve to microtubule-based endosome-to-trans-Golgi network traffic of furin. (PMID:19056739)
• PIKfyve is a potent stimulator of ClC-2-activity and contributes to SGK1-dependent regulation of ClC-2. (PMID:19232516)
• Results suggest that PIKfyve inhibition may render the late endosome/lysosome compartment refractory to fusion with both autophagosomes and with EGFR-containing multivesicular bodies. (PMID:19582903)
• PIKfyve-ArPIKfyve-Sac3 core complex: contact sites and their consequence for Sac3 phosphatase activity and endocytic membrane homeostasis (PMID:19840946)
• PIKfyve-dependent channel degradation is essential to prevent Ca2+-induced toxicity in neurons. (PMID:19841139)
• these results demonstrate that PIKfyve regulates CFTR activity, and suggest a novel mechanism of CFTR regulation. (PMID:19852935)
• Coexpression of PIKfyve is followed by a marked increase of glutamate induced currents in EAAT2 expressing oocytes. (PMID:19910676)
• Data conclude that PIKfyve participates in the regulation of TRPV6. (PMID:20041238)
• The recent advances in Arf6/PIP5K signaling and its linkage to cellular functions, are reviewed. (PMID:20945365)
• A novel c.3060-3063 delCCTT (p.P968Vfs23) mutation in the PIKFYVE gene has been described in a five generation Greek family, which segregated with the fleck corneal dystrophy. (PMID:22065932)
• The results provide the first experimental evidence that the principal pathway for PtdIns5P intracellular production is through PIKfyve. (PMID:22621786)
• Production of phosphatidylinositol 5-phosphate via PIKfyve and MTMR3 regulates cell migration. (PMID:23154468)
• the present observations show that PKB in conjunction with PIKfyve activates Kir2.1 channels. (PMID:23188060)
• PIP5Kalpha promotes TLR4-associated microglial inflammation by mediating PIP(2)-dependent recruitment of TIRAP to the plasma membrane (PMID:23297396)
• Data indicate that AKT promotes EGFR recycling by phosphorylating and activating PIKfyve. (PMID:23757022)
• Data indicate that pharmacological or genetic inactivation of PIKfyve rapidly induces expression of the transcription repressor ATF3, which is necessary and sufficient for suppression of type I IFN expression. (PMID:24600036)
• Data suggest PIKFYVE, MTMR3 (myotubularin related protein 3) and their product phosphatidylinositol 5-phosphate are involved in activation of RAC1 (rho family small GTP binding protein); this process regulates migration/invasion of carcinoma/sarcoma. (PMID:24840251)
• APP functionally cooperates with PIKfyve in vivo. This regulation is required for maintaining endosomal and neuronal function. (PMID:26125944)
• The PIKfyve complex is required for APP trafficking, suggesting a feedback loop in which APP, by binding to and stimulating phosphatidylinositol-3,5-bisphosphate vesicle formation may control its own trafficking. (PMID:26216398)
• A novel heterozygous frameshift mutation (c.3151dupA) and a copy number variations in PIKFYVE gene have been found in two unrelated Fleck corneal dystrophy patients. (PMID:26396486)
• data identify a novel role of the ArPIKfyve-Sac3 complex in the mechanisms controlling aggregate formation of Sph1 and suggest that Sac3 protein deficiency or overproduction may facilitate aggregation of aggregation-prone proteins (PMID:26405034)
• A cell-permeable tool for analysing APP intracellular domain function and manipulation of PIKfyve activity. (PMID:26934981)
• in PC-3 cells inhibition of PIKfyve by apilimod or depletion by siRNA increased the secretion of the exosomal fraction. (PMID:27438886)
• Here we identify the lipid kinase PIKfyve as a regulator of an alternative pathway that distributes engulfed contents in support of intracellular macromolecular synthesis during macropinocytosis, entosis, and phagocytosis. We find that PIKfyve regulates vacuole size in part through its downstream effector, the cationic transporter TRPML1 (PMID:27623384)
• this study shows that PIKfyve coordinates the neutrophil immune response through the activation of the Rac GTPase (PMID:28779020)
• PIKfyve inhibition leads to impaired degradative capacity, ion dysregulation, abated autophagic flux and a massive enlargement of lysosomes. (PMID:29661845)
• Transcriptional Regulation of PIK3CD and PIKFYVE in T-Cell Acute Lymphoblastic Leukemia by IKAROS and Protein Kinase CK2. (PMID:33467550)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	pikfyve	ENSDARG00000056112
mus_musculus	Pikfyve	ENSMUSG00000025949
rattus_norvegicus	Pikfyve	ENSRNOG00000015158
drosophila_melanogaster	fab1	FBGN0028741
caenorhabditis_elegans		WBGENE00004089

Paralogs (13): CCT4 (ENSG00000115484), TCP1 (ENSG00000120438), MKKS (ENSG00000125863), CCT6B (ENSG00000132141), CCT7 (ENSG00000135624), HSPD1 (ENSG00000144381), CCT6A (ENSG00000146731), CCT5 (ENSG00000150753), CCT8 (ENSG00000156261), CCT3 (ENSG00000163468), CCT2 (ENSG00000166226), BBS12 (ENSG00000181004), CCT8L2 (ENSG00000198445)

Protein

Protein identifiers

1-phosphatidylinositol 3-phosphate 5-kinase — Q9Y2I7 (reviewed: Q9Y2I7)

Alternative names: FYVE finger-containing phosphoinositide kinase, PIKfyve, Phosphatidylinositol 3-phosphate 5-kinase type III, Serine-protein kinase PIKFYVE

All UniProt accessions (4): C9JL08, E9PDH4, Q9Y2I7, F8WEZ0

UniProt curated annotations — full annotation on UniProt →

Function. Dual specificity kinase implicated in myriad essential cellular processes such as maintenance of endomembrane homeostasis, and endocytic-vacuolar pathway, lysosomal trafficking, nuclear transport, stress- or hormone-induced signaling and cell cycle progression. The PI(3,5)P2 regulatory complex regulates both the synthesis and turnover of phosphatidylinositol 3,5-bisphosphate (PtdIns(3,5)P2). Sole enzyme to catalyze the phosphorylation of phosphatidylinositol 3-phosphate on the fifth hydroxyl of the myo-inositol ring, to form (PtdIns(3,5)P2). Also catalyzes the phosphorylation of phosphatidylinositol on the fifth hydroxyl of the myo-inositol ring, to form phosphatidylinositol 5-phosphate (PtdIns(5)P). Has serine-protein kinase activity and is able to autophosphorylate and transphosphorylate. Autophosphorylation inhibits its own phosphatidylinositol 3-phosphate 5-kinase activity, stimulates FIG4 lipid phosphatase activity and down-regulates lipid product formation. Involved in key endosome operations such as fission and fusion in the course of endosomal cargo transport. Required for the maturation of early into late endosomes, phagosomes and lysosomes. Regulates vacuole maturation and nutrient recovery following engulfment of macromolecules, initiates the redistribution of accumulated lysosomal contents back into the endosome network. Critical regulator of the morphology, degradative activity, and protein turnover of the endolysosomal system in macrophages and platelets. In neutrophils, critical to perform chemotaxis, generate ROS, and undertake phagosome fusion with lysosomes. Plays a key role in the processing and presentation of antigens by major histocompatibility complex class II (MHC class II) mediated by CTSS. Regulates melanosome biogenesis by controlling the delivery of proteins from the endosomal compartment to the melanosome. Essential for systemic glucose homeostasis, mediates insulin-induced signals for endosome/actin remodeling in the course of GLUT4 translocation/glucose uptake activation. Supports microtubule-based endosome-to-trans-Golgi network cargo transport, through association with SPAG9 and RABEPK. Mediates EGFR trafficking to the nucleus. (Microbial infection) Required for cell entry of coronaviruses SARS-CoV and SARS-CoV-2, as well as human coronavirus EMC (HCoV-EMC) by endocytosis.

Subunit / interactions. Component of the PI(3,5)P2 regulatory complex/PAS complex, at least composed of PIKFYVE, FIG4 and VAC14. VAC14 nucleates the assembly of the complex and serves as a scaffold by pentamerizing into a star-shaped structure, which can bind a single copy each of PIKFYVE and FIG4 and coordinates their activities. Interacts (via chaperonin-like domain) with RABEPK; the interaction recruits RABEPK to the endosomal membrane. Interacts with SPAG9. Interacts with EGFR.

Subcellular location. Endosome membrane. Early endosome membrane. Cytoplasmic vesicle. Phagosome membrane. Late endosome membrane.

Post-translational modifications. Autophosphorylates which inhibits its own phosphatidylinositol 3-phosphate 5-kinase activity, stimulates FIG4 lipid phosphatase activity and down-regulates lipid product formation. Dephosphorylated by FIG4 in the PI(3,5)P2 regulatory complex, at Ser-48, Ser-1669 and Ser-2053. Phosphorylated in response to insulin at Ser-318 in a protein kinase B (PKB)-dependent manner.

Disease relevance. Corneal dystrophy, fleck (CFD) [MIM:121850] A form of stromal corneal dystrophy characterized by numerous small white flecks scattered in all levels of the stroma, with configurations varying from semicircular to wreath-like, curvilinear, or punctate. Although CFD may occasionally cause mild photophobia, patients are typically asymptomatic and have normal vision. The disease is caused by variants affecting the gene represented in this entry.

Activity regulation. Inhibited by apilimod and YM201636.

Domain organisation. Interaction of FYVE-type domain with phosphatidylinositol 3-phosphate (PtdIns(3)P) is necessary for targeting to the membranes of the late endocytic pathway.

Isoforms (4)

UniProt ID	Names	Canonical?
Q9Y2I7-1	1	yes
Q9Y2I7-2	2
Q9Y2I7-3	3
Q9Y2I7-4	4

RefSeq proteins (3): NP_001171471, NP_055855, NP_689884 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000306	Znf_FYVE	Domain
IPR000591	DEP_dom	Domain
IPR002423	Cpn60/GroEL/TCP-1	Family
IPR002498	PInositol-4-P-4/5-kinase_core	Domain
IPR011011	Znf_FYVE_PHD	Homologous_superfamily
IPR013083	Znf_RING/FYVE/PHD	Homologous_superfamily
IPR017455	Znf_FYVE-rel	Domain
IPR027409	GroEL-like_apical_dom_sf	Homologous_superfamily
IPR027410	TCP-1-like_intermed_sf	Homologous_superfamily
IPR027483	PInositol-4-P-4/5-kinase_C_sf	Homologous_superfamily
IPR027484	PInositol-4-P-5-kinase_N	Homologous_superfamily
IPR036388	WH-like_DNA-bd_sf	Homologous_superfamily
IPR036390	WH_DNA-bd_sf	Homologous_superfamily
IPR037378	PIKfyve_DEP	Domain
IPR043548	PIKfyve	Family
IPR044769	PIKfyve_PIPKc	Domain

Pfam: PF00118, PF00610, PF01363, PF01504

Enzyme classification (BRENDA):

• EC 2.7.1.150 — 1-phosphatidylinositol-3-phosphate 5-kinase (BRENDA: 13 organisms, 22 substrates, 6 inhibitors, 0 Km, 0 kcat entries)
• EC 2.7.1.68 — 1-phosphatidylinositol-4-phosphate 5-kinase (BRENDA: 15 organisms, 50 substrates, 41 inhibitors, 41 Km, 0 kcat entries)

Substrate kinetics (BRENDA)

8 substrates with measured Km, best-characterized 8. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
1-PHOSPHATIDYL-1D-MYO-INOSITOL 4-PHOSPHATE	0.0012–4.1	14
ATP	0.002–0.2	13
1-STEAROYL-2-ARACHIDONOYL PHOSPHATIDYL-1D-MYO-IN	4.9–16	3
1-STEAROYL-2-OLEOYL PHOSPHATIDYL-1D-MYO-INOSITOL	1.6–3.7	3
1-PHOSPHATIDYL-1D-MYO-INOSITOL 3-PHOSPHATE	0.005–0.065	2
PHOSPHATIDYLINOSITOL 3,4-BISPHOSPHATE	0.006–0.08	2
GTP	0.133	1
PHOSPHATIDYLINOSITOL 3-PHOSPHATE	0.12	1

Catalyzed reactions (Rhea), 3 shown:

• a 1,2-diacyl-sn-glycero-3-phospho-(1D-myo-inositol-3-phosphate) + ATP = a 1,2-diacyl-sn-glycero-3-phospho-(1D-myo-inositol-3,5-bisphosphate) + ADP + H(+) (RHEA:13609)
• L-seryl-[protein] + ATP = O-phospho-L-seryl-[protein] + ADP + H(+) (RHEA:17989)
• a 1,2-diacyl-sn-glycero-3-phospho-(1D-myo-inositol) + ATP = a 1,2-diacyl-sn-glycero-3-phospho-(1D-myo-inositol-5-phosphate) + ADP + H(+) (RHEA:44680)

UniProt features (68 total): modified residue 17, region of interest 10, sequence variant 10, compositionally biased region 9, binding site 8, splice variant 4, mutagenesis site 3, domain 2, sequence conflict 2, initiator methionine 1, chain 1, zinc finger region 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
7K2V	ELECTRON MICROSCOPY	6.6

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9Y2I7-F1	64.17	0.30

Functional residue map

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

Ligand- & substrate-binding residues (8): 164; 167; 180; 183; 188; 191; 210; 213

Post-translational modifications (17): 2, 23, 48, 88, 299, 307, 312, 318, 329, 475, 1522, 1544, 1549, 1669, 1754, 1969, 2053

Mutagenesis-validated functional residues (3):

Position	Phenotype
1877	loss of autophosphorylation. loss of phosphatidylinositol 3-phosphate 5-kinase activity.
2053	no effect on phosphatidylinositol 3-phosphate 5-kinase activity.
2053	reduces 2-folds phosphatidylinositol 3-phosphate 5-kinase activity.

Function

Pathways and Gene Ontology

Reactome pathways

3 pathways

ID	Pathway
R-HSA-1660514	Synthesis of PIPs at the Golgi membrane
R-HSA-1660516	Synthesis of PIPs at the early endosome membrane
R-HSA-1660517	Synthesis of PIPs at the late endosome membrane

MSigDB gene sets: 348 (showing top): GSE18804_SPLEEN_MACROPHAGE_VS_TUMORAL_MACROPHAGE_UP, GOBP_ANTIGEN_PROCESSING_AND_PRESENTATION_OF_PEPTIDE_OR_POLYSACCHARIDE_ANTIGEN_VIA_MHC_CLASS_II, GOBP_PHOSPHOLIPID_METABOLIC_PROCESS, GOBP_PHOSPHATIDYLINOSITOL_METABOLIC_PROCESS, GOBP_MYELOID_LEUKOCYTE_MIGRATION, GOBP_CELL_CHEMOTAXIS, GOBP_VACUOLE_ORGANIZATION, GOCC_VACUOLAR_MEMBRANE, GOBP_VESICLE_ORGANIZATION, TTTGTAG_MIR520D, GOBP_PEPTIDYL_SERINE_MODIFICATION, GOBP_MEMBRANE_FUSION, GOBP_PROTEIN_TARGETING, TATTATA_MIR374, GOBP_CELLULAR_PIGMENTATION

GO Biological Process (20): protein targeting to membrane (GO:0006612), phosphatidylinositol biosynthetic process (GO:0006661), receptor-mediated endocytosis of virus by host cell (GO:0019065), antigen processing and presentation of exogenous peptide antigen via MHC class II (GO:0019886), neutrophil chemotaxis (GO:0030593), melanosome organization (GO:0032438), protein localization to nucleus (GO:0034504), intracellular signal transduction (GO:0035556), peptidyl-serine autophosphorylation (GO:0036289), retrograde transport, endosome to Golgi (GO:0042147), phagosome maturation (GO:0090382), phagosome-lysosome fusion (GO:0090385), 1-phosphatidyl-1D-myo-inositol 3,5-bisphosphate metabolic process (GO:1903100), regulation of reactive oxygen species biosynthetic process (GO:1903426), phosphatidylinositol 5-phosphate metabolic process (GO:1904562), regulation of autophagosome assembly (GO:2000785), lipid metabolic process (GO:0006629), intracellular protein localization (GO:0008104), phosphatidylinositol-3-phosphate biosynthetic process (GO:0036092), phosphatidylinositol metabolic process (GO:0046488)

GO Molecular Function (14): 1-phosphatidylinositol-3-phosphate 5-kinase activity (GO:0000285), protein serine/threonine kinase activity (GO:0004674), ATP binding (GO:0005524), zinc ion binding (GO:0008270), 1-phosphatidylinositol-4-phosphate 5-kinase activity (GO:0016308), phosphatidylinositol-3,5-bisphosphate 5-phosphatase activity (GO:0043813), 1-phosphatidylinositol-5-kinase activity (GO:0052810), protein serine kinase activity (GO:0106310), nucleotide binding (GO:0000166), protein binding (GO:0005515), kinase activity (GO:0016301), transferase activity (GO:0016740), metal ion binding (GO:0046872), phosphatidylinositol kinase activity (GO:0052742)

GO Cellular Component (11): Golgi membrane (GO:0000139), cytosol (GO:0005829), endosome membrane (GO:0010008), vesicle membrane (GO:0012506), phagocytic vesicle membrane (GO:0030670), cytoplasmic vesicle (GO:0031410), early endosome membrane (GO:0031901), late endosome membrane (GO:0031902), membrane raft (GO:0045121), endosome (GO:0005768), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
PI Metabolism	3

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
phosphatidylinositol kinase activity	3
phagolysosome assembly	2
glycerophospholipid metabolic process	2
protein kinase activity	2
bounding membrane of organelle	2
cytoplasm	2
cellular anatomical structure	2
endosome membrane	2
protein targeting	1
establishment of protein localization to membrane	1
biosynthetic process	1
phosphatidylinositol metabolic process	1
receptor-mediated endocytosis	1
symbiont entry into host cell	1
endocytosis involved in viral entry into host cell	1
antigen processing and presentation of exogenous peptide antigen	1
antigen processing and presentation of peptide antigen via MHC class II	1
granulocyte chemotaxis	1
neutrophil migration	1
pigment granule organization	1
protein localization to organelle	1
intracellular anatomical structure	1
signal transduction	1
peptidyl-serine phosphorylation	1
protein autophosphorylation	1
intercellular transport	1
endosomal transport	1
cytosolic transport	1
exocytosis	1
organelle organization	1
vesicle fusion	1
regulation of biosynthetic process	1
reactive oxygen species biosynthetic process	1
regulation of reactive oxygen species metabolic process	1
autophagosome assembly	1
regulation of vacuole organization	1
regulation of organelle assembly	1
primary metabolic process	1
macromolecule localization	1
phosphatidylinositol phosphate biosynthetic process	1

Protein interactions and networks

STRING

2308 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PIKFYVE	FIG4	Q92562	999
PIKFYVE	VAC14	Q08AM6	999
PIKFYVE	ARF6	P26438	856
PIKFYVE	MAP1LC3A	Q9H492	746
PIKFYVE	PIK3C3	Q8NEB9	744
PIKFYVE	LAMP2	P13473	710
PIKFYVE	MCOLN1	Q9GZU1	677
PIKFYVE	HGS	O14964	671
PIKFYVE	WIPI1	Q5MNZ9	666
PIKFYVE	TPCN2	Q8NHX9	662
PIKFYVE	TGOLN2	O43493	652
PIKFYVE	SLC6A8	P48029	644
PIKFYVE	AKT1	P31749	639
PIKFYVE	CDC42	P21181	626
PIKFYVE	PI4KB	P78405	625

IntAct

29 interactions, top by confidence:

A	B	Type	Score
PIKFYVE	VAC14	psi-mi:“MI:0915”(physical association)	0.800
FIG4	VAC14	psi-mi:“MI:0914”(association)	0.800
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
PIKFYVE	FIG4	psi-mi:“MI:0915”(physical association)	0.560
NEURL4	APBB1	psi-mi:“MI:0914”(association)	0.530
WDR83	SH2B2	psi-mi:“MI:0914”(association)	0.530
Dlg4	PIKFYVE	psi-mi:“MI:0407”(direct interaction)	0.440
PIKFYVE	NPM1	psi-mi:“MI:0915”(physical association)	0.400
PIKFYVE	GTPBP3	psi-mi:“MI:0915”(physical association)	0.400
NBEAL2	HAX1	psi-mi:“MI:0914”(association)	0.350
NEURL4	CCDC85C	psi-mi:“MI:0914”(association)	0.350
NPTN	RTL8C	psi-mi:“MI:0914”(association)	0.350
VAC14	NUDT19	psi-mi:“MI:0914”(association)	0.350
FIG4	YEATS4	psi-mi:“MI:0914”(association)	0.350
ANK1	VAC14	psi-mi:“MI:0914”(association)	0.350
VAC14	MGST3	psi-mi:“MI:0914”(association)	0.350
WDR83	ISY1-RAB43	psi-mi:“MI:0914”(association)	0.350
SLC30A4	ESYT2	psi-mi:“MI:0914”(association)	0.350
SLC30A7	ESYT2	psi-mi:“MI:0914”(association)	0.350
SLC7A9	CDC7	psi-mi:“MI:0914”(association)	0.350
1C		psi-mi:“MI:0914”(association)	0.350
TGOLN2	BLTP3B	psi-mi:“MI:2364”(proximity)	0.270

BioGRID (79): PIKFYVE (Two-hybrid), PIKFYVE (Affinity Capture-MS), PIKFYVE (Affinity Capture-MS), PIKFYVE (Affinity Capture-MS), PIKFYVE (Synthetic Lethality), PIKFYVE (Co-crystal Structure), PIKFYVE (Affinity Capture-MS), PIKFYVE (Affinity Capture-MS), PIKFYVE (Affinity Capture-MS), PIKFYVE (Affinity Capture-MS), PIKFYVE (Affinity Capture-MS), PIKFYVE (Biochemical Activity), PIKFYVE (Affinity Capture-RNA), PIKFYVE (Affinity Capture-MS), PIKFYVE (Affinity Capture-MS)

ESM2 similar proteins: A0A1B0GVS7, A2CE83, A2VDU1, A5D992, A8KBE0, O43597, O43609, O43610, P28290, Q02223, Q08AD1, Q08E39, Q14CH0, Q1L0X2, Q2PFN5, Q2TBG9, Q3UUD2, Q4R815, Q5R959, Q5RGQ8, Q5TB30, Q66H35, Q6AYK4, Q6DD45, Q6GPM0, Q6NRB7, Q6P995, Q6PEM6, Q6ZUJ8, Q7ZX27, Q866R9, Q86VY9, Q8BGN6, Q8C3K5, Q8C817, Q8IYD9, Q8N957, Q96HH4, Q9BZD6, Q9C004

Diamond homologs: A0A0D1E015, A0JMD2, A1CEK1, A1DFP5, A2QWA2, A4QTV1, A8QCE4, A8XJZ8, B0G126, B0WAQ0, B3MT31, B3P851, B4G2G5, B4IC49, B4JHI7, B4K982, B4M140, B4NFJ7, B4PRU6, D2H5P6, D3ZVP7, D4A8G9, E1BLZ4, F1MM41, F7EP40, O13821, O14964, O59722, O76902, O95405, O96838, P0CS26, P0CS27, P34756, P40343, Q05B78, Q08CN9, Q0CJV3, Q0P4S0, Q0U4Z8

SIGNOR signaling

5 interactions.

A	Effect	B	Mechanism
AKT	up-regulates	PIKFYVE	phosphorylation
AKT1	up-regulates	PIKFYVE	phosphorylation
PIKFYVE	“form complex”	“PAS complex”	binding
SGK3	“up-regulates activity”	PIKFYVE	phosphorylation
AMPK	“up-regulates activity”	PIKFYVE	phosphorylation

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	11
Likely pathogenic	13
Uncertain significance	290
Likely benign	44
Benign	88

Top pathogenic / likely-pathogenic (24)

Variant ID	HGVS	Classification
1072717	NM_015040.4(PIKFYVE):c.4428dup (p.Val1477fs)	Pathogenic
1300207	NM_015040.4(PIKFYVE):c.2344C>T (p.Arg782Ter)	Pathogenic
1300208	NM_015040.4(PIKFYVE):c.4511G>A (p.Trp1504Ter)	Pathogenic
1698	NM_015040.4(PIKFYVE):c.3308A>G (p.Lys1103Arg)	Pathogenic
1699	NM_015040.4(PIKFYVE):c.2962C>T (p.Gln988Ter)	Pathogenic
223248	NM_015040.4(PIKFYVE):c.3150dup (p.Asp1051fs)	Pathogenic
223249	NM_015040.3(PIKFYVE):c.2008_2190del (p.Ile670_Gln730del)	Pathogenic
2636706	NM_015040.4(PIKFYVE):c.3112C>T (p.Arg1038Ter)	Pathogenic
41924	NM_015040.4(PIKFYVE):c.4167_4170del (p.Glu1389fs)	Pathogenic
4281476	NM_015040.4(PIKFYVE):c.3588_3610del (p.Ile1197fs)	Pathogenic
938366	NM_015040.4(PIKFYVE):c.853_854del (p.Leu285fs)	Pathogenic
1324912	NM_015040.4(PIKFYVE):c.935C>G (p.Ser312Ter)	Likely pathogenic
1723222	NM_015040.4(PIKFYVE):c.904C>T (p.Arg302Ter)	Likely pathogenic
225438	NM_015040.4(PIKFYVE):c.3500C>G (p.Ser1167Ter)	Likely pathogenic
2628581	NM_015040.4(PIKFYVE):c.1031del (p.Asp344fs)	Likely pathogenic
2630113	NM_015040.4(PIKFYVE):c.1510C>T (p.Gln504Ter)	Likely pathogenic
3367109	NM_015040.4(PIKFYVE):c.4142+1del	Likely pathogenic
3780122	NM_015040.4(PIKFYVE):c.2331+1G>C	Likely pathogenic
3780123	NM_015040.4(PIKFYVE):c.353dup (p.Gly119fs)	Likely pathogenic
4077425	NM_015040.4(PIKFYVE):c.4807G>T (p.Glu1603Ter)	Likely pathogenic
4292566	NM_015040.4(PIKFYVE):c.3187C>T (p.Arg1063Ter)	Likely pathogenic
841625	NM_015040.4(PIKFYVE):c.322+1G>A	Likely pathogenic
852268	NM_015040.4(PIKFYVE):c.5845-2A>T	Likely pathogenic
943526	NM_015040.4(PIKFYVE):c.3618+1G>A	Likely pathogenic

SpliceAI

6798 predictions. Top by Δscore:

Variant	Effect	Δscore
2:208266413:CAGG:C	donor_loss	1.0000
2:208266414:AGGTA:A	donor_loss	1.0000
2:208266416:G:GC	donor_loss	1.0000
2:208266417:T:A	donor_loss	1.0000
2:208271505:TTTCA:T	acceptor_loss	1.0000
2:208271506:TTCAG:T	acceptor_loss	1.0000
2:208271507:TCAGA:T	acceptor_loss	1.0000
2:208271508:CAGA:C	acceptor_loss	1.0000
2:208271510:GACT:G	acceptor_gain	1.0000
2:208271510:GACTC:G	acceptor_gain	1.0000
2:208271632:A:G	donor_gain	1.0000
2:208276700:A:AG	acceptor_gain	1.0000
2:208276701:A:G	acceptor_gain	1.0000
2:208276705:A:AG	acceptor_gain	1.0000
2:208276706:A:G	acceptor_gain	1.0000
2:208276710:A:AG	acceptor_gain	1.0000
2:208276710:AGA:A	acceptor_loss	1.0000
2:208276711:G:GC	acceptor_loss	1.0000
2:208276711:G:GG	acceptor_gain	1.0000
2:208288727:A:AG	acceptor_gain	1.0000
2:208288727:AGTTT:A	acceptor_gain	1.0000
2:208288728:G:GG	acceptor_gain	1.0000
2:208288728:GTTT:G	acceptor_gain	1.0000
2:208288728:GTTTG:G	acceptor_gain	1.0000
2:208301047:A:T	donor_gain	1.0000
2:208301051:G:GT	donor_gain	1.0000
2:208302225:T:A	acceptor_gain	1.0000
2:208302227:T:TA	acceptor_gain	1.0000
2:208302228:G:A	acceptor_gain	1.0000
2:208302234:T:A	acceptor_gain	1.0000

AlphaMissense

13899 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
2:208276802:T:C	L138P	1.000
2:208277558:T:A	W155R	1.000
2:208277558:T:C	W155R	1.000
2:208277560:G:C	W155C	1.000
2:208277560:G:T	W155C	1.000
2:208277562:T:C	M156T	1.000
2:208277567:G:C	D158H	1.000
2:208277585:T:A	C164S	1.000
2:208277585:T:C	C164R	1.000
2:208277586:G:A	C164Y	1.000
2:208277586:G:C	C164S	1.000
2:208277586:G:T	C164F	1.000
2:208277587:C:G	C164W	1.000
2:208277594:T:A	C167S	1.000
2:208277594:T:C	C167R	1.000
2:208277595:G:A	C167Y	1.000
2:208277595:G:C	C167S	1.000
2:208277595:G:T	C167F	1.000
2:208277596:T:G	C167W	1.000
2:208277606:T:C	F171L	1.000
2:208277607:T:C	F171S	1.000
2:208277607:T:G	F171C	1.000
2:208277608:T:A	F171L	1.000
2:208277608:T:G	F171L	1.000
2:208277615:T:C	F174L	1.000
2:208277616:T:C	F174S	1.000
2:208277616:T:G	F174C	1.000
2:208277617:T:A	F174L	1.000
2:208277617:T:G	F174L	1.000
2:208277619:G:C	R175T	1.000

dbSNP variants (sampled 300 via entrez): RS1000059727 (2:208312269 T>C), RS1000100073 (2:208275336 A>G), RS1000116974 (2:208319774 C>T), RS1000158576 (2:208338846 A>G), RS1000235711 (2:208284700 A>G), RS1000288400 (2:208321078 A>G), RS1000314423 (2:208344185 A>G), RS1000369588 (2:208357561 A>C,G), RS1000452753 (2:208268415 C>T), RS1000531375 (2:208319602 T>A), RS1000568356 (2:208285947 A>G), RS1000590316 (2:208338255 C>G,T), RS1000590846 (2:208292656 A>G), RS1000594589 (2:208335740 T>A,C,G), RS1000665969 (2:208279973 G>C)

Disease associations

OMIM: gene MIM:609414 | disease phenotypes: MIM:121850

GenCC curated gene-disease

Disease	Classification	Inheritance
fleck corneal dystrophy	Definitive	Autosomal dominant

Mondo (1): fleck corneal dystrophy (MONDO:0007376)

Orphanet (1): Fleck corneal dystrophy (Orphanet:98970)

HPO phenotypes

3 total (3 of 3 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000613	Photophobia
HP:0007962	Speckled corneal dystrophy

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST003262_601	Post bronchodilator FEV1	3.000000e-06
GCST003833_13	Adult asthma	3.000000e-06

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004314	forced expiratory volume

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
C563256	Corneal Dystrophy, Fleck (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (2): CHEMBL1938222 (SINGLE PROTEIN), CHEMBL5465237 (PROTEIN-PROTEIN INTERACTION)

Molecules with ChEMBL bioactivity

1 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 781 (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
CHEMBL4297643	APILIMOD	2	781

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

GtoPdb / IUPHAR curated pharmacology

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

Target class: enzyme — 1-phosphatidylinositol-3-phosphate 5-kinase family

Most potent curated ligand interactions (4 total), top 4:

Ligand	Action	Affinity	Parameter
AMG28	Inhibition	8.66	pIC50
compound 17 [PMID: 36111834]	Inhibition	8.16	pIC50
apilimod	Inhibition	7.19	pKd
RMC-113	Binding	6.43	pKd

Binding affinities (BindingDB)

397 measured of 445 human assays (445 total across all organisms); most potent 50 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
4-[2-(1-methylpyrazol-4-yl)-5-[3-(m- tolyl)pyrazol-1-yl]pyrazolo[1,5- a]pyrimidin-7-yl]morpholine	IC50	0.7 nM	US-12486274: Substituted pyrazolo-pyrimidines and uses thereof
4-[2-(1,5-dimethylpyrazol-3-yl)-5-[3- (m-tolyl)pyrazol-1-yl]pyrazolo[1,5- a]pyrimidin-7-yl]morpholine	IC50	0.9 nM	US-12486274: Substituted pyrazolo-pyrimidines and uses thereof
4-[2-(5-methyl-1H-pyrazol-3-yl)-5-[3- (m-tolyl)pyrazol-1-yl]pyrazolo[1,5- a]pyrimidin-7-yl]morpholine	IC50	1.7 nM	US-12486274: Substituted pyrazolo-pyrimidines and uses thereof
4-[2-(3-methylisoxazol-5-yl)-5-[3-(m- tolyl)pyrazol-1-yl]pyrazolo[1,5- a]pyrimidin-7-yl]morpholine	IC50	2.2 nM	US-12486274: Substituted pyrazolo-pyrimidines and uses thereof
4-[2-(1-methylpyrazol-3-yl)-5-[3-(m- tolyl)pyrazol-1-yl]pyrazolo[1,5- a]pyrimidin-7-yl]morpholine	IC50	2.4 nM	US-12486274: Substituted pyrazolo-pyrimidines and uses thereof
4-[5-[3-(m-tolyl)pyrazol-1-yl]-2-(1H- pyrazol-4-yl)pyrazolo[1,5- a]pyrimidin-7-yl]morpholine	IC50	2.5 nM	US-12486274: Substituted pyrazolo-pyrimidines and uses thereof
4-[2-(2,5-dimethylpyrazol-3-yl)-5-[3- (m-tolyl)pyrazol-1-yl]pyrazolo[1,5- a]pyrimidin-7-yl]morpholine	IC50	2.6 nM	US-12486274: Substituted pyrazolo-pyrimidines and uses thereof
4-[5-[3-(m-tolyl)pyrazol-1-yl]-2- thiazol-2-yl-pyrazolo[1,5-a]pyrimidin- 7-yl]morpholine	IC50	2.7 nM	US-12486274: Substituted pyrazolo-pyrimidines and uses thereof
4-[5-[3-(3-methylphenyl)pyrazol-1-yl]-2-pyridin-4-ylpyrazolo[1,5-a]pyrimidin-7-yl]morpholine	IC50	4.3 nM	US-12486274: Substituted pyrazolo-pyrimidines and uses thereof
4-[5-[3-(3-methylphenyl)pyrazol-1-yl]-2-pyridin-3-ylpyrazolo[1,5-a]pyrimidin-7-yl]morpholine	IC50	6.8 nM	US-12486274: Substituted pyrazolo-pyrimidines and uses thereof
4-[5-[3-(3-methoxyphenyl)pyrazol-1- yl]-2-(3-pyridyl)pyrazolo[1,5- a]pyrimidin-7-yl]morpholine	IC50	7.1 nM	US-12486274: Substituted pyrazolo-pyrimidines and uses thereof
2-[3-[5-[3-(3-methoxyphenyl)pyrazol- 1-yl]-7-morpholino-pyrazolo[1,5- a]pyrimidin-2-yl]-5-methyl-pyrazol-1- yl]-N,N-dimethyl-ethanamine	IC50	8.4 nM	US-12486274: Substituted pyrazolo-pyrimidines and uses thereof
N,N-dimethyl-2-[5-methyl-3-[7- morpholino-5-[3-(m-tolyl)pyrazol-1- yl]pyrazolo[1,5-a]pyrimidin-2- yl]pyrazol-1-yl]ethanamine	IC50	9.4 nM	US-12486274: Substituted pyrazolo-pyrimidines and uses thereof
(S)-N-(1-cyclopropylethyl)-7- morpholino-5-(3-(m-tolyl)-1H- pyrazol-1-yl)pyrazolo[1,5- a]pyrimidine-2-carboxamide	IC50	12.6 nM	US-12486274: Substituted pyrazolo-pyrimidines and uses thereof
4-[5-[3-(m-tolyl)pyrazol-1-yl]-2-(1H- pyrazol-3-yl)pyrazolo[1,5- a]pyrimidin-7-yl]morpholine	IC50	15.8 nM	US-12486274: Substituted pyrazolo-pyrimidines and uses thereof
7-morpholino-5-[3-(m-tolyl)pyrazol-1- yl]-N-[(3S)-tetrahydrofuran-3- yl]pyrazolo[1,5-a]pyrimidine-2- carboxamide	IC50	18.4 nM	US-12486274: Substituted pyrazolo-pyrimidines and uses thereof
4-[5-[3-(3-bromophenyl)pyrazol-1-yl]- 2-(3-pyridyl)pyrazolo[1,5- a]pyrimidin-7-yl]morpholine	IC50	19.9 nM	US-12486274: Substituted pyrazolo-pyrimidines and uses thereof
(R)-N-(1-cyclopropylethyl)-7- morpholino-5-(3-(m-tolyl)-1H- pyrazol-1-yl)pyrazolo[1,5- a]pyrimidine-2-carboxamide	IC50	21.6 nM	US-12486274: Substituted pyrazolo-pyrimidines and uses thereof
N-cyclopentyl-7-morpholino-5-(3-(m- tolyl)-1H-pyrazol-1-yl)pyrazolo[1,5- a]pyrimidine-2-carboxamide	IC50	21.6 nM	US-12486274: Substituted pyrazolo-pyrimidines and uses thereof
N,N-dimethyl-2-[3-methyl-5-[7- morpholino-5-[3-(m-tolyl)pyrazol-1- yl]pyrazolo[1,5-a]pyrimidin-2- yl]pyrazol-1-yl]ethanamine	IC50	22.6 nM	US-12486274: Substituted pyrazolo-pyrimidines and uses thereof
N-isopropyl-7-morpholino-5-(3-(m- tolyl)-1H-pyrazol-1-yl)pyrazolo[1,5- a]pyrimidine-2-carboxamide	IC50	25.7 nM	US-12486274: Substituted pyrazolo-pyrimidines and uses thereof
N-[(3S)-1-methyl-3-piperidyl]-7- morpholino-5-[3-(m-tolyl)pyrazol-1- yl]pyrazolo[1,5-a]pyrimidine-2- carboxamide	IC50	26.8 nM	US-12486274: Substituted pyrazolo-pyrimidines and uses thereof
N-[(3R)-1-methyl-3-piperidyl]-7- morpholino-5-[3-(m-tolyl)pyrazol-1- yl]pyrazolo[1,5-a]pyrimidine-2- carboxamide	IC50	28.4 nM	US-12486274: Substituted pyrazolo-pyrimidines and uses thereof
4-(2-(pyridin-2-yl)-5-(3-(m-tolyl)-1H- pyrazol-1-yl)pyrazolo[1,5- a]pyrimidin-7-yl)morpholine	IC50	29.6 nM	US-12486274: Substituted pyrazolo-pyrimidines and uses thereof
5-[7-morpholino-5-(3-phenylpyrazol- 1-yl)pyrazolo[1,5-a]pyrimidin-2- yl]pyridin-2-amine	IC50	29.9 nM	US-12486274: Substituted pyrazolo-pyrimidines and uses thereof
2-amino-3-(3-hydroxy-2,6-dimethylphenyl)-7-methyl-3,6,11-triazatricyclo[6.4.1.04,13]trideca-1,4,6,8(13)-tetraen-12-one	IC50	30 nM	US-20250145624: MEMBRANE-ASSOCIATED TYROSINE- AND THREONINE-SPECIFIC CDC2-INHIBITORY KINASE (PKMYT1) INHIBITORS AND USES THEREOF
N-cyclopropyl-7-morpholino-5-(3-(m- tolyl)-1H-pyrazol-1-yl)pyrazolo[1,5- a]pyrimidine-2-carboxamide	IC50	30.2 nM	US-12486274: Substituted pyrazolo-pyrimidines and uses thereof
4-[2-(1,5-dimethylpyrazol-3-yl)-5-(3- phenylpyrazol-1-yl)pyrazolo[1,5- a]pyrimidin-7-yl]morpholine	IC50	32.2 nM	US-12486274: Substituted pyrazolo-pyrimidines and uses thereof
N-(4-(dimethylamino)butyl)-7- morpholino-5-(3-(m-tolyl)-1H- pyrazol-1-yl)pyrazolo[1,5- a]pyrimidine-2-carboxamide	IC50	32.4 nM	US-12486274: Substituted pyrazolo-pyrimidines and uses thereof
4-[2-(5-methyl-1H-pyrazol-3-yl)-5-(3- phenylpyrazol-1-yl)pyrazolo[1,5- a]pyrimidin-7-yl]morpholine	IC50	34.3 nM	US-12486274: Substituted pyrazolo-pyrimidines and uses thereof
1-(7-morpholino-2-(pyridin-4- yl)pyrazolo[1,5-a]pyrimidin-5-yl)-3- phenyl-1H-pyrazol-5-amine	IC50	38.4 nM	US-12486274: Substituted pyrazolo-pyrimidines and uses thereof
4-[5-[3-(3-chlorophenyl)pyrazol-1-yl]- 2-(1-methylpyrazol-3-yl)pyrazolo[1,5- a]pyrimidin-7-yl]morpholine	IC50	41 nM	US-12486274: Substituted pyrazolo-pyrimidines and uses thereof
N-[(3S)-1-methylpyrrolidin-3-yl]-7- morpholino-5-[3-(m-tolyl)pyrazol-1- yl]pyrazolo[1,5-a]pyrimidine-2- carboxamide	IC50	41.3 nM	US-12486274: Substituted pyrazolo-pyrimidines and uses thereof
7-morpholino-N-(oxetan-3-ylmethyl)- 5-(3-(m-tolyl)-1H-pyrazol-1- yl)pyrazolo[1,5-a]pyrimidine-2- carboxamide	IC50	46.4 nM	US-12486274: Substituted pyrazolo-pyrimidines and uses thereof
4-[2-morpholin-4-yl-4-(pyridin-3-ylmethoxy)-5,6-dihydropyrrolo[2,3-d]pyrimidin-7-yl]benzonitrile	IC50	55 nM	US-20250145642: BICYCLIC HETEROARENES AND METHODS OF THEIR USE
4-[4-[2-(1-methylpiperidin-3-yl)ethoxy]-7-pyridin-3-yl-5,6-dihydropyrrolo[2,3-d]pyrimidin-2-yl]morpholine	IC50	55 nM	US-20250145642: BICYCLIC HETEROARENES AND METHODS OF THEIR USE
4-[7-(3-methoxyphenyl)-4-[(1-methylpiperidin-3-yl)methoxy]-5,6-dihydropyrrolo[2,3-d]pyrimidin-2-yl]morpholine	IC50	55 nM	US-20250145642: BICYCLIC HETEROARENES AND METHODS OF THEIR USE
4-[7-phenyl-4-(pyrimidin-5-ylmethoxy)-5,6-dihydropyrrolo[2,3-d]pyrimidin-2-yl]morpholine	IC50	55 nM	US-20250145642: BICYCLIC HETEROARENES AND METHODS OF THEIR USE
4-[7-phenyl-4-(pyrazin-2-ylmethoxy)-5,6-dihydropyrrolo[2,3-d]pyrimidin-2-yl]morpholine	IC50	55 nM	US-20250145642: BICYCLIC HETEROARENES AND METHODS OF THEIR USE
4-[4-(oxetan-3-ylmethoxy)-7-phenyl-5,6-dihydropyrrolo[2,3-d]pyrimidin-2-yl]morpholine	IC50	55 nM	US-20250145642: BICYCLIC HETEROARENES AND METHODS OF THEIR USE
4-[7-phenyl-4-(pyridin-2-ylmethoxy)-5,6-dihydropyrrolo[2,3-d]pyrimidin-2-yl]morpholine	IC50	55 nM	US-20250145642: BICYCLIC HETEROARENES AND METHODS OF THEIR USE
4-[7-phenyl-4-(pyridazin-3-ylmethoxy)-5,6-dihydropyrrolo[2,3-d]pyrimidin-2-yl]morpholine	IC50	55 nM	US-20250145642: BICYCLIC HETEROARENES AND METHODS OF THEIR USE
4-[4-[2-(oxolan-2-yl)ethoxy]-7-pyridin-3-yl-5,6-dihydropyrrolo[2,3-d]pyrimidin-2-yl]morpholine	IC50	55 nM	US-20250145642: BICYCLIC HETEROARENES AND METHODS OF THEIR USE
4-[7-phenyl-4-(2-pyridin-2-ylethoxy)-5,6-dihydropyrrolo[2,3-d]pyrimidin-2-yl]morpholine	IC50	55 nM	US-20250145642: BICYCLIC HETEROARENES AND METHODS OF THEIR USE
2-methyl-1-(2-morpholin-4-yl-7-phenyl-5,6-dihydropyrrolo[2,3-d]pyrimidin-4-yl)propan-2-ol	IC50	55 nM	US-20250145642: BICYCLIC HETEROARENES AND METHODS OF THEIR USE
4-(7-phenyl-4-pyridin-2-yloxy-5,6-dihydropyrrolo[2,3-d]pyrimidin-2-yl)morpholine	IC50	55 nM	US-20250145642: BICYCLIC HETEROARENES AND METHODS OF THEIR USE
4-(7-phenyl-4-pyridin-3-yloxy-5,6-dihydropyrrolo[2,3-d]pyrimidin-2-yl)morpholine	IC50	55 nM	US-20250145642: BICYCLIC HETEROARENES AND METHODS OF THEIR USE
4-(7-phenyl-4-pyridin-4-yloxy-5,6-dihydropyrrolo[2,3-d]pyrimidin-2-yl)morpholine	IC50	55 nM	US-20250145642: BICYCLIC HETEROARENES AND METHODS OF THEIR USE
4-[7-(3-fluorophenyl)-4-pyridin-3-yloxy-5,6-dihydropyrrolo[2,3-d]pyrimidin-2-yl]morpholine	IC50	55 nM	US-20250145642: BICYCLIC HETEROARENES AND METHODS OF THEIR USE

ChEMBL bioactivities

200 potent at pChembl≥5 of 209 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
10.12	Kd	0.075	nM	APILIMOD
9.51	IC50	0.312	nM	APILIMOD
9.51	IC50	0.309	nM	APILIMOD
9.51	IC50	0.31	nM	APILIMOD
9.46	IC50	0.35	nM	CHEMBL6162267
9.33	Kd	0.47	nM	CHEMBL5572490
9.22	IC50	0.6	nM	CHEMBL6162267
9.09	IC50	0.82	nM	CHEMBL2178735
9.04	Kd	0.91	nM	CHEMBL5555919
8.92	IC50	1.19	nM	CHEMBL4303292
8.92	IC50	1.202	nM	CHEMBL4303292
8.78	Kd	1.65	nM	CHEMBL5568998
8.74	IC50	1.8	nM	CHEMBL5189479
8.74	IC50	1.8	nM	CHEMBL5557909
8.74	IC50	1.8	nM	CHEMBL6162009
8.72	IC50	1.9	nM	CHEMBL5193848
8.70	IC50	2	nM	CHEMBL6151993
8.68	IC50	2.1	nM	CHEMBL3128057
8.66	IC50	2.2	nM	CHEMBL2334586
8.66	IC50	2.2	nM	CHEMBL5279159
8.48	IC50	3.3	nM	CHEMBL5181163
8.47	IC50	3.4	nM	APILIMOD
8.47	IC50	3.4	nM	CHEMBL6133388
8.47	IC50	3.4	nM	CHEMBL6120537
8.43	IC50	3.7	nM	CHEMBL4303292
8.43	Kd	3.75	nM	CHEMBL2032358
8.43	IC50	3.7	nM	CHEMBL6160568
8.40	IC50	4.01	nM	CHEMBL5174830
8.40	IC50	3.981	nM	CHEMBL5174830
8.40	IC50	4	nM	APILIMOD
8.40	IC50	4	nM	CHEMBL5174830
8.39	IC50	4.05	nM	CHEMBL5171359
8.39	IC50	4.1	nM	CHEMBL2334589
8.30	IC50	5.05	nM	CHEMBL2032358
8.29	IC50	5.1	nM	CHEMBL6102522
8.28	IC50	5.2	nM	CHEMBL4303292
8.28	Kd	5.3	nM	CHEMBL2032358
8.28	IC50	5.3	nM	CHEMBL6168421
8.26	Kd	5.5	nM	CHEMBL6063022
8.26	Kd	5.5	nM	CHEMBL5754487
8.26	Kd	5.5	nM	CHEMBL5978922
8.26	Kd	5.5	nM	CHEMBL5845309
8.26	Kd	5.5	nM	CHEMBL5911375
8.26	Kd	5.5	nM	CHEMBL5866518
8.26	Kd	5.5	nM	CHEMBL5968729
8.26	Kd	5.5	nM	CHEMBL5907931
8.21	IC50	6.1	nM	CHEMBL5181163
8.21	IC50	6.2	nM	CHEMBL5198944
8.21	IC50	6.2	nM	CHEMBL6151397
8.20	IC50	6.3	nM	CHEMBL6150496

PubChem BioAssay actives

106 with measured affinity, of 262 total; 47 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
N-[(E)-(3-methylphenyl)methylideneamino]-6-morpholin-4-yl-2-(2-pyridin-2-ylethoxy)pyrimidin-4-amine	1856593: Binding affinity to human wild type partial length PIKFYVE (F1512 to C2098 residues) mammalian expression assessed as dissociation constant by Kinomescan method	kd	0.0001	uM
7-(4-aminocyclohexyl)-5-(5-methyl-1-benzofuran-2-yl)pyrrolo[2,3-d]pyrimidin-4-amine	2092785: Binding affinity to PIKfyve (unknown origin) assessed as dissociation constant incubated for 1 hr by qPCR analysis	kd	0.0005	uM
6-amino-N-[3-(6-morpholin-4-yl-8-oxa-3,5,10-triazatricyclo[7.4.0.02,7]trideca-1(9),2(7),3,5,10,12-hexaen-4-yl)phenyl]pyridine-3-carboxamide	1856580: Inhibition of human GST tagged PIKFYVE (1493 to end residues) expressed in baculovirus-infected Sf9 cells using PI(3)P:PS as substrate incubated for 60 mins in presence of ATP by ADP-Glo assay	ic50	0.0008	uM
2-N-[(E)-1H-indol-3-ylmethylideneamino]-6-morpholin-4-yl-4-N-phenyl-1,3,5-triazine-2,4-diamine	2067015: Binding affinity to N-terminal His-tagged human PIKfyve expressed in Sf9 cells assessed as dissociation constant	kd	0.0009	uM
N-[(E)-(3-methylphenyl)methylideneamino]-7-morpholin-4-yl-2-pyridin-4-ylpyrazolo[1,5-a]pyrimidin-5-amine	1856581: Inhibition of PIKFYVE in HEK293 cells by NanoBRET assay	ic50	0.0012	uM
7-(4-aminocyclohexyl)-5-(1-benzofuran-2-yl)pyrrolo[2,3-d]pyrimidin-4-amine	2092785: Binding affinity to PIKfyve (unknown origin) assessed as dissociation constant incubated for 1 hr by qPCR analysis	kd	0.0016	uM
3-(4-amino-3,5,12-triazatetracyclo[9.7.0.02,7.013,18]octadeca-1(11),2,4,6,13(18),14,16-heptaen-16-yl)pentan-3-ol	1856580: Inhibition of human GST tagged PIKFYVE (1493 to end residues) expressed in baculovirus-infected Sf9 cells using PI(3)P:PS as substrate incubated for 60 mins in presence of ATP by ADP-Glo assay	ic50	0.0018	uM
3-(5-amino-4,6,12-triazatetracyclo[9.7.0.03,8.013,18]octadeca-1(11),3,5,7,13(18),14,16-heptaen-16-yl)pentan-3-ol	2067019: Inhibition of PIKfyve (unknown origin)	ic50	0.0018	uM
2-(4-amino-3,5,12-triazatetracyclo[9.7.0.02,7.013,18]octadeca-1(11),2,4,6,13(18),14,16-heptaen-16-yl)butan-2-ol	1856580: Inhibition of human GST tagged PIKFYVE (1493 to end residues) expressed in baculovirus-infected Sf9 cells using PI(3)P:PS as substrate incubated for 60 mins in presence of ATP by ADP-Glo assay	ic50	0.0019	uM
4-(4-amino-3,5,12-triazatetracyclo[9.7.0.02,7.013,18]octadeca-1(11),2,4,6,13(18),14,16-heptaen-16-yl)-2-methylbut-3-yn-2-ol	1856569: Inhibition of human wild type partial length PIKfyve (F1512 to C2098 residues) expressed in mammalian expression system by Kinomescan assay	ic50	0.0022	uM
(E)-3-(5-methoxy-2-methyl-1H-indol-3-yl)-1-pyridin-4-ylprop-2-en-1-one	2092785: Binding affinity to PIKfyve (unknown origin) assessed as dissociation constant incubated for 1 hr by qPCR analysis	kd	0.0037	uM
16-[3-(dimethylamino)prop-1-ynyl]-3,5,12-triazatetracyclo[9.7.0.02,7.013,18]octadeca-1(11),2,4,6,13(18),14,16-heptaen-4-amine	1856581: Inhibition of PIKFYVE in HEK293 cells by NanoBRET assay	ic50	0.0040	uM
1-(4-amino-3,5,12-triazatetracyclo[9.7.0.02,7.013,18]octadeca-1(11),2,4,6,13(18),14,16-heptaen-16-yl)ethanol	1856581: Inhibition of PIKFYVE in HEK293 cells by NanoBRET assay	ic50	0.0040	uM
4-[3-(2-aminopyrimidin-4-yl)-1H-indol-5-yl]-2-methylbut-3-yn-2-ol	1856580: Inhibition of human GST tagged PIKFYVE (1493 to end residues) expressed in baculovirus-infected Sf9 cells using PI(3)P:PS as substrate incubated for 60 mins in presence of ATP by ADP-Glo assay	ic50	0.0061	uM
16-(2-methoxypropan-2-yl)-3,5,12-triazatetracyclo[9.7.0.02,7.013,18]octadeca-1(11),2,4,6,13(18),14,16-heptaen-4-amine	1856580: Inhibition of human GST tagged PIKFYVE (1493 to end residues) expressed in baculovirus-infected Sf9 cells using PI(3)P:PS as substrate incubated for 60 mins in presence of ATP by ADP-Glo assay	ic50	0.0062	uM
4-methoxy-3-[(4-pyridin-3-yl-5H-pyrrolo[3,2-d]pyrimidin-2-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	1968255: Binding affinity to PIKFYVE (unknown origin) assessed as dissociation constant	kd	0.0064	uM
16-[(dimethylamino)methyl]-4,6,12-triazatetracyclo[9.7.0.03,8.013,18]octadeca-1(11),3,5,7,13(18),14,16-heptaen-5-amine	2067019: Inhibition of PIKfyve (unknown origin)	ic50	0.0069	uM
10-(4-fluorophenyl)-6,7-dihydro-5H-pyrimido[5,4-c]carbazol-2-amine	1856580: Inhibition of human GST tagged PIKFYVE (1493 to end residues) expressed in baculovirus-infected Sf9 cells using PI(3)P:PS as substrate incubated for 60 mins in presence of ATP by ADP-Glo assay	ic50	0.0082	uM
2-N-[(E)-(3-iodophenyl)methylideneamino]-6-morpholin-4-yl-4-N,4-N-diphenyl-1,3,5-triazine-2,4-diamine	1876290: Inhibition of PIKFYVE (unknown origin)	ic50	0.0090	uM
16-(4-fluorophenyl)-3,5,12-triazatetracyclo[9.7.0.02,7.013,18]octadeca-1(11),2,4,6,13(18),14,16-heptaen-4-amine	1856580: Inhibition of human GST tagged PIKFYVE (1493 to end residues) expressed in baculovirus-infected Sf9 cells using PI(3)P:PS as substrate incubated for 60 mins in presence of ATP by ADP-Glo assay	ic50	0.0093	uM
16-(4-fluorophenyl)-4,6,12-triazatetracyclo[9.7.0.03,8.013,18]octadeca-1(11),3,5,7,13(18),14,16-heptaen-5-amine	2067019: Inhibition of PIKfyve (unknown origin)	ic50	0.0093	uM
16-(2-pyridin-4-ylethynyl)-3,5,12-triazatetracyclo[9.7.0.02,7.013,18]octadeca-1(11),2,4,6,13(18),14,16-heptaen-4-amine	1856580: Inhibition of human GST tagged PIKFYVE (1493 to end residues) expressed in baculovirus-infected Sf9 cells using PI(3)P:PS as substrate incubated for 60 mins in presence of ATP by ADP-Glo assay	ic50	0.0220	uM
16-(1-methylpyrazol-4-yl)-3,5,12-triazatetracyclo[9.7.0.02,7.013,18]octadeca-1(11),2,4,6,13(18),14,16-heptaen-4-amine	1856580: Inhibition of human GST tagged PIKFYVE (1493 to end residues) expressed in baculovirus-infected Sf9 cells using PI(3)P:PS as substrate incubated for 60 mins in presence of ATP by ADP-Glo assay	ic50	0.0260	uM
10-(1-methylpyrazol-4-yl)-6,7-dihydro-5H-pyrimido[5,4-c]carbazol-2-amine	1856580: Inhibition of human GST tagged PIKFYVE (1493 to end residues) expressed in baculovirus-infected Sf9 cells using PI(3)P:PS as substrate incubated for 60 mins in presence of ATP by ADP-Glo assay	ic50	0.0340	uM
2-(4-amino-3,5,12-triazatetracyclo[9.7.0.02,7.013,18]octadeca-1(11),2,4,6,13(18),14,16-heptaen-16-yl)ethanol	1856581: Inhibition of PIKFYVE in HEK293 cells by NanoBRET assay	ic50	0.0400	uM
4-[[(E)-4-(dimethylamino)but-2-enoyl]amino]-N-[3-[[6-(1H-indol-3-yl)pyrimidin-4-yl]amino]phenyl]benzamide	1547849: Inhibition of N-terminal GST-tagged full length human PIKFYVE (1 to 2098 residues) using PI(3)P and Phosphatidylserine as substrate by ADP-Glo assay	ic50	0.0401	uM
1-(4-amino-3,5,12-triazatetracyclo[9.7.0.02,7.013,18]octadeca-1(11),2,4,6,13(18),14,16-heptaen-16-yl)-4-methylpent-1-yn-3-ol	1856581: Inhibition of PIKFYVE in HEK293 cells by NanoBRET assay	ic50	0.0457	uM
4-(4-amino-3,5,13-triazatetracyclo[10.7.0.02,7.014,19]nonadeca-1(12),2,4,6,14(19),15,17-heptaen-17-yl)-2-methylbut-3-yn-2-ol	1856580: Inhibition of human GST tagged PIKFYVE (1493 to end residues) expressed in baculovirus-infected Sf9 cells using PI(3)P:PS as substrate incubated for 60 mins in presence of ATP by ADP-Glo assay	ic50	0.0610	uM
17-(2-cyclopropylethynyl)-3,5,13-triazatetracyclo[10.7.0.02,7.014,19]nonadeca-1(12),2,4,6,14(19),15,17-heptaen-4-amine	1856580: Inhibition of human GST tagged PIKFYVE (1493 to end residues) expressed in baculovirus-infected Sf9 cells using PI(3)P:PS as substrate incubated for 60 mins in presence of ATP by ADP-Glo assay	ic50	0.0750	uM
10-[2-(3-methylimidazol-4-yl)ethynyl]-6,7-dihydro-5H-pyrimido[5,4-c]carbazol-2-amine	1856580: Inhibition of human GST tagged PIKFYVE (1493 to end residues) expressed in baculovirus-infected Sf9 cells using PI(3)P:PS as substrate incubated for 60 mins in presence of ATP by ADP-Glo assay	ic50	0.0770	uM
N-[4-methyl-3-[(6-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridin-4-yl)amino]phenyl]-3-(trifluoromethyl)benzamide	2092785: Binding affinity to PIKfyve (unknown origin) assessed as dissociation constant incubated for 1 hr by qPCR analysis	kd	0.1150	uM
10-[3-(dimethylamino)prop-1-ynyl]-6,7-dihydro-5H-pyrimido[5,4-c]carbazol-2-amine	1856581: Inhibition of PIKFYVE in HEK293 cells by NanoBRET assay	ic50	0.1230	uM
N-[2-(4-amino-3,5,12-triazatetracyclo[9.7.0.02,7.013,18]octadeca-1(11),2,4,6,13(18),14,16-heptaen-16-yl)propan-2-yl]methanesulfonamide	1856580: Inhibition of human GST tagged PIKFYVE (1493 to end residues) expressed in baculovirus-infected Sf9 cells using PI(3)P:PS as substrate incubated for 60 mins in presence of ATP by ADP-Glo assay	ic50	0.1400	uM
4-(2-amino-6,7-dihydro-5H-pyrimido[5,4-c]carbazol-10-yl)-2-methylbut-3-yn-2-ol	1856581: Inhibition of PIKFYVE in HEK293 cells by NanoBRET assay	ic50	0.2200	uM
(E)-4-(dimethylamino)-N-[4-[(3S)-3-[[4-(2-phenylpyrazolo[1,5-a]pyridin-3-yl)pyrimidin-2-yl]amino]pyrrolidine-1-carbonyl]phenyl]but-2-enamide	1968176: Binding affinity to wild type partial length human PIKFYVE (F1512 to C2098 residues) expressed in mammalian expression system by KdELECT kinase assay	kd	0.2700	uM
17-[2-(3-methylimidazol-4-yl)ethynyl]-3,5,13-triazatetracyclo[10.7.0.02,7.014,19]nonadeca-1(12),2,4,6,14(19),15,17-heptaen-4-amine	1856580: Inhibition of human GST tagged PIKFYVE (1493 to end residues) expressed in baculovirus-infected Sf9 cells using PI(3)P:PS as substrate incubated for 60 mins in presence of ATP by ADP-Glo assay	ic50	0.2900	uM
1-(4-amino-3,5,12-triazatetracyclo[9.7.0.02,7.013,18]octadeca-1(11),2,4,6,13(18),14,16-heptaen-16-yl)-2-methylpropan-2-ol	1856581: Inhibition of PIKFYVE in HEK293 cells by NanoBRET assay	ic50	0.2900	uM
10-(2-cyclopropylethynyl)-6,7-dihydro-5H-pyrimido[5,4-c]carbazol-2-amine	1856581: Inhibition of PIKFYVE in HEK293 cells by NanoBRET assay	ic50	0.3000	uM
17-[3-(dimethylamino)prop-1-ynyl]-3,5,13-triazatetracyclo[10.7.0.02,7.014,19]nonadeca-1(12),2,4,6,14(19),15,17-heptaen-4-amine	1856580: Inhibition of human GST tagged PIKFYVE (1493 to end residues) expressed in baculovirus-infected Sf9 cells using PI(3)P:PS as substrate incubated for 60 mins in presence of ATP by ADP-Glo assay	ic50	0.4300	uM
17-(2-pyridin-4-ylethynyl)-3,5,13-triazatetracyclo[10.7.0.02,7.014,19]nonadeca-1(12),2,4,6,14(19),15,17-heptaen-4-amine	1856580: Inhibition of human GST tagged PIKFYVE (1493 to end residues) expressed in baculovirus-infected Sf9 cells using PI(3)P:PS as substrate incubated for 60 mins in presence of ATP by ADP-Glo assay	ic50	0.5800	uM
17-cyclopropyl-3,5,13-triazatetracyclo[10.7.0.02,7.014,19]nonadeca-1(12),2,4,6,14(19),15,17-heptaen-4-amine	1856580: Inhibition of human GST tagged PIKFYVE (1493 to end residues) expressed in baculovirus-infected Sf9 cells using PI(3)P:PS as substrate incubated for 60 mins in presence of ATP by ADP-Glo assay	ic50	0.7200	uM
5-(6-bromo-5-methoxy-1H-indol-3-yl)-2-(1H-pyrrol-2-yl)-1,3-oxazole	1541240: Binding affinity to wild-type human partial length PIKFYVE (F1512 to C2098 residues) expressed in mammalian expression system by active-site directed competition binding assay based Kinomescan method	kd	1.0000	uM
1-(2-amino-6,7-dihydro-5H-pyrimido[5,4-c]carbazol-10-yl)-4-methylpent-1-yn-3-ol	1856581: Inhibition of PIKFYVE in HEK293 cells by NanoBRET assay	ic50	1.1700	uM
2-(4-amino-3,5,12-triazatetracyclo[9.7.0.02,7.013,18]octadeca-1(11),2,4,6,13(18),14,16-heptaen-16-yl)-2-methylpropan-1-ol	1856581: Inhibition of PIKFYVE in HEK293 cells by NanoBRET assay	ic50	2.1600	uM
17-(4-fluorophenyl)-3,5,13-triazatetracyclo[10.7.0.02,7.014,19]nonadeca-1(12),2,4,6,14(19),15,17-heptaen-4-amine	1856581: Inhibition of PIKFYVE in HEK293 cells by NanoBRET assay	ic50	2.5600	uM
10-(2-pyridin-4-ylethynyl)-6,7-dihydro-5H-pyrimido[5,4-c]carbazol-2-amine	1856581: Inhibition of PIKFYVE in HEK293 cells by NanoBRET assay	ic50	2.9800	uM
(E)-4-(dimethylamino)-N-[4-[(3S,4S)-3-methyl-4-[[4-(2-phenylpyrazolo[1,5-a]pyridin-3-yl)pyrimidin-2-yl]amino]pyrrolidine-1-carbonyl]phenyl]but-2-enamide	1968176: Binding affinity to wild type partial length human PIKFYVE (F1512 to C2098 residues) expressed in mammalian expression system by KdELECT kinase assay	kd	5.0000	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
apilimod	decreases activity, decreases reaction, increases expression, decreases response to substance, affects binding	8
sodium arsenite	increases expression	2
Benzo(a)pyrene	decreases expression, increases expression	2
Tretinoin	increases expression, decreases expression	2
Valproic Acid	affects expression, decreases expression	2
FR900359	affects phosphorylation	1
triphenyl phosphate	affects expression	1
bisphenol A	decreases methylation	1
arsenite	affects binding, decreases reaction	1
tris(1,3-dichloro-2-propyl)phosphate	increases expression	1
tamibarotene	decreases expression	1
di-n-butylphosphoric acid	affects expression	1
perfluorooctane sulfonic acid	decreases expression	1
K 7174	increases expression	1
vacuolin-1	decreases activity	1
bisphenol S	affects cotreatment, decreases methylation	1
Resveratrol	affects cotreatment, increases expression	1
Sunitinib	increases expression	1
Fulvestrant	affects cotreatment, decreases methylation	1
Acetaminophen	increases expression	1
Caffeine	affects phosphorylation	1
Dimethyl Sulfoxide	affects expression	1
Endosulfan	decreases expression	1
Mercury	decreases expression	1
Plant Extracts	affects cotreatment, increases expression	1
Thiram	increases expression	1
Urethane	increases expression	1
7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide	decreases expression	1
Palmitic Acid	decreases phosphorylation	1
Particulate Matter	increases expression	1

ChEMBL screening assays

117 unique, capped per target: 116 binding, 1 functional

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1942475	Binding	Inhibition of human PIP5K3 in HL-60 cells lysate assessed as reduction of labeling of acyl-phosphate ATP probe at 100 nM	6-Position optimization of tricyclic 4-quinolone-based inhibitors of glycogen synthase kinase-3β: discovery of nitrile derivatives with picomolar potency. — Bioorg Med Chem Lett
CHEMBL5209946	Functional	Affinity Phenotypic Cellular interaction (PtdIns(3;5)P2 production in serum-starved NIH3T3) EUB0000014b PIKFYVE	Affinity Phenotypic Cellular Literature for EUbOPEN Chemogenomics Library wave 3

Cellosaurus cell lines

6 cell lines: 5 cancer cell line, 1 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_D7XE	Ubigene A-549 PIKFYVE KO	Cancer cell line	Male
CVCL_D8SW	Ubigene HCT 116 PIKFYVE KO	Cancer cell line	Male
CVCL_D9NC	Ubigene HEK293 PIKFYVE KO	Transformed cell line	Female
CVCL_E0KQ	Ubigene HeLa PIKFYVE KO	Cancer cell line	Female
CVCL_TD74	HAP1 PIKFYVE (-) 1	Cancer cell line	Male
CVCL_TD75	HAP1 PIKFYVE (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

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