MPL

Summary

MPL (MPL proto-oncogene, thrombopoietin receptor, HGNC:7217) is a protein-coding gene on chromosome 1p34.2, encoding Thrombopoietin receptor (P40238). Receptor for thrombopoietin that regulates hematopoietic stem cell renewal, megakaryocyte differentiation, and platelet formation.

In 1990 an oncogene, v-mpl, was identified from the murine myeloproliferative leukemia virus that was capable of immortalizing bone marrow hematopoietic cells from different lineages. In 1992 the human homologue, named, c-mpl, was cloned. Sequence data revealed that c-mpl encoded a protein that was homologous with members of the hematopoietic receptor superfamily. Presence of anti-sense oligodeoxynucleotides of c-mpl inhibited megakaryocyte colony formation. The ligand for c-mpl, thrombopoietin, was cloned in 1994. Thrombopoietin was shown to be the major regulator of megakaryocytopoiesis and platelet formation. The protein encoded by the c-mpl gene, CD110, is a 635 amino acid transmembrane domain, with two extracellular cytokine receptor domains and two intracellular cytokine receptor box motifs . TPO-R deficient mice were severely thrombocytopenic, emphasizing the important role of CD110 and thrombopoietin in megakaryocyte and platelet formation. Upon binding of thrombopoietin CD110 is dimerized and the JAK family of non-receptor tyrosine kinases, as well as the STAT family, the MAPK family, the adaptor protein Shc and the receptors themselves become tyrosine phosphorylated.

Source: NCBI Gene 4352 — RefSeq curated summary.

At a glance

• Gene–disease (curated): thrombocythemia 2 (Definitive, ClinGen) — +3 more curated relationships
• GWAS associations: 11
• Clinical variants (ClinVar): 966 total — 76 pathogenic, 93 likely-pathogenic (top 3% of genes corpus-wide)
• Regional missense constraint (gnomAD): 1 of 3 regions constrained (≈3% of expected missense variation)
• GTEx eGene: eQTL in 11 tissues, sQTL in 0 (q < 0.05)
• Phenotypes (HPO): 80
• Drug target: yes — 7 curated mechanism-of-action drugs; 2 molecules with ChEMBL bioactivity
• Approved drugs (ChEMBL mechanism of action): 5 — Avatrombopag, Eltrombopag Choline, Eltrombopag Olamine, +2 more
• Cancer driver (intOGen): ambiguous (mixed evidence) across 1 cancer types (inferred from mutation patterns)
• Constraint (gnomAD): pLI 0.00 (LoF-tolerant), LOEUF 1.02 (unconstrained)
• MANE Select transcript: NM_005373

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:7217
Approved symbol	MPL
Name	MPL proto-oncogene, thrombopoietin receptor
Location	1p34.2
Locus type	gene with protein product
Status	Approved
Aliases	CD110, TPOR, THPOR
Ensembl gene	ENSG00000117400
Ensembl biotype	protein_coding
OMIM	159530
Entrez	4352

Gene structure

Transcript identifiers

Ensembl transcripts: 5 — 4 protein_coding, 1 retained_intron

MANE Select: ENST00000372470

Transcript support level (Ensembl TSL; 1 = fully mRNA-supported): TSL 1: 3

ENST00000372470, ENST00000413998, ENST00000638732, ENST00000643351, ENST00000967221

RefSeq mRNA: 1 — MANE Select: NM_005373 NM_005373

CCDS: CCDS483

Canonical transcript exons

ENST00000372470 — 12 exons

Exon	Start	End
ENSE00000769664	43352216	43352303
ENSE00000769665	43349263	43349359
ENSE00000769667	43348843	43349002
ENSE00000769669	43346792	43346934
ENSE00000769670	43346445	43346629
ENSE00000769671	43340387	43340513
ENSE00000769672	43339964	43340126
ENSE00000769673	43339271	43339569
ENSE00000769674	43338542	43338720
ENSE00000769675	43338099	43338231
ENSE00003897233	43352518	43354466
ENSE00003897867	43337818	43337927

Expression profiles

Bgee: expression breadth ubiquitous, 166 present calls, max score 78.45.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.4222 / max 128.3385, expressed in 42 samples.

Highest expression (Bgee): male germ line stem cell (sensu Vertebrata) in testis, mononuclear cell, monocyte, leukocyte, parotid gland.

Genetic regulation across tissues (GTEx eQTL / sQTL)

MPL is an eGene in GTEx v10 — its expression is genetically regulated (eQTL) in 11 tissues and its splicing (sQTL) in 0 (q < 0.05). Strongest associations first; slope = normalized effect of the lead variant’s alternative allele.

11 significant tissue × QTL associations:

Tissue	QTL	q-value	Slope	Lead variant
Testis	eqtl	9.5e-06	+0.23	1:43358734:C:CCCCGCCCTGT
Muscle Skeletal	eqtl	1.3e-03	-0.20	1:43377156:T:A
Skin Sun Exposed Lower leg	eqtl	8.1e-03	-0.20	1:43328228:C:A
Brain Hypothalamus	eqtl	1.2e-02	-3.04	1:42973784:T:TA
Adipose Visceral Omentum	eqtl	1.3e-02	+0.21	1:43176739:A:G
Nerve Tibial	eqtl	1.5e-02	+0.14	1:43304079:C:CG
Artery Tibial	eqtl	1.8e-02	+0.13	1:43599477:C:T
Adipose Subcutaneous	eqtl	2.5e-02	+0.14	1:43304250:T:C
Brain Anterior cingulate cortex BA24	eqtl	2.9e-02	+1.28	1:43227650:G:A
Lung	eqtl	4.8e-02	-0.59	1:42924983:G:A
Artery Aorta	eqtl	4.8e-02	+0.16	1:43110532:C:T

FANTOM5 promoters

1 alternative TSS:

Promoter ID	TPM avg	Samples expressed
2508	0.4222	42

Top tissues by expression

showing 100 of 288 tissues by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	78.45	gold quality
mononuclear cell	CL:0000842	74.20	gold quality
monocyte	CL:0000576	74.15	gold quality
leukocyte	CL:0000738	73.33	gold quality
parotid gland	UBERON:0001831	66.20	gold quality
right frontal lobe	UBERON:0002810	64.57	gold quality
bone marrow cell	CL:0002092	63.58	silver quality
endothelial cell	CL:0000115	63.36	gold quality
bronchial epithelial cell	CL:0002328	63.27	silver quality
sural nerve	UBERON:0015488	62.90	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	62.75	gold quality
epithelium of bronchus	UBERON:0002031	62.12	silver quality
left ovary	UBERON:0002119	62.01	gold quality
Brodmann (1909) area 9	UBERON:0013540	61.66	gold quality
prefrontal cortex	UBERON:0000451	61.57	gold quality
bronchus	UBERON:0002185	61.51	silver quality
ovary	UBERON:0000992	61.36	gold quality
heart left ventricle	UBERON:0002084	61.04	gold quality
cardiac ventricle	UBERON:0002082	60.74	gold quality
apex of heart	UBERON:0002098	60.71	gold quality
vena cava	UBERON:0004087	60.59	gold quality
blood	UBERON:0000178	60.33	gold quality
cingulate cortex	UBERON:0003027	60.25	gold quality
right coronary artery	UBERON:0001625	60.18	gold quality
islet of Langerhans	UBERON:0000006	60.06	gold quality
anterior cingulate cortex	UBERON:0009835	60.01	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	59.90	gold quality
bone marrow	UBERON:0002371	59.80	gold quality
blood vessel layer	UBERON:0004797	59.52	silver quality
C1 segment of cervical spinal cord	UBERON:0006469	59.46	gold quality
right lobe of thyroid gland	UBERON:0001119	59.41	gold quality
right uterine tube	UBERON:0001302	59.13	gold quality
frontal cortex	UBERON:0001870	59.05	gold quality
left lobe of thyroid gland	UBERON:0001120	58.96	gold quality
right atrium auricular region	UBERON:0006631	58.89	gold quality
neocortex	UBERON:0001950	58.77	gold quality
heart	UBERON:0000948	58.76	gold quality
popliteal artery	UBERON:0002250	58.70	gold quality
tibial artery	UBERON:0007610	58.70	gold quality
oviduct epithelium	UBERON:0004804	58.60	silver quality
lower esophagus muscularis layer	UBERON:0035833	58.57	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	58.56	gold quality
lower esophagus	UBERON:0013473	58.51	gold quality
smooth muscle tissue	UBERON:0001135	58.36	gold quality
hindlimb stylopod muscle	UBERON:0004252	58.36	gold quality
thyroid gland	UBERON:0002046	58.18	gold quality
pigmented layer of retina	UBERON:0001782	58.13	gold quality
cardiac atrium	UBERON:0002081	58.12	gold quality
right ovary	UBERON:0002118	58.09	gold quality
spinal cord	UBERON:0002240	58.05	gold quality
heart right ventricle	UBERON:0002080	58.03	gold quality
amygdala	UBERON:0001876	57.97	gold quality
substantia nigra	UBERON:0002038	57.79	gold quality
upper lobe of left lung	UBERON:0008952	57.77	gold quality
granulocyte	CL:0000094	57.61	gold quality
adipose tissue	UBERON:0001013	57.46	gold quality
upper lobe of lung	UBERON:0008948	57.45	gold quality
pancreas	UBERON:0001264	57.41	gold quality
cauda epididymis	UBERON:0004360	57.38	silver quality
mucosa of stomach	UBERON:0001199	57.25	gold quality
aorta	UBERON:0000947	57.21	gold quality
subcutaneous adipose tissue	UBERON:0002190	57.21	gold quality
right lung	UBERON:0002167	57.18	gold quality
connective tissue	UBERON:0002384	57.17	gold quality
myocardium	UBERON:0002349	57.03	gold quality
fallopian tube	UBERON:0003889	56.88	gold quality
nucleus accumbens	UBERON:0001882	56.86	gold quality
cerebral cortex	UBERON:0000956	56.75	gold quality
muscle layer of sigmoid colon	UBERON:0035805	56.62	gold quality
putamen	UBERON:0001874	56.60	gold quality
caudate nucleus	UBERON:0001873	56.51	gold quality
body of uterus	UBERON:0009853	56.40	gold quality
body of pancreas	UBERON:0001150	56.24	gold quality
midbrain	UBERON:0001891	56.22	gold quality
buccal mucosa cell	CL:0002336	56.10	gold quality
telencephalon	UBERON:0001893	56.09	gold quality
nasal cavity epithelium	UBERON:0005384	56.07	gold quality
descending thoracic aorta	UBERON:0002345	56.06	gold quality
left coronary artery	UBERON:0001626	55.93	gold quality
testis	UBERON:0000473	55.84	gold quality
sigmoid colon	UBERON:0001159	55.73	gold quality
forebrain	UBERON:0001890	55.72	gold quality
thoracic aorta	UBERON:0001515	55.47	gold quality
prostate gland	UBERON:0002367	55.43	gold quality
coronary artery	UBERON:0001621	55.40	gold quality
left testis	UBERON:0004533	55.40	gold quality
ectocervix	UBERON:0012249	55.24	gold quality
esophagus	UBERON:0001043	55.20	gold quality
ascending aorta	UBERON:0001496	55.16	gold quality
central nervous system	UBERON:0001017	55.06	gold quality
tibial nerve	UBERON:0001323	55.02	gold quality
adenohypophysis	UBERON:0002196	54.98	gold quality
brain	UBERON:0000955	54.96	gold quality
right testis	UBERON:0004534	54.90	gold quality
corpus epididymis	UBERON:0004359	54.89	gold quality
right adrenal gland cortex	UBERON:0035827	54.85	gold quality
hypothalamus	UBERON:0001898	54.81	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	54.58	gold quality
urinary bladder	UBERON:0001255	54.55	gold quality
multicellular organism	UBERON:0000468	54.54	gold quality

Single-cell (SCXA)

Detected in 6 experiment(s), a significant marker in 6.

Experiment	Marker?	Max mean expression
E-CURD-6	yes	5635.34
E-GEOD-76312	yes	3624.53
E-MTAB-9067	yes	632.83
E-GEOD-130473	yes	442.59
E-ANND-3	yes	5.93
E-MTAB-9801	yes	5.88

HPA expression

RNA tissue specificity: Low tissue specificity

showing 60 of 75 HPA tissues / cells by nTPM:

Tissue / cell	Axis	nTPM
Corpus callosum	tissue	5.2
Nucleus accumbens	tissue	4.6
Locus coeruleus	tissue	3.9
Hippocampus	tissue	3.6
Choroid plexus	tissue	3.3
Postcentral gyrus	tissue	3.2
Medulla oblongata	tissue	2.2
Substantia nigra	tissue	2.2
Spinal cord	tissue	2.1
Ovary	tissue	1.9
Midbrain	tissue	1.9
Thalamus	tissue	1.7
Periaqueductal gray	tissue	1.7
Pons	tissue	1.6
Superior colliculi	tissue	1.6
Bone marrow	tissue	1.6
Ventral forebrain	tissue	1.5
Retina	tissue	1.4
Putamen	tissue	1.4
Hypothalamus	tissue	1.4
Olfactory bulb	tissue	1.3
Epididymis	tissue	1.2
Hippocampal formation	tissue	1.2
Testis	tissue	1.1
Cerebral cortex	tissue	1.1
Septum	tissue	1.1
Retrosplenial cortex	tissue	1.1
Prefrontal cortex	tissue	1.0
Motor cortex	tissue	1.0
Amygdala	tissue	1.0
Somatosensory cortex	tissue	1.0
Occipital cortex	tissue	1.0
Insular cortex	tissue	1.0
Heart muscle	tissue	0.9
Thyroid gland	tissue	0.9
Prostate	tissue	0.9
Frontal cortex	tissue	0.8
Retrosplenial and cingulate cortex	tissue	0.8
Fallopian tube	tissue	0.8
Seminal vesicle	tissue	0.7
Smooth muscle	tissue	0.7
Pancreas	tissue	0.7
Basal ganglia	tissue	0.7
Cerebellum	tissue	0.7
Entorhinal cortex	tissue	0.7
Temporal cortex	tissue	0.7
Skeletal muscle	tissue	0.6
Endometrium 1	tissue	0.6
Lung	tissue	0.6
Skin 1	tissue	0.5
Breast	tissue	0.5
Stomach 1	tissue	0.5
Adipose tissue	tissue	0.5
Esophagus	tissue	0.5
Pituitary gland	tissue	0.4
Salivary gland	tissue	0.4
Liver	tissue	0.4
Kidney	tissue	0.4
Adrenal gland	tissue	0.4
Cervix	tissue	0.3

Brain sub-regions (HPA Brain Atlas): detected in 189; highest nTPM — Parieto-temporal junction (white matter) (8.3), Temporal white matter (7.6), Corpus callosum, genu (white matter) (6.6), Corpus callosum, splenium (white matter) (6.4), Globus pallidus, internus (6.4).

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): ETS1, FLI1, GATA1, MBD2, PLAGL2, RUNX1, SP1, ZBTB16

miRNA regulators (miRDB)

Targeting MPL by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific).

showing 30 of 94 miRNAs:

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-30A-5P	100.00	76.31	3233
HSA-MIR-30B-5P	100.00	76.29	3248
HSA-MIR-30C-5P	100.00	76.29	3248
HSA-MIR-30D-5P	100.00	76.32	3233
HSA-MIR-30E-5P	100.00	76.32	3242
HSA-MIR-3689D	100.00	66.14	1181
HSA-MIR-6851-5P	100.00	65.63	1294
HSA-MIR-6867-5P	100.00	82.21	3464
HSA-MIR-1252-5P	100.00	69.80	2774
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-5696	99.98	72.36	4487
HSA-MIR-4267	99.96	66.53	2368
HSA-MIR-3658	99.96	73.87	4379
HSA-MIR-128-3P	99.95	71.17	2484
HSA-MIR-216A-3P	99.95	71.19	2505
HSA-MIR-6845-3P	99.94	66.88	1439
HSA-MIR-7-1-3P	99.91	71.53	4384
HSA-MIR-7-2-3P	99.91	71.40	4394
HSA-MIR-5680	99.91	69.83	3421
HSA-MIR-4493	99.90	66.48	977
HSA-MIR-4731-5P	99.89	67.23	2537
HSA-MIR-3681-3P	99.88	70.46	2254
HSA-MIR-6780A-5P	99.88	66.69	2776
HSA-MIR-3151-5P	99.86	63.83	1069
HSA-MIR-4447	99.85	67.81	2900
HSA-MIR-4728-5P	99.85	69.39	4718
HSA-MIR-6785-5P	99.82	68.68	4428
HSA-MIR-8080	99.82	67.52	1342
HSA-MIR-489-3P	99.80	66.46	839
HSA-MIR-636	99.80	69.58	1500

Functional genomics

gnomAD constraint: pLI 3.34e-21, LOEUF 1.02, missense Z 1.71 — population loss-of-function intolerance (pLI ≥ 0.9 = LoF-intolerant; lower LOEUF = more constrained). gnomAD

Regional missense constraint (gnomAD)

ENST00000372470 splits into 3 regions with different missense tolerance; 1 is missense-constrained (≈3% of the expected missense variation). Missense variants in a constrained region (low observed/expected) are more likely to be pathogenic. gnomAD

Region (GRCh38)	Missense obs / exp	o/e	Constrained
1:43,337,849–43,346,796	384 / 481.5	0.80	no
1:43,346,797–43,346,861	9 / 25.2	0.36	yes (p 1.3e-03)
1:43,346,862–43,352,769	266 / 276.3	0.96	no

Literature-anchored findings (GeneRIF, showing 40)

• binding to platelet thrombopoietin receptor is directly involved in human thrombopoietin plasma level regulation (PMID:11961237)
• expressed in megakaryocytes in essential thrombocythemia (PMID:12010817)
• The expression pattern of c-mpl in megakaryocytes correlates with thrombotic risk in essential thrombocythemia. (PMID:12091373)
• A new mutation of MPL, Trp(508) to Ser(508) in the intracellular domain of MPL, induces factor-independent growth in Ba/F3 cells & constitutively activates 3 distinct signaling pathways, SHC-Ras-Raf-MAPK/JNK, JAK-STAT, and PI3K-Akt-Bad. (PMID:12145691)
• The cytoplasmic domain of Mpl receptor transduces exclusive signals in embryonic and fetal hematopoietic cells. (PMID:12200367)
• Asn505 is an activating mutation with respect to the intracellular signaling and survival of cells in familial essential thrombocythemia deriving from a dominant-positive activating mutation of the c-MPL gene. (PMID:14764528)
• the promoter activity of myeloproliferative leukemia virus oncogene is modulated by transcription through a PKC-dependent pathway (PMID:14995067)
• c-Mpl truncated isoform with an essential C-terminal peptide is required for a proteolytic process (PMID:15210714)
• K39N represents an identified functional Mpl polymorphism and is associated with altered protein expression of Mpl and a clinical phenotype of thrombocytosis. (PMID:15269348)
• may play a role in hematopoietic inhibition during HIV-1 infection, and control of its expression levels may aid in hematopoietic recovery and thereby reduce the incidence of cytopenias occurring in infected individuals (PMID:15452260)
• expression of TPO receptor on platelets until 1 month after birth cause a decreased TPO clearance and keep a high level of free TPO in blood, resulting in the subsequent thrombocytosis in preterm infants. (PMID:15647951)
• a C-terminal AML1 mutation leads to a decrease in Mpl receptor expression in familial thrombocytopenia (PMID:15741216)
• Interaction with JAK2 or Tyk2 appears to protect the receptor from proteasome degradation. Sequences encompassing Box1 and Box2 regions of the receptor cytosolic domain and an intact JAK2 or Tyk2 FERM domain are required for these effects. (PMID:15899890)
• PRV-1 overexpression is associated with a significantly increased risk of thrombosis, whereas decreased c-Mpl expression is not (PMID:15951300)
• In this study, we report the binding of hNUDC to the extracellular domain of the thrombopoietin receptor (Mpl) as detected by the yeast two-hybrid system, GST pull-down, and co-immunoprecipitation. (PMID:16088917)
• in HIV infected patients, both the serum thrombopoietin (TPO) levels and the TPO-c-Mpl complexes on the platelet surface were significantly elevated (PMID:16454716)
• analysis of MPL mutations in patients suffering from congenital amegakaryocytic thrombocytopenia (PMID:16470591)
• Activation of JAK-STAT signaling via a somatic activating mutation in the transmembrane domain of MPL (MPLW515L) is an important pathogenetic event in patients with JAK2V617F-negative MF. (PMID:16834459)
• MPLW515L or MPLW515K mutations are present in patients with MMM or ET at a frequency of approximately 5% and 1%, respectively, but are not observed in patients with polycythemia vera (PV) or other myeloid disorders (PMID:16868251)
• expression of JAK2 stabilizes mature TpoR and thus further increases its surface expression. This JAK2 effect depends on the Box 1 region, the only JAK2 interacting site in the TpoR (PMID:17052978)
• The expression of mRNA of C-MPL in platelets is a clear band by RT-PCR methods. (PMID:17157161)
• THPO upregulates c-mpl expression during formation of CD34+ cells. (PMID:17379761)
• it was concluded that the oncogenic event in idiopathic myelofibrosis associated with the MPLW515L/K mutations probably occurs in a progenitor cell common to both myeloid and lymphoid cells, such as the pluripotent haematopoietic stem cell (PMID:17408398)
• MPL mutation in myelofibrosis characterises patients with more severe anaemic phenotype (PMID:17408465)
• MPLW515K, but not JAK2V617F, is expressed in in vitro expanded CD4+ T lymphocytes from primary myelofibrosis patients (PMID:17507998)
• Clonal myelopoiesis antedates acquisition of JAK2V617F or MPLW515L/K mutations. (PMID:17540852)
• hNUDC binds to cell surface-captured Mpl.Co-expression of Mpl-EGFP and hNUDC-DsRed led to the release of hNUDC-DsRed into the culture medium (PMID:17658515)
• Mutations in MPL is associated with congenital amegakaryocytic thrombocytopenia (PMID:17666371)
• The MPL W515L or K mutation induces a spontaneous megakaryocyte (MK) differentiation. (PMID:17709604)
• MPL gene mutations were not associated with erythrocytosis, but segregated primarily with the phenotypes of thrombocytosis, extramedullary disease, myelofibrosis, and osteosclerosis. (PMID:17920755)
• Expression of c-mpl in CD34+ BMHCs and platelets of polycythemia vera patients was not obviously abnormal. (PMID:17956691)
• no MPL (myeloproliferative leukemia virus oncogene thrombopoietin recept) W515L/K mutations were found in any patients with refractory anemia with ringed sideroblasts associated with marked thrombocytosis (RARS-T) (PMID:18040685)
• These data demonstrate that dimerization of a single cytokine receptor can deliver a profound expansion signal in both uncommitted and lymphoid-committed human hematopoietic progenitors. (PMID:18174381)
• diagnostic and prognostic value of JAK2 and MPL515 mutations in 241 SVT patients (PMID:18250227)
• Sp1 sites in the c-mpl promoter enhancer region and Ets elements in front of the transcription start site are critical for c-mpl gene expression. (PMID:18295514)
• review of roles of Jak2, Jak3, and MPL mutations in signal transduction and etiology of myeloid malignancies (PMID:18297515)
• a severe clinical course of congenital amegakaryocytic thrombocytopenia may be expected when mutations lead to absent Mpl expression or signalling in patients with missense mutations (PMID:18422784)
• MPL mutations lacked prognostic significance with respect to thrombosis, major hemorrhage, myelofibrotic transformation or survival. (PMID:18451306)
• MPL W515L mutations may contribute to the primary molecular pathogenesis of Chinese patients with ET (PMID:18464114)
• c-Mpl cytoplasmic YRRL motifs are responsible for both Tpo-mediated internalization via interactions with AP2 and lysosomal targeting after endocytosis. (PMID:18487512)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	mpl	ENSDARG00000039222
mus_musculus	Mpl	ENSMUSG00000006389
rattus_norvegicus	Mpl	ENSRNOG00000028377

Paralogs (7): IL4R (ENSG00000077238), CSF2RB (ENSG00000100368), IL2RB (ENSG00000100385), IL21R (ENSG00000103522), IL9R (ENSG00000124334), IL7R (ENSG00000168685), EPOR (ENSG00000187266)

Mouse-model phenotypes

Observed phenotypes of the mouse ortholog (MGI:97076) from MGI (Alliance of Genome Resources) — knockout/mutant phenotypes, ranked by annotation count. 36 distinct phenotype terms.

Mouse phenotype (MP)	Records
thrombocytopenia	6
enlarged spleen	3
abnormal megakaryocyte progenitor cell morphology	3
abnormal definitive hematopoiesis	2
increased mean platelet volume	2
thrombocytosis	2
absent megakaryocytes	2
decreased hematocrit	1
decreased leukocyte cell number	1
decreased neutrophil cell number	1
abnormal salivary gland morphology	1
abnormal spleen morphology	1
abnormal thymus morphology	1
enlarged thymus	1
abnormal vocalization	1
anemia	1
abnormal seminal vesicle morphology	1
abnormal skin morphology	1
abnormal bone marrow morphology	1
abnormal megakaryocyte morphology	1
decreased hemoglobin content	1
decreased erythrocyte cell number	1
enlarged seminal vesicle	1
abnormal heart left ventricle morphology	1
decreased hematopoietic stem cell number	1

+11 more (showing top 25).

Additional cross-species homologs

Sequence homologs in species beyond Ensembl Compara’s model organisms, by Diamond local protein alignment (% sequence identity; best hit per species). Lower-identity rows are more distant homologs. The matched accessions’ gene symbols aren’t in biobtree yet, so each row shows the UniProt accession.

Organism	UniProt	Identity	Method
Myeloproliferative leukemia virus	P40931	100.0%	Diamond

Genomic neighbors (locus context)

Genes flanking this one on the chromosome (NCBI/Entrez gene neighborhood). Positional context only — some neighbors share regulatory elements (bidirectional promoters, antisense/overlapping transcripts), but chromosomal adjacency is not itself a functional relationship (see Interactions for that).

Symbol	Type	Entrez
MIR6734	ncRNA	102466723
ELOVL1	protein-coding	64834
TIE1	protein-coding	7075
CDC20	protein-coding	991
CDC20-DT	ncRNA	105378687
TMEM125	protein-coding	128218
C1orf210	protein-coding	149466
CFAP57	protein-coding	149465

Protein

Protein identifiers

Thrombopoietin receptor — P40238 (reviewed: P40238)

Alternative names: Myeloproliferative leukemia protein, Proto-oncogene c-Mpl

All UniProt accessions (3): A0A2R8YE13, P40238, Q5JUY5

UniProt curated annotations — full annotation on UniProt →

Function. Receptor for thrombopoietin that regulates hematopoietic stem cell renewal, megakaryocyte differentiation, and platelet formation. Upon activation by THPO, induces rapid tyrosine phosphorylation and activation of JAK2, providing docking sites for many signaling proteins such as STAT5, SHIP/INPP5D, GRB2, SOS1 and PI3K. In turn, These signaling cascades lead to the proliferation, survival, and differentiation of megakaryocytes, ultimately leading to increased platelet production.

Subunit / interactions. Homodimer. Interacts with ATXN2L. Interacts with JAK2 and TYK2; these interactions increase MPL localization to the cell membrane. Interacts with THPO. Interacts with SHIP/INPP5D. Interacts with BTK. Interacts with SYK; this interaction negatively regulates THPO-mediated ERK1/2 signaling.

Subcellular location. Cell membrane. Golgi apparatus. Cell surface.

Tissue specificity. Expressed at a low level in a large number of cells of hematopoietic origin. Isoform 1 and isoform 2 are always found to be coexpressed.

Post-translational modifications. Phosphorylated at Tyr-591 in response to THPO stimulation. Ubiquitination at Lys-553 and Lys-573 targets MPL for degradation by both the lysosomal and proteasomal pathways. The E3 ubiquitin-protein ligase CBL significantly contributes to this ubiquitination.

Disease relevance. Amegakaryocytic thrombocytopenia, congenital, 1 (CAMT1) [MIM:604498] An autosomal recessive form of congenital amegakaryocytic thrombocytopenia, a hematologic disorder characterized by severe reduction of megakaryocytes and platelets at birth, and evolving into generalized bone marrow aplasia during childhood. The disease is caused by variants affecting the gene represented in this entry. Thrombocythemia 2 (THCYT2) [MIM:601977] A myeloproliferative disorder characterized by excessive platelet production, resulting in increased numbers of circulating platelets. It can be associated with spontaneous hemorrhages and thrombotic episodes. The disease is caused by variants affecting the gene represented in this entry. Myelofibrosis with myeloid metaplasia (MMM) [MIM:254450] A chronic myeloproliferative disorder characterized by replacement of the bone marrow by fibrous tissue, extramedullary hematopoiesis, anemia, leukoerythroblastosis and hepatosplenomegaly. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. The WSXWS motif appears to be necessary for proper protein folding and thereby efficient intracellular transport and cell-surface receptor binding. The box 1 motif is required for JAK interaction and/or activation.

Similarity. Belongs to the type I cytokine receptor family. Type 1 subfamily.

Isoforms (2)

UniProt ID	Names	Canonical?
P40238-1	1, C-mpl-P	yes
P40238-2	2, C-mpl-K

RefSeq proteins (1): NP_005364* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR003528	Long_hematopoietin_rcpt_CS	Conserved_site
IPR003961	FN3_dom	Domain
IPR013783	Ig-like_fold	Homologous_superfamily
IPR015152	Growth/epo_recpt_lig-bind	Domain
IPR036116	FN3_sf	Homologous_superfamily

Pfam: PF09067

UniProt features (91 total): strand 31, sequence variant 17, helix 10, disulfide bond 6, glycosylation site 4, modified residue 3, mutagenesis site 3, turn 3, topological domain 2, cross-link 2, splice variant 2, domain 2, short sequence motif 2, signal peptide 1, chain 1, transmembrane region 1, region of interest 1

Structure

Experimental structures (PDB)

1 structures by resolution:

PDB	Title	Method	Resolution (Å)
8G04	Structure of signaling thrombopoietin-MPL receptor complex	ELECTRON MICROSCOPY	3.4

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P40238-F1	73.44	0.33

Human Protein Atlas

Protein class: CD markers, Predicted membrane proteins, Predicted intracellular proteins, Cancer-related genes, Disease related genes, FDA approved drug targets, Biotech drugs, Small molecule drugs, Human disease related genes

Protein evidence: Evidence at protein level

Subcellular location (HPA, imaging): plasma membrane; nuclear membrane

Antibody reliability (HPA): IF supported

Functional residue map

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

Post-translational modifications (5)

Type	Positions
Phosphotyrosine	591, 626, 631
Glycyl lysine isopeptide (lys-gly) (interchain with g-cter in ubiquitin)	553, 573

Disulfide bonds (6)

Type	Positions
Disulfide bond	40–50, 77–93, 193–323, 194–241, 291–301, 334–352

Glycosylation sites (4)

Type	Positions
N-linked (glcnac…) asparagine	117, 178, 298, 358

Mutagenesis-validated functional residues (3)

Position	Phenotype
528	about 75% loss of cell surface expression; when associated with a-529.
529	about 75% loss of cell surface expression; when associated with a-528.
591	exhibits enhanced and prolonged erk1/2 activation upon thpo stimulation.

Function

Pathways and Gene Ontology

Reactome pathways

0 curated (TAS) of 3; 0 disease pathways. Curated-first; evidence = TAS (manually curated) vs IEA (electronic inference).

3 pathways:

ID	Pathway	Evidence
R-HSA-109582	Hemostasis	—
R-HSA-76009	Platelet Aggregation (Plug Formation)	electronic
R-HSA-76002	Platelet activation, signaling and aggregation	—

MSigDB gene sets: 305 (showing top): GOBP_MYELOID_CELL_DIFFERENTIATION, GOBP_REGULATION_OF_CELL_ACTIVATION, VERHAAK_AML_WITH_NPM1_MUTATED_DN, GOBP_REGULATION_OF_LEUKOCYTE_PROLIFERATION, GOBP_MYELOID_CELL_HOMEOSTASIS, GOBP_REGULATION_OF_CELL_MORPHOGENESIS, GOBP_RESPONSE_TO_PEPTIDE, REACTOME_PLATELET_AGGREGATION_PLUG_FORMATION, REACTOME_PLATELET_ACTIVATION_SIGNALING_AND_AGGREGATION, SP3_Q3, GOCC_CELL_SURFACE, BIOCARTA_TPO_PATHWAY, GOBP_POSITIVE_REGULATION_OF_LEUKOCYTE_PROLIFERATION, IRF7_01, GOBP_REGULATION_OF_HEMOPOIESIS

GO Biological Process (10): neutrophil homeostasis (GO:0001780), platelet formation (GO:0030220), monocyte homeostasis (GO:0035702), thrombopoietin-mediated signaling pathway (GO:0038163), positive regulation of lymphocyte proliferation (GO:0050671), cellular response to hypoxia (GO:0071456), regulation of hemopoiesis (GO:1903706), positive regulation of platelet formation (GO:1905221), eosinophil homeostasis (GO:1990959), basophil homeostasis (GO:1990960)

GO Molecular Function (3): thrombopoietin receptor activity (GO:0038164), cytokine receptor activity (GO:0004896), protein binding (GO:0005515)

GO Cellular Component (6): Golgi apparatus (GO:0005794), plasma membrane (GO:0005886), external side of plasma membrane (GO:0009897), cell surface (GO:0009986), neuronal cell body (GO:0043025), membrane (GO:0016020)

Reactome top-level categories

2 top-level categories:

Category	Pathways
Platelet activation, signaling and aggregation	1
Hemostasis	1

GO top-level categories

39 GO namespaces:

Category	Terms
leukocyte homeostasis	4
myeloid cell homeostasis	4
cellular anatomical structure	2
myeloid cell differentiation	1
platelet morphogenesis	1
anatomical structure formation involved in morphogenesis	1
chemokine-mediated signaling pathway	1
positive regulation of mononuclear cell proliferation	1
lymphocyte proliferation	1
regulation of lymphocyte proliferation	1
positive regulation of lymphocyte activation	1
response to hypoxia	1
cellular response to stress	1
cellular response to decreased oxygen levels	1
regulation of immune system process	1
hemopoiesis	1
regulation of cell development	1
regulation of multicellular organismal development	1
positive regulation of cell morphogenesis	1
platelet formation	1
positive regulation of myeloid cell differentiation	1
regulation of platelet formation	1
cytokine receptor activity	1
thrombopoietin-mediated signaling pathway	1
transmembrane signaling receptor activity	1
cytokine-mediated signaling pathway	1
cytokine binding	1
immune receptor activity	1
binding	1
cytoplasm	1
endomembrane system	1
intracellular membrane-bounded organelle	1
membrane	1
cell periphery	1
plasma membrane	1
cell surface	1
side of membrane	1
somatodendritic compartment	1
cell body	1

Experimentally-supported GO annotations

GO terms backed by direct experimental evidence (ECO experimental codes) — 6 of 19 annotations. The rest are phylogenetic / computational / electronic (IEA).

6 experimentally-supported GO terms:

GO term	NS	Evidence
regulation of hemopoiesis	BP	direct assay
thrombopoietin-mediated signaling pathway	BP	direct assay
Golgi apparatus	CC	direct assay
cell surface	CC	direct assay
plasma membrane	CC	direct assay
thrombopoietin receptor activity	MF	mutant phenotype

Protein interactions and networks

STRING

showing 15 of 868 interactions by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
MPL	THPO	P40225	967
MPL	CD34	P28906	779
MPL	KITLG	P21583	764
MPL	JAK2	O60674	750
MPL	SH2B3	Q9UQQ2	743
MPL	CALR	P27797	719
MPL	ITGA2B	P08514	700
MPL	CSF3	P09919	680
MPL	KIT	P10721	670
MPL	NUDC	Q9Y266	663
MPL	EPO	P01588	652
MPL	TET2	Q6N021	634
MPL	CD38	P28907	609
MPL	IL3	P08700	606
MPL	IL3RA	P26951	585

IntAct

Human interaction partners of MPL in IntAct, one row per partner (best MIscore; records = supporting IntAct interaction records).

7 partners by confidence:

Partner	Interaction type	MIscore	Records
THPO	direct interaction	0.600	3
JAK2	physical association	0.520	6
EGFR	proximity	0.480	1
ATXN2L	physical association	0.370	2
FAM171A2	association	0.350	1
PTEN	proximity	0.270	1
TP53	proximity	0.270	1

BioGRID (38 interactions; top human partners by supporting records): ATXN2L (Two-hybrid; 2 records), SOCS1 (Affinity Capture-MS; 2 records), ACOT9 (Affinity Capture-MS), ALCAM (Affinity Capture-MS), ALX1 (Affinity Capture-MS), ANKRA2 (Protein-peptide), ATP2A3 (Affinity Capture-MS), BAG3 (Affinity Capture-Luminescence), BTN2A2 (Affinity Capture-MS), C17orf70 (Affinity Capture-MS), CCDC51 (Affinity Capture-MS), CISD2 (Affinity Capture-MS), CTDNEP1 (Affinity Capture-MS), CTH (Affinity Capture-MS), EGFR (Affinity Capture-MS)

SIGNOR signaling

4 signaling interactions:

A	Effect	B	Mechanism
ATXN2L	down-regulates	MPL	binding
THPO	up-regulates	MPL	binding
GATA1	“up-regulates quantity by expression”	MPL	“transcriptional regulation”
FLI1	“up-regulates quantity by expression”	MPL	“transcriptional regulation”

Protein complexes (CORUM) (1)

Experimentally-characterized complexes this protein is a subunit of (★ = the complex contains a known drug target).

1 complexes by size:

Complex	Subunits	Members
★ MPL-THPO complex	2	MPL, THPO

Ligand–receptor pairs (CellPhoneDB) (1)

Curated ligand–receptor partners (cell-cell communication), distinct from the protein–protein interactions above.

1 ligand–receptor pairs:

Partner	This gene’s role	Signaling class
THPO	receptor

Disease & clinical

Cancer significance

From intOGen — cancer-driver classification: ambiguous (mixed evidence) across 1 cancer types — HNSC.

intOGen’s role is a computational inference from cohort mutation patterns and may diverge from the gene’s curated/literature role; read it alongside the evidence above.

Genetic variants

Variant evidence for MPL: 966 ClinVar records (169 pathogenic / likely pathogenic); 11 GWAS associations. Per-variant detail is on Sugi Variant.

ClinVar

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

Classification	Count (floor)
Pathogenic	76
Likely pathogenic	93
Uncertain significance	312
Likely benign	377
Benign	13

Top pathogenic / likely-pathogenic (15)

Showing the 15 best-reviewed of 169 pathogenic / likely-pathogenic ClinVar records, ranked by ClinVar review status (expert panel → multiple submitters → single submitter), then by number of submitting labs.

Variant ID	HGVS	Classification	Review	Submitters
14158	NM_005373.3(MPL):c.305G>C (p.Arg102Pro)	Pathogenic	criteria provided, multiple submitters, no conflicts	26
371574	NM_005373.3(MPL):c.127C>T (p.Arg43Ter)	Pathogenic	criteria provided, multiple submitters, no conflicts	12
134822	NM_005373.3(MPL):c.235_236del (p.Leu79fs)	Pathogenic	criteria provided, multiple submitters, no conflicts	10
265249	NM_005373.3(MPL):c.378del (p.Phe126fs)	Pathogenic	criteria provided, multiple submitters, no conflicts	10
956954	NM_005373.3(MPL):c.268C>T (p.Arg90Ter)	Pathogenic	criteria provided, multiple submitters, no conflicts	7
14163	NM_005373.3(MPL):c.1514G>A (p.Ser505Asn)	Pathogenic	criteria provided, multiple submitters, no conflicts	5
14154	NM_005373.3(MPL):c.556C>T (p.Gln186Ter)	Pathogenic	criteria provided, multiple submitters, no conflicts	4
1301356	NM_005373.3(MPL):c.367C>T (p.Arg123Ter)	Pathogenic	criteria provided, multiple submitters, no conflicts	4
660904	NM_005373.3(MPL):c.1069C>T (p.Arg357Ter)	Pathogenic	criteria provided, multiple submitters, no conflicts	3
2940570	NM_005373.3(MPL):c.417dup (p.Lys140fs)	Pathogenic	criteria provided, multiple submitters, no conflicts	2
665962	NM_005373.3(MPL):c.981-1G>C	Likely pathogenic	criteria provided, multiple submitters, no conflicts	4
2445438	NM_005373.3(MPL):c.407C>G (p.Pro136Arg)	Likely pathogenic	criteria provided, multiple submitters, no conflicts	4
1379348	NM_005373.3(MPL):c.407C>A (p.Pro136His)	Likely pathogenic	criteria provided, multiple submitters, no conflicts	3
1492963	NM_005373.3(MPL):c.1566-1G>A	Likely pathogenic	criteria provided, multiple submitters, no conflicts	3
1523230	NM_005373.3(MPL):c.1166-1G>C	Likely pathogenic	criteria provided, multiple submitters, no conflicts	3

Per-variant reference — Sugi Variant

Explore MPL’s pathogenic and likely-pathogenic variants individually — each with its ClinVar classification and conditions, applied ACMG criteria (ClinGen expert panel, where curated), the calibrated in-silico predictors (AlphaMissense, REVEL, SaProt, conservation), gnomAD frequency, and the predictor-disagreement QC signal — on Sugi Variant.

SpliceAI

Top 10 splice-impact sites by Δscore (adjacent positions with the same effect merged into one range; 24 predictions of 1,206):

Position(s)	Effect	Δscore	Sites
1:43339962	acceptor_gain	0.9900
1:43349051	donor_gain	0.9900
1:43337928–43337929	donor_loss	0.9800	5
1:43338540–43338541	acceptor_loss	0.9800	4
1:43338721–43338722	donor_loss	0.9800	5
1:43337929	donor_loss	0.9700
1:43338539–43338541	acceptor_loss	0.9700	3
1:43349009	donor_gain	0.9700
1:43337927	donor_loss	0.9600
1:43338155	acceptor_gain	0.9600	2

AlphaMissense

690 missense substitutions predicted likely pathogenic (of 4,079 scored), across 205 residues. Top 20 hotspot residues, ranked by the number of likely-pathogenic substitutions (of those reachable by a single-nucleotide change), then by mean score:

Residue	Likely-pathogenic substitutions	Mean am_pathogenicity	Max am_pathogenicity
F383	8	0.867	0.969
F354	8	0.857	0.968
C301	7	0.966	0.983
C291	7	0.959	0.983
C50	7	0.957	0.981
C93	7	0.950	0.977
W477	7	0.950	0.992
W474	7	0.937	0.989
W410	7	0.936	0.990
C352	7	0.935	0.975
C40	7	0.932	0.976
F45	7	0.929	0.974
C77	7	0.929	0.967
W52	7	0.922	0.992
F104	7	0.917	0.974
W303	7	0.914	0.993
C334	7	0.909	0.947
W272	7	0.895	0.980
W154	7	0.893	0.978
W435	7	0.872	0.972

HPA cancer prognostics

RNA cancer specificity: Low cancer specificity

Human Protein Atlas survival analysis — favorable = higher expression predicts better survival.

1 prognostic cancer types:

Cancer	Prognostic	p-value
Kidney Renal Papillary Cell Carcinoma (TCGA)	favorable	0.000169

Disease associations

OMIM: gene MIM:159530 | disease phenotypes: MIM:604498, MIM:254450, MIM:601977, MIM:613688

GenCC curated gene-disease

4 curated gene-disease records:

Disease	Classification	Inheritance	Records
thrombocythemia 2	Definitive	Autosomal dominant	5
congenital amegakaryocytic thrombocytopenia	Definitive	Autosomal recessive	3
congenital amegakaryocytic thrombocytopenia 1	Strong	Autosomal recessive
familial thrombocytosis	Supportive	Autosomal dominant

ClinGen Gene-Disease Validity

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

2 validity classifications:

Disease	Classification	Inheritance
thrombocythemia 2	Definitive	AD
congenital amegakaryocytic thrombocytopenia 1	Definitive	AR

Genomics England panels (PanelApp)

Clinical diagnostic gene panels including this gene (6 panels, 5 green/diagnostic-grade). Confidence: green = diagnostic, amber = moderate.

6 panels:

Panel	Rating
Bleeding and platelet disorders	green
Cytopenia - NOT Fanconi anaemia	green
Cytopenias and congenital anaemias	green
Inherited bleeding disorders	green
Thrombocythaemia	green
Fetal anomalies	amber

Mondo (10): essential thrombocythemia (MONDO:0005029), congenital amegakaryocytic thrombocytopenia (MONDO:0800451), primary myelofibrosis (MONDO:0009692), thrombocythemia 2 (MONDO:0011173), congenital amegakaryocytic thrombocytopenia 1 (MONDO:0800452), thrombocytopenia (MONDO:0002049), long QT syndrome 2 (MONDO:0013367), myelofibrosis with myeloid metaplasia (MONDO:0800305), (MONDO:0011469), familial thrombocytosis (MONDO:0019111)

Orphanet (5): Essential thrombocythemia (Orphanet:3318), Congenital amegakaryocytic thrombocytopenia (Orphanet:3319), Primary myelofibrosis (Orphanet:824), Romano-Ward syndrome (Orphanet:101016), Congenital long QT syndrome (Orphanet:768)

HPO phenotypes

showing 60 of 80 phenotypes (HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000007	Autosomal recessive inheritance
HP:0000505	Visual impairment
HP:0000967	Petechiae
HP:0000975	Hyperhidrosis
HP:0000978	Bruising susceptibility
HP:0000979	Purpura
HP:0000980	Pallor
HP:0000989	Pruritus
HP:0001028	Hemangioma
HP:0001123	Visual field defect
HP:0001250	Seizure
HP:0001260	Dysarthria
HP:0001279	Syncope
HP:0001320	Cerebellar vermis hypoplasia
HP:0001409	Portal hypertension
HP:0001433	Hepatosplenomegaly
HP:0001442	Typified by somatic mosaicism
HP:0001658	Myocardial infarction
HP:0001744	Splenomegaly
HP:0001824	Weight loss
HP:0001871	Abnormality of blood and blood-forming tissues
HP:0001872	Abnormality of thrombocytes
HP:0001873	Thrombocytopenia
HP:0001876	Pancytopenia
HP:0001892	Abnormal bleeding
HP:0001894	Thrombocytosis
HP:0001903	Anemia
HP:0001945	Fever
HP:0001974	Increased total leukocyte count
HP:0001977	Abnormal thrombosis
HP:0001978	Extramedullary hematopoiesis
HP:0002039	Anorexia
HP:0002076	Migraine
HP:0002092	Pulmonary arterial hypertension
HP:0002240	Hepatomegaly
HP:0002315	Headache
HP:0002321	Vertigo
HP:0002326	Transient ischemic attack
HP:0002488	Acute leukemia
HP:0002637	Cerebral ischemia
HP:0002716	Lymphadenopathy
HP:0002863	Myelodysplasia
HP:0003010	Prolonged bleeding time
HP:0003388	Easy fatigability
HP:0003401	Paresthesia
HP:0003593	Infantile onset
HP:0004326	Cachexia
HP:0004377	Hematological neoplasm
HP:0004420	Arterial thrombosis
HP:0004447	Poikilocytosis
HP:0004808	Acute myeloid leukemia
HP:0004859	Amegakaryocytic thrombocytopenia
HP:0004936	Venous thrombosis
HP:0004950	Peripheral arterial stenosis
HP:0005268	Miscarriage
HP:0005506	Chronic myelogenous leukemia
HP:0005513	Increased megakaryocyte count
HP:0005547	Myeloproliferative disorder
HP:0005548	Megakaryocytopenia

GWAS associations

11 associations:

Study	Trait	p-value
GCST90002400_411	Plateletcrit	6e-24
GCST90002400_412	Plateletcrit	9e-17
GCST010702_132	Subcortical volume (MOSTest)	8e-15
GCST010699_67	Brain morphology (min-P)	9e-14
GCST90002402_541	Platelet count	5e-13
GCST010703_251	Brain morphology (MOSTest)	1e-11
GCST010700_24	Cortical thickness (MOSTest)	1e-10
GCST010698_88	Subcortical volume (min-P)	3e-9
GCST010701_124	Cortical surface area (MOSTest)	1e-8
GCST010696_20	Cortical thickness (min-P)	3e-8
GCST010697_7	Cortical surface area (min-P)	4e-8

EFO canonical traits (from GWAS)

4 canonical traits:

EFO ID	Trait name
EFO:0004346	neuroimaging measurement
EFO:0004840	cortical thickness
EFO:0007985	platelet crit
EFO:0004309	platelet count

MeSH disease descriptors

5 disease descriptors:

Descriptor	Name	Tree numbers
D055728	Primary Myelofibrosis	C15.378.190.636.765
D013920	Thrombocythemia, Essential	C15.378.100.832; C15.378.140.860.800; C15.378.190.636.860.800; C15.378.463.825
D013921	Thrombocytopenia	C15.378.140.855; C15.378.243.937
C535982	Congenital amegakaryocytic thrombocytopenia *(supp.)*
C563614	Long Qt Syndrome 2 *(supp.)*

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL1864 (SINGLE PROTEIN)

Drugs by curated mechanism of action (ChEMBL)

Drugs whose curated ChEMBL mechanism of action targets the MPL protein itself — single-protein targets only (drugs acting on a protein family or complex that merely includes it are excluded). Includes antibodies and oligonucleotides that bioactivity screening does not capture.

7 curated-mechanism drugs:

Drug	Modality	Max phase
AVATROMBOPAG	Small molecule	4
ELTROMBOPAG CHOLINE	Small molecule	4
ELTROMBOPAG OLAMINE	Small molecule	4
LUSUTROMBOPAG	Small molecule	4
ROMIPLOSTIM	Protein	4
HETROMBOPAG OLAMINE	Unknown	3
RAFUTROMBOPAG	Small molecule	3

Molecules with ChEMBL bioactivity

Phase ≥1, by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 757 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

2 molecules by phase:

Molecule	Name	Phase	Patents
CHEMBL2107831	LUSUTROMBOPAG	4	132
CHEMBL461101	ELTROMBOPAG	4	625

PharmGKB: 1 entry (CPIC guideline: no)

GtoPdb / IUPHAR curated pharmacology

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

Target class: catalytic receptor — Prolactin receptor family

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

Ligand	Action	Affinity	Parameter
eltrombopag	Agonist	7.42	pEC50

Binding affinities (BindingDB)

241 measured of 289 human assays (289 total across all organisms); most potent 50 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value
1-(2-(1-(1-(2,3-dihydro-1H-inden-5-yl)-3-methyl-5-oxo-1H-pyrazol-4(5H)-ylidene)ethyl)hydrazinecarbonothioyl)indoline-5-carboxylic acid	EC50	3 nM
1-(2-(1-(1-(3,4-dimethylphenyl)-3-methyl-5-oxo-1H-pyrazol-4(5H)-ylidene)ethyl)hydrazinecarbonothioyl)indoline-5-carboxylic acid	EC50	6 nM
N-(4-(2-fluoro-3-(trifluoromethoxy)phenyl)thiazol-2-yl)-4-(6-(3-hydroxyazetidin-1-yl)pyrimidin-4-ylamino)benzamide	EC50	7 nM
N-(4-(2-fluoro-3-(trifluoromethyl)phenyl)thiazol-2-yl)-4-(6-(3-hydroxyazetidin-1-yl)pyrimidin-4-ylamino)benzamide	EC50	9 nM
1-(2,6-dichloro-4-(4-(2-fluoro-3-(trifluoromethyl)phenyl)thiazol-2-ylcarbamoyl)phenyl)piperidine-4-carboxylic acid	EC50	10 nM
N-(5-chloro-4-(4-fluoro-3-(trifluoromethyl)phenyl)thiazol-2-yl)-4-(6-(dimethylamino)pyrimidin-4-ylamino)benzamide	EC50	11 nM
N-(3-(4-fluoro-3-(trifluoromethyl)phenyl)-1,2,4-thiadiazol-5-yl)-4-(6-(3-hydroxyazetidin-1-yl)pyrimidin-4-ylamino)benzamide	EC50	13 nM
4-{N’-[1-(4-tert-Butyl-phenyl)-3-methyl-5-oxo-1,5-dihydro-pyrazol-4-ylidene]-hydrazino}-3-hydroxy-naphthalene-1-sulfonic acid	EC50	20 nM
2-(7-(4-butylphenyl)-6-fluoro-5,10-dihydroindeno[1,2-b]indol-2-ylamino)-2-oxoacetic acid	EC50	21 nM
N-(4-(2-fluoro-3-(trifluoromethyl)phenyl)thiazol-2-yl)-4-(6-((2-hydroxyethyl)(methyl)amino)pyrimidin-4-ylamino)benzamide	EC50	22 nM
1-(2-(1-(1-(3,4-dimethylphenyl)-3-methyl-5-oxo-1H-pyrazol-4(5H)-ylidene)ethyl)hydrazinecarbonothioyl)-N-methylindoline-5-carboxamide	EC50	22 nM
4-(6-(azetidin-1-yl)pyrimidin-4-ylamino)-N-(4-(2-fluoro-3-(trifluoromethyl)phenyl)thiazol-2-yl)benzamide	EC50	23 nM
N-(7-(4-butylphenyl)-6-fluoro-5,10-dihydroindeno[1,2-b]indol-2-yl)acetamide	EC50	25 nM
9-(4-butylphenyl)-2-hydroxy-6,11-dihydro-5H-benzo[a]carbazole-3-carboxylic acid	EC50	26 nM
6-fluoro-7-(4-fluoro-3-methylphenyl)-5,10-dihydroindeno[1,2-b]indole-2-carboxylic acid	EC50	26 nM
1-(2-(1-(1-(3,4-dimethylphenyl)-3-methyl-5-oxo-1H-pyrazol-4(5H)-ylidene)ethyl)hydrazinecarbonothioyl)-N-ethylindoline-5-carboxamide	EC50	26 nM
4-(pyrimidin-4-ylamino)-N-(7-trifluoromethyl-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-2-yl)-benzamide	EC50	27 nM
(Z)-N-(4-(3,4-difluorophenyl)thiazol-2-yl)-4-((2,4-dioxothiazolidin-5-ylidene)methyl)benzamide	EC50	28 nM
6-(4-carbamoylpiperidin-1-yl)-5-chloro-N-(4-(2-fluoro-3-(trifluoromethyl)phenyl)thiazol-2-yl)nicotinamide	EC50	28 nM
N-(3-(4-fluoro-3-(trifluoromethyl)phenyl)-1,2,4-thiadiazol-5-yl)-4-(6-((2-hydroxy-1-(hydroxyamino)ethyl)(methyl)amino)pyrimidin-4-ylamino)benzamide	EC50	29 nM
N-(3-(4-fluoro-3-(trifluoromethyl)phenyl)-1,2,4-thiadiazol-5-yl)-4-(6-(2-hydroxyethylamino)pyrimidin-4-ylamino)benzamide	EC50	30 nM
N’-(1-(1-(3,4-dimethylphenyl)-3-methyl-5-oxo-1H-pyrazol-4(5H)-ylidene)ethyl)-5-(morpholine-4-carbonyl)indoline-1-carbothiohydrazide	EC50	31 nM
N-(4-(2-fluoro-3-(trifluoromethoxy)phenyl)thiazol-2-yl)-4-(pyrimidin-4-ylamino)benzamide	EC50	32 nM
CHEMBL408853	EC50	32 nM
N-(4-(2,4-difluoro-3-(trifluoromethyl)phenyl)thiazol-2-yl)-4-(pyrimidin-4-ylamino)benzamide	EC50	33 nM
1-(3-chloro-5-(4-(2-fluoro-3-(trifluoromethyl)phenyl)thiazol-2-ylcarbamoyl)pyridin-2-yl)piperidine-4-carboxylic acid	EC50	33 nM
5-chloro-N-(4-(2-fluoro-3-(trifluoromethyl)phenyl)thiazol-2-yl)-6-(4-sulfamoylpiperidin-1-yl)nicotinamide	EC50	34 nM
N-(4-(2-fluoro-3-isobutylphenyl)thiazol-2-yl)-4-(pyrimidin-4-ylamino)benzamide	EC50	35 nM
9-(4-fluoro-3-methylphenyl)-2-hydroxy-6,11-dihydro-5H-benzo[a]carbazole-3-carboxylic acid	EC50	35 nM
1-(2-(1-(1-(2,3-dihydro-1H-inden-5-yl)-3-methyl-5-oxo-1H-pyrazol-4(5H)-ylidene)ethyl)hydrazinecarbonothioyl)-1,2,3,4-tetrahydroquinoline-6-carboxylic acid	EC50	35 nM
6-fluoro-7-(4-propylphenyl)-5,10-dihydroindeno[1,2-b]indole-2-carboxylic acid	EC50	37 nM
N-(4-(2-fluoro-3-(trifluoromethyl)phenyl)thiazol-2-yl)-4-(6-methoxypyrimidin-4-ylamino)benzamide	EC50	38 nM
3-Hydroxy-4-{N’-[3-methyl-5-oxo-1-(3-trifluoromethyl-phenyl)-1,5-dihydro-pyrazol-4-ylidene]-hydrazino}-naphthalene-1-sulfonic acid	EC50	40 nM
4-{N’-[1-(3,4-Dimethyl-phenyl)-3-methyl-5-oxo-1,5-dihydro-pyrazol-4-ylidene]-hydrazino}-3-hydroxy-naphthalene-1-sulfonic acid	EC50	40 nM
2-hydroxy-9-(4-propoxyphenyl)-6,11-dihydro-5H-benzo[a]carbazole-3-carboxylic acid	EC50	41 nM
1-(2-(1-(1-(3,4-dimethylphenyl)-3-methyl-5-oxo-1H-pyrazol-4(5H)-ylidene)ethyl)hydrazinecarbonyl)indoline-5-carboxylic acid	EC50	42 nM
4-(6-(dimethylamino)pyrimidin-4-ylamino)-N-(3-(4-fluoro-3-(trifluoromethyl)phenyl)-1,2,4-thiadiazol-5-yl)benzamide	EC50	43 nM
N-(4-(2-fluoro-3-(trifluoromethyl)phenyl)thiazol-2-yl)-4-(6-methylpyrimidin-4-ylamino)benzamide	EC50	43 nM
(4R)-1-(3-chloro-5-(4-(2-fluoro-3-(trifluoromethyl)phenyl)thiazol-2-ylcarbamoyl)pyridin-2-yl)-4-methylpyrrolidine-3-carboxylic acid	EC50	43 nM
2-hydroxy-9-(3-propoxyphenyl)-6,11-dihydro-5H-benzo[a]carbazole-3-carboxylic acid	EC50	43 nM
4-(2-(1-(5-fluoro-2-oxo-1-p-tolylindolin-3-ylidene)ethyl)hydrazinecarbonothioyl)benzoic acid	EC50	44 nM
4-(6-(dimethylamino)pyrimidin-4-ylamino)-N-(4-(4-fluoro-3-(trifluoromethyl)phenyl)-5-methylthiazol-2-yl)benzamide	EC50	45 nM
1-(2-(1-(1-(2,3-dihydro-1H-inden-5-yl)-3-methyl-5-oxo-1H-pyrazol-4(5H)-ylidene)ethyl)hydrazinecarbonyl)indoline-5-carboxylic acid	EC50	46 nM
1-(3-bromo-5-(4-(2-fluoro-3-(trifluoromethyl)phenyl)thiazol-2-ylcarbamoyl)pyridin-2-yl)piperidine-4-carboxylic acid	EC50	50 nM
4-(6-(4-butylphenyl)-7-fluoro-1H-indol-2-yl)-2-hydroxybenzoic acid	EC50	51 nM
N-(4-(3-butyl-2-fluorophenyl)thiazol-2-yl)-4-(pyrimidin-4-ylamino)benzamide	EC50	53 nM
4-(6-(dimethylamino)pyrimidin-4-ylamino)-N-(4-(2-fluoro-3-(trifluoromethyl)phenyl)thiazol-2-yl)benzamide	EC50	54 nM
9-(4-butylphenyl)-10-fluoro-6,11-dihydro-5H-benzo[a]carbazole-3-carboxylic acid	EC50	55 nM
1-(2-chloro-4-(4-(2-fluoro-3-(trifluoromethyl)phenyl)thiazol-2-ylcarbamoyl)phenyl)piperidine-4-carboxylic acid	EC50	56 nM
(R)-2-(3-chloro-5-(4-(2-fluoro-3-(trifluoromethyl)phenyl)thiazol-2-ylcarbamoyl)pyridin-2-ylamino)propanoic acid	EC50	57 nM

ChEMBL bioactivities

281 potent at pChembl≥5 of 281 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
10.05	ED50	0.09	nM	CHEMBL3924507
8.96	ED50	1.09	nM	LUSUTROMBOPAG
8.85	ED50	1.4	nM	CHEMBL3961997
8.68	ED50	2.08	nM	CHEMBL3959282
8.52	EC50	3	nM	CHEMBL1257604
8.51	ED50	3.09	nM	CHEMBL3910159
8.22	EC50	6	nM	CHEMBL1257603
8.15	EC50	7	nM	CHEMBL429295
8.05	EC50	9	nM	CHEMBL248218
8.00	EC50	10	nM	CHEMBL455654
7.96	EC50	11	nM	CHEMBL248390
7.89	EC50	13	nM	CHEMBL249471
7.70	EC50	20	nM	CHEMBL3144775
7.68	EC50	21	nM	CHEMBL498173
7.66	EC50	22	nM	CHEMBL440231
7.66	EC50	22	nM	CHEMBL1257846
7.64	EC50	23	nM	CHEMBL248217
7.60	EC50	25	nM	CHEMBL498581
7.58	EC50	26	nM	CHEMBL496123
7.58	EC50	26	nM	CHEMBL479081
7.58	EC50	26	nM	CHEMBL1257962
7.57	EC50	27	nM	CHEMBL245795
7.55	EC50	28	nM	CHEMBL251095
7.55	EC50	28	nM	CHEMBL462874
7.54	EC50	29	nM	CHEMBL249672
7.52	EC50	30	nM	CHEMBL248428
7.51	EC50	31	nM	CHEMBL1257847
7.50	EC50	32	nM	CHEMBL247606
7.50	EC50	32	nM	CHEMBL408853
7.48	EC50	33	nM	CHEMBL247645
7.48	EC50	33	nM	CHEMBL523975
7.47	EC50	34	nM	CHEMBL516993
7.46	EC50	35	nM	CHEMBL247041
7.46	EC50	35	nM	CHEMBL477381
7.46	EC50	35	nM	CHEMBL1257724
7.43	EC50	37	nM	CHEMBL496122
7.42	EC50	38	nM	CHEMBL246847
7.42	EC50	38	nM	ELTROMBOPAG
7.40	EC50	40	nM	CHEMBL3144844
7.40	EC50	40	nM	CHEMBL3144661
7.39	EC50	41	nM	CHEMBL518285
7.38	EC50	42	nM	CHEMBL1257963
7.37	EC50	43	nM	CHEMBL245794
7.37	EC50	43	nM	CHEMBL247240
7.37	EC50	43	nM	CHEMBL461174
7.37	EC50	43	nM	CHEMBL479083
7.36	EC50	44	nM	CHEMBL1222640
7.35	EC50	45	nM	CHEMBL248389
7.34	EC50	46	nM	CHEMBL1258074
7.30	EC50	50	nM	CHEMBL459474

PubChem BioAssay actives

276 with measured affinity, of 555 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
1-[[(E)-1-[2-(2,3-dihydro-1H-inden-5-yl)-5-methyl-3-oxo-1H-pyrazol-4-yl]ethylideneamino]carbamothioyl]-2,3-dihydroindole-5-carboxylic acid	516716: Inhibition of human TPOR expressed in human BaF3 cells	ec50	0.0030	uM
1-[[(E)-1-[2-(3,4-dimethylphenyl)-5-methyl-3-oxo-1H-pyrazol-4-yl]ethylideneamino]carbamothioyl]-2,3-dihydroindole-5-carboxylic acid	516716: Inhibition of human TPOR expressed in human BaF3 cells	ec50	0.0060	uM
N-[4-[2-fluoro-3-(trifluoromethoxy)phenyl]-1,3-thiazol-2-yl]-4-[[6-(3-hydroxyazetidin-1-yl)pyrimidin-4-yl]amino]benzamide	309208: Agonist activity at human TPOr expressed in BaF3 cells by reporter assay	ec50	0.0070	uM
N-[4-[2-fluoro-3-(trifluoromethyl)phenyl]-1,3-thiazol-2-yl]-4-[[6-(3-hydroxyazetidin-1-yl)pyrimidin-4-yl]amino]benzamide	309208: Agonist activity at human TPOr expressed in BaF3 cells by reporter assay	ec50	0.0090	uM
1-[2,6-dichloro-4-[[4-[2-fluoro-3-(trifluoromethyl)phenyl]-1,3-thiazol-2-yl]carbamoyl]phenyl]piperidine-4-carboxylic acid	395498: Agonist activity at human thrombopoietin receptor transfected in mouse BAF3 cells assessed as stimulation of beta lactamase activity incubated in dark up to 1 hr	ec50	0.0100	uM
N-[5-chloro-4-[4-fluoro-3-(trifluoromethyl)phenyl]-1,3-thiazol-2-yl]-4-[[6-(dimethylamino)pyrimidin-4-yl]amino]benzamide	309208: Agonist activity at human TPOr expressed in BaF3 cells by reporter assay	ec50	0.0110	uM
N-[3-[4-fluoro-3-(trifluoromethyl)phenyl]-1,2,4-thiadiazol-5-yl]-4-[[6-(3-hydroxyazetidin-1-yl)pyrimidin-4-yl]amino]benzamide	309208: Agonist activity at human TPOr expressed in BaF3 cells by reporter assay	ec50	0.0130	uM
4-[[2-(4-tert-butylphenyl)-5-methyl-3-oxo-1H-pyrazol-4-yl]diazenyl]-3-hydroxynaphthalene-1-sulfonic acid	210168: Effective concentration for thrombopoietin luciferase activity was determined in BAF-3 cells	ec50	0.0200	uM
2-[[7-(4-butylphenyl)-6-fluoro-5,10-dihydroindeno[1,2-b]indol-2-yl]amino]-2-oxoacetic acid	349040: Agonist activity at human thrombopoietin receptor expressed in mouse Ba/F3 cells by kinase activation based reporter gene assay	ec50	0.0210	uM
1-[[(E)-1-[2-(3,4-dimethylphenyl)-5-methyl-3-oxo-1H-pyrazol-4-yl]ethylideneamino]carbamothioyl]-N-methyl-2,3-dihydroindole-5-carboxamide	516716: Inhibition of human TPOR expressed in human BaF3 cells	ec50	0.0220	uM
N-[4-[2-fluoro-3-(trifluoromethyl)phenyl]-1,3-thiazol-2-yl]-4-[[6-[2-hydroxyethyl(methyl)amino]pyrimidin-4-yl]amino]benzamide	309208: Agonist activity at human TPOr expressed in BaF3 cells by reporter assay	ec50	0.0220	uM
4-[[6-(azetidin-1-yl)pyrimidin-4-yl]amino]-N-[4-[2-fluoro-3-(trifluoromethyl)phenyl]-1,3-thiazol-2-yl]benzamide	309208: Agonist activity at human TPOr expressed in BaF3 cells by reporter assay	ec50	0.0230	uM
N-[7-(4-butylphenyl)-6-fluoro-5,10-dihydroindeno[1,2-b]indol-2-yl]acetamide	349040: Agonist activity at human thrombopoietin receptor expressed in mouse Ba/F3 cells by kinase activation based reporter gene assay	ec50	0.0250	uM
1-[[(E)-1-[2-(3,4-dimethylphenyl)-5-methyl-3-oxo-1H-pyrazol-4-yl]ethylideneamino]carbamothioyl]-N-ethyl-2,3-dihydroindole-5-carboxamide	516716: Inhibition of human TPOR expressed in human BaF3 cells	ec50	0.0260	uM
6-fluoro-7-(4-fluoro-3-methylphenyl)-5,10-dihydroindeno[1,2-b]indole-2-carboxylic acid	349040: Agonist activity at human thrombopoietin receptor expressed in mouse Ba/F3 cells by kinase activation based reporter gene assay	ec50	0.0260	uM
9-(4-butylphenyl)-2-hydroxy-6,11-dihydro-5H-benzo[a]carbazole-3-carboxylic acid	387558: Agonist activity at human thrombopoietin receptor in Ba/F3 cells assessed as activation of Stat5 response element-driven reporter gene expression	ec50	0.0260	uM
4-(pyrimidin-4-ylamino)-N-[7-(trifluoromethyl)-4,5-dihydro-[1]benzoxepino[5,4-d][1,3]thiazol-2-yl]benzamide	309208: Agonist activity at human TPOr expressed in BaF3 cells by reporter assay	ec50	0.0270	uM
6-(4-carbamoylpiperidin-1-yl)-5-chloro-N-[4-[2-fluoro-3-(trifluoromethyl)phenyl]-1,3-thiazol-2-yl]pyridine-3-carboxamide	395498: Agonist activity at human thrombopoietin receptor transfected in mouse BAF3 cells assessed as stimulation of beta lactamase activity incubated in dark up to 1 hr	ec50	0.0280	uM
N-[4-(3,4-difluorophenyl)-1,3-thiazol-2-yl]-4-[(Z)-(2,4-dioxo-1,3-thiazolidin-5-ylidene)methyl]benzamide	309208: Agonist activity at human TPOr expressed in BaF3 cells by reporter assay	ec50	0.0280	uM
N-[3-[4-fluoro-3-(trifluoromethyl)phenyl]-1,2,4-thiadiazol-5-yl]-4-[[6-[[2-hydroxy-1-(hydroxyamino)ethyl]-methylamino]pyrimidin-4-yl]amino]benzamide	309208: Agonist activity at human TPOr expressed in BaF3 cells by reporter assay	ec50	0.0290	uM
N-[3-[4-fluoro-3-(trifluoromethyl)phenyl]-1,2,4-thiadiazol-5-yl]-4-[[6-(2-hydroxyethylamino)pyrimidin-4-yl]amino]benzamide	309208: Agonist activity at human TPOr expressed in BaF3 cells by reporter assay	ec50	0.0300	uM
N-[(E)-1-[2-(3,4-dimethylphenyl)-5-methyl-3-oxo-1H-pyrazol-4-yl]ethylideneamino]-5-(morpholine-4-carbonyl)-2,3-dihydroindole-1-carbothioamide	516716: Inhibition of human TPOR expressed in human BaF3 cells	ec50	0.0310	uM
N-[4-[2-fluoro-3-(trifluoromethoxy)phenyl]-1,3-thiazol-2-yl]-4-(pyrimidin-4-ylamino)benzamide	309208: Agonist activity at human TPOr expressed in BaF3 cells by reporter assay	ec50	0.0320	uM
4-[2-fluoro-3-(trifluoromethoxy)phenyl]-1,3-thiazol-2-amine	331576: Agonist activity at TPO receptor	ec50	0.0320	uM
N-[4-[2,4-difluoro-3-(trifluoromethyl)phenyl]-1,3-thiazol-2-yl]-4-(pyrimidin-4-ylamino)benzamide	309208: Agonist activity at human TPOr expressed in BaF3 cells by reporter assay	ec50	0.0330	uM
1-[3-chloro-5-[[4-[2-fluoro-3-(trifluoromethyl)phenyl]-1,3-thiazol-2-yl]carbamoyl]-2-pyridinyl]piperidine-4-carboxylic acid	395498: Agonist activity at human thrombopoietin receptor transfected in mouse BAF3 cells assessed as stimulation of beta lactamase activity incubated in dark up to 1 hr	ec50	0.0330	uM
5-chloro-N-[4-[2-fluoro-3-(trifluoromethyl)phenyl]-1,3-thiazol-2-yl]-6-(4-sulfamoylpiperidin-1-yl)pyridine-3-carboxamide	395498: Agonist activity at human thrombopoietin receptor transfected in mouse BAF3 cells assessed as stimulation of beta lactamase activity incubated in dark up to 1 hr	ec50	0.0340	uM
1-[[(E)-1-[2-(2,3-dihydro-1H-inden-5-yl)-5-methyl-3-oxo-1H-pyrazol-4-yl]ethylideneamino]carbamothioyl]-3,4-dihydro-2H-quinoline-6-carboxylic acid	516716: Inhibition of human TPOR expressed in human BaF3 cells	ec50	0.0350	uM
9-(4-fluoro-3-methylphenyl)-2-hydroxy-6,11-dihydro-5H-benzo[a]carbazole-3-carboxylic acid	387558: Agonist activity at human thrombopoietin receptor in Ba/F3 cells assessed as activation of Stat5 response element-driven reporter gene expression	ec50	0.0350	uM
N-[4-[2-fluoro-3-(2-methylpropyl)phenyl]-1,3-thiazol-2-yl]-4-(pyrimidin-4-ylamino)benzamide	309208: Agonist activity at human TPOr expressed in BaF3 cells by reporter assay	ec50	0.0350	uM
6-fluoro-7-(4-propylphenyl)-5,10-dihydroindeno[1,2-b]indole-2-carboxylic acid	349040: Agonist activity at human thrombopoietin receptor expressed in mouse Ba/F3 cells by kinase activation based reporter gene assay	ec50	0.0370	uM
3-[3-[[2-(3,4-dimethylphenyl)-5-methyl-3-oxo-1H-pyrazol-4-yl]diazenyl]-2-hydroxyphenyl]benzoic acid	349040: Agonist activity at human thrombopoietin receptor expressed in mouse Ba/F3 cells by kinase activation based reporter gene assay	ec50	0.0380	uM
N-[4-[2-fluoro-3-(trifluoromethyl)phenyl]-1,3-thiazol-2-yl]-4-[(6-methoxypyrimidin-4-yl)amino]benzamide	309208: Agonist activity at human TPOr expressed in BaF3 cells by reporter assay	ec50	0.0380	uM
3-hydroxy-4-[[5-methyl-3-oxo-2-[3-(trifluoromethyl)phenyl]-1H-pyrazol-4-yl]diazenyl]naphthalene-1-sulfonic acid	210168: Effective concentration for thrombopoietin luciferase activity was determined in BAF-3 cells	ec50	0.0400	uM
4-[[2-(3,4-dimethylphenyl)-5-methyl-3-oxo-1H-pyrazol-4-yl]diazenyl]-3-hydroxynaphthalene-1-sulfonic acid	210168: Effective concentration for thrombopoietin luciferase activity was determined in BAF-3 cells	ec50	0.0400	uM
2-hydroxy-9-(4-propoxyphenyl)-6,11-dihydro-5H-benzo[a]carbazole-3-carboxylic acid	387558: Agonist activity at human thrombopoietin receptor in Ba/F3 cells assessed as activation of Stat5 response element-driven reporter gene expression	ec50	0.0410	uM
1-[[(E)-1-[2-(3,4-dimethylphenyl)-5-methyl-3-oxo-1H-pyrazol-4-yl]ethylideneamino]carbamoyl]-2,3-dihydroindole-5-carboxylic acid	516716: Inhibition of human TPOR expressed in human BaF3 cells	ec50	0.0420	uM
4-[[6-(dimethylamino)pyrimidin-4-yl]amino]-N-[3-[4-fluoro-3-(trifluoromethyl)phenyl]-1,2,4-thiadiazol-5-yl]benzamide	309208: Agonist activity at human TPOr expressed in BaF3 cells by reporter assay	ec50	0.0430	uM
N-[4-[2-fluoro-3-(trifluoromethyl)phenyl]-1,3-thiazol-2-yl]-4-[(6-methylpyrimidin-4-yl)amino]benzamide	309208: Agonist activity at human TPOr expressed in BaF3 cells by reporter assay	ec50	0.0430	uM
2-hydroxy-9-(3-propoxyphenyl)-6,11-dihydro-5H-benzo[a]carbazole-3-carboxylic acid	387558: Agonist activity at human thrombopoietin receptor in Ba/F3 cells assessed as activation of Stat5 response element-driven reporter gene expression	ec50	0.0430	uM
(4R)-1-[3-chloro-5-[[4-[2-fluoro-3-(trifluoromethyl)phenyl]-1,3-thiazol-2-yl]carbamoyl]-2-pyridinyl]-4-methylpyrrolidine-3-carboxylic acid	395498: Agonist activity at human thrombopoietin receptor transfected in mouse BAF3 cells assessed as stimulation of beta lactamase activity incubated in dark up to 1 hr	ec50	0.0430	uM
4-[[(E)-1-[5-fluoro-2-hydroxy-1-(4-methylphenyl)indol-3-yl]ethylideneamino]carbamothioyl]benzoic acid	502110: Agonist activity at human recombinant TPO receptor expressed in mouse BaF3 cells after 24 hrs	ec50	0.0440	uM
4-[[6-(dimethylamino)pyrimidin-4-yl]amino]-N-[4-[4-fluoro-3-(trifluoromethyl)phenyl]-5-methyl-1,3-thiazol-2-yl]benzamide	309208: Agonist activity at human TPOr expressed in BaF3 cells by reporter assay	ec50	0.0450	uM
1-[[(E)-1-[2-(2,3-dihydro-1H-inden-5-yl)-5-methyl-3-oxo-1H-pyrazol-4-yl]ethylideneamino]carbamoyl]-2,3-dihydroindole-5-carboxylic acid	516716: Inhibition of human TPOR expressed in human BaF3 cells	ec50	0.0460	uM
1-[3-bromo-5-[[4-[2-fluoro-3-(trifluoromethyl)phenyl]-1,3-thiazol-2-yl]carbamoyl]-2-pyridinyl]piperidine-4-carboxylic acid	395498: Agonist activity at human thrombopoietin receptor transfected in mouse BAF3 cells assessed as stimulation of beta lactamase activity incubated in dark up to 1 hr	ec50	0.0500	uM
4-[6-(4-butylphenyl)-7-fluoro-1H-indol-2-yl]-2-hydroxybenzoic acid	349040: Agonist activity at human thrombopoietin receptor expressed in mouse Ba/F3 cells by kinase activation based reporter gene assay	ec50	0.0510	uM
N-[4-(3-butyl-2-fluorophenyl)-1,3-thiazol-2-yl]-4-(pyrimidin-4-ylamino)benzamide	309208: Agonist activity at human TPOr expressed in BaF3 cells by reporter assay	ec50	0.0530	uM
4-[[6-(dimethylamino)pyrimidin-4-yl]amino]-N-[4-[2-fluoro-3-(trifluoromethyl)phenyl]-1,3-thiazol-2-yl]benzamide	309208: Agonist activity at human TPOr expressed in BaF3 cells by reporter assay	ec50	0.0540	uM
9-(4-butylphenyl)-10-fluoro-6,11-dihydro-5H-benzo[a]carbazole-3-carboxylic acid	387558: Agonist activity at human thrombopoietin receptor in Ba/F3 cells assessed as activation of Stat5 response element-driven reporter gene expression	ec50	0.0550	uM
1-[2-chloro-4-[[4-[2-fluoro-3-(trifluoromethyl)phenyl]-1,3-thiazol-2-yl]carbamoyl]phenyl]piperidine-4-carboxylic acid	395498: Agonist activity at human thrombopoietin receptor transfected in mouse BAF3 cells assessed as stimulation of beta lactamase activity incubated in dark up to 1 hr	ec50	0.0560	uM

CTD chemical–gene interactions

28 total (human), top 28 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	decreases expression	2
Nickel	decreases expression	2
triphenyl phosphate	affects expression	1
potassium perchlorate	increases expression	1
trichostatin A	affects cotreatment, increases expression, increases reaction	1
anagrelide	decreases reaction, increases expression	1
aflatoxin B2	decreases methylation	1
hydroquinone	increases expression, increases reaction, decreases methylation, affects cotreatment	1
benzamide	affects binding, increases activity	1
midostaurin	increases expression	1
CGP 52608	affects binding, increases reaction	1
perfluoro-n-nonanoic acid	increases expression	1
perfluorohexanesulfonic acid	increases expression	1
eltrombopag	affects binding, increases activity	1
theaflavin-3,3’-digallate	affects expression	1
Decitabine	increases expression, increases reaction, affects cotreatment	1
Arsenic Trioxide	decreases expression	1
Vehicle Emissions	decreases expression	1
Benzene	decreases expression	1
Benzo(a)pyrene	increases methylation	1
Cadmium	decreases expression	1
Diethylhexyl Phthalate	decreases expression	1
Smoke	decreases expression	1
Thiram	decreases expression	1
Urethane	decreases expression	1
Antirheumatic Agents	increases expression	1
Lactic Acid	decreases expression	1
Particulate Matter	decreases expression	1

ChEMBL screening assays

23 unique, capped per target: 15 functional, 7 binding, 1 admet

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1019476	Functional	Agonist activity at human thrombopoietin receptor transfected in mouse BAF3 cells assessed as stimulation of beta lactamase activity incubated in dark up to 1 hr	The identification of orally bioavailable thrombopoietin agonists. — *Bioorg Med Chem Lett*
CHEMBL1260125	Binding	Inhibition of human TPOR expressed in human BaF3 cells	Novel indoline-1- or 3,4-dihydroquinoline-1(2H)-substituted carbothiohydrazides as TPO receptor agonists. — *Bioorg Med Chem Lett*
CHEMBL4623763	ADMET	Agonist activity at recombinant human c-Mpl receptor transfected in BA/F3 cells assessed as increase in cell proliferation by cell counting analysis	Discovery and structure-activity relationships study of positive allosteric modulators of the M3 muscarinic acetylcholine receptor. — *Bioorg Med Chem*

Cellosaurus cell lines

5 cell lines: 2 cancer cell line, 1 transformed cell line, 1 factor-dependent cell line, 1 induced pluripotent stem cell

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

Cellosaurus	Name	Category	Sex
CVCL_6992	Marimo	Cancer cell line	Female
CVCL_A8CI	HEK-Blue TPO	Transformed cell line	Female
CVCL_D6I2	hMPL-32D	Factor-dependent cell line	Male
CVCL_E3EB	10101	Cancer cell line	Male
CVCL_JL80	M494	Induced pluripotent stem cell	Female

Clinical trials (associated diseases)

Via MONDO — disease-level, not drug-specific.

showing 60 of 110 trials:

NCT	Phase	Status	Title
NCT03232177	Phase 4	COMPLETED	Anagre Cap. in Patients With High-Risk Essential Thrombocythemia
NCT01214915	Phase 3	COMPLETED	Effect of SPD422 on Platelet Lowering and Safety in Japanese Adults With At Risk Essential Thrombocythaemia
NCT01387763	Phase 3	COMPLETED	A Study of Low Dose Interferon Alpha Versus Hydroxyurea in Treatment of Chronic Myeloid Neoplasms
NCT01467661	Phase 3	COMPLETED	Long-term Safety of SPD422 in Japanese Adults With Essential Thrombocythaemia
NCT02076815	Phase 3	COMPLETED	Anagrelide Retard in Essential Thrombocythemia
NCT02611973	Phase 3	UNKNOWN	Hydroxyurea Versus Aspirin and Hydroxyurea in Essential Thrombocythemia
NCT04285086	Phase 3	ACTIVE_NOT_RECRUITING	Ropeginterferon Alfa-2b (P1101) vs. Anagrelide in Essential Thrombocythemia Patients With Hydroxyurea Resistance or Intolerance
NCT05198960	Phase 3	RECRUITING	AVAJAK: Apixaban/Rivaroxaban Versus Aspirin for Primary Prevention of Thrombo-embolic Complications in JAK2V617F-positive Myeloproliferative Neoplasms
NCT06079879	Phase 3	ACTIVE_NOT_RECRUITING	A Study of Bomedemstat (IMG-7289/MK-3543) Compared to Best Available Therapy (BAT) in Participants With Essential Thrombocythemia and an Inadequate Response or Intolerance of Hydroxyurea (MK-3543-006)
NCT06456346	Phase 3	ACTIVE_NOT_RECRUITING	Bomedemstat vs Hydroxyurea for Essential Thrombocythemia (MK-3543-007)
NCT07623200	Phase 3	RECRUITING	A Phase 3 Study of INCA033989 Versus Best Available Therapy in Participants With Essential Thrombocythemia
NCT00039416	Phase 2	COMPLETED	Imatinib Mesylate in Treating Patients With Myelofibrosis
NCT00047190	Phase 2	COMPLETED	Tipifarnib in Treating Patients With Myelofibrosis and Myeloid Metaplasia
NCT00089011	Phase 2	COMPLETED	Tacrolimus and Mycophenolate Mofetil in Preventing Graft-Versus-Host Disease in Patients Who Have Undergone Total-Body Irradiation With or Without Fludarabine Phosphate Followed by Donor Peripheral Blood Stem Cell Transplant for Hematologic Cancer
NCT00227591	Phase 2	COMPLETED	Lenalidomide and Prednisone in Treating Patients With Myelofibrosis
NCT00381550	Phase 2	COMPLETED	3-AP and Fludarabine in Treating Patients With Myeloproliferative Disorders, Chronic Myelomonocytic Leukemia, or Accelerated Phase or Blastic Phase Chronic Myelogenous Leukemia
NCT00397813	Phase 2	COMPLETED	Fludarabine Phosphate and Total Body Irradiation Followed by a Donor Peripheral Stem Cell Transplant in Treating Patients With Myelodysplastic Syndromes or Myeloproliferative Disorders
NCT00489203	Phase 2	COMPLETED	Beclomethasone Dipropionate in Preventing Acute Graft-Versus-Host Disease in Patients Undergoing a Donor Stem Cell Transplant for Hematologic Cancer
NCT00586651	Phase 2	COMPLETED	Open-Label Study of Oral CEP-701 (Lestaurtinib) in Patients With Polycythemia Vera or Essential Thrombocytosis
NCT00866762	Phase 2	UNKNOWN	A Study of the Efficacy of MK-0683 in Patients With Polycythaemia Vera and Essential Thrombocythaemia
NCT01243073	Phase 2	COMPLETED	Open Label Study to Evaluate the Activity of Imetelstat in Patients With Essential Thrombocythemia or Polycythemia Vera
NCT01384513	Phase 2	COMPLETED	A Two-Step Approach to Reduced Intensity Bone Marrow Transplant for Patients With Hematological Malignancies
NCT01998828	Phase 2	TERMINATED	Safety and Efficacy of Momelotinib in Subjects With Polycythemia Vera or Essential Thrombocythemia
NCT02124746	Phase 2	COMPLETED	Long-term Safety and Efficacy of Momelotinib in Subjects With Primary Myelofibrosis, Post-polycythemia Vera Myelofibrosis, Post-essential Thrombocythemia Myelofibrosis, Polycythemia Vera or Essential Thrombocythemia
NCT02311569	Phase 2	COMPLETED	Sympathicomimetic Agonist in Patients With Myeloproliferative Neoplasms With JAK2-mutation
NCT02556931	Phase 2	COMPLETED	Shorter Course Tacro After NMA, Related Donor PBSCT With High-dose Posttransplant Cy for Hard-to-Engraft Malignancies
NCT02577926	Phase 2	ACTIVE_NOT_RECRUITING	The Ruxo-BEAT Trial in Patients With High-risk Polycythemia Vera or High-risk Essential Thrombocythemia
NCT03289910	Phase 2	ACTIVE_NOT_RECRUITING	Topotecan Hydrochloride and Carboplatin With or Without Veliparib in Treating Advanced Myeloproliferative Disorders and Acute Myeloid Leukemia or Chronic Myelomonocytic Leukemia
NCT04243122	Phase 2	COMPLETED	Assessing Feasibility of Thromboprophylaxis With Apixaban in JAK2-positive Myeloproliferative Neoplasm Patients
NCT04254978	Phase 2	COMPLETED	Study of Bomedemstat in Participants With Essential Thrombocythemia (IMG-7289-CTP-201/MK-3543-003)
NCT04262141	Phase 2	ACTIVE_NOT_RECRUITING	IMG-7289 in Patients With Essential Thrombocythemia (ET) or Polycythemia Vera (PV)
NCT04282187	Phase 2	RECRUITING	Decitabine With Ruxolitinib, Fedratinib or Pacritinib for the Treatment of Accelerated/Blast Phase Myeloproliferative Neoplasms
NCT04644211	Phase 2	RECRUITING	Ruxolitinib in Thrombocythemia and Polycythemia Vera
NCT05031897	Phase 2	RECRUITING	Two Step Haplo With Radiation Conditioning
NCT05482971	Phase 2	ACTIVE_NOT_RECRUITING	A Single-arm, Multicenter Study to Assess the Efficacy, Safety, and Tolerability of P1101 in Adults With ET
NCT06063486	Phase 2	RECRUITING	Curcumin to Improve Inflammation and Symptoms in Patients With Clonal Cytopenia of Undetermined Significance, Low Risk Myelodysplastic Syndrome, and Myeloproliferative Neoplasms
NCT06541249	Phase 2	RECRUITING	MethoTRExATE in MyelOpRolifErative Neoplasms (TREATMORE) Trial
NCT06552429	Phase 2	RECRUITING	Peginterferon α-2b Injection for Hydroxyurea Resistant or Intolerant ET
NCT06661915	Phase 2	RECRUITING	A Randomized Study of ASTX727 With or Without Iadademstat in Advanced Myeloproliferative Neoplasms (MPNs)
NCT00301834	Phase 2	COMPLETED	Alemtuzumab, Fludarabine, and Busulfan Followed By Donor Stem Cell Transplant in Treating Young Patients With Hematologic Disorders
NCT01529827	Phase 2	COMPLETED	Fludarabine Phosphate, Melphalan, and Low-Dose Total-Body Irradiation Followed by Donor Peripheral Blood Stem Cell Transplant in Treating Patients With Hematologic Malignancies
NCT03333486	Phase 2	TERMINATED	Fludarabine Phosphate, Cyclophosphamide, Total Body Irradiation, and Donor Stem Cell Transplant in Treating Patients With Blood Cancer
NCT04965597	Phase 2	COMPLETED	Treosulfan-Based Conditioning Regimen Before a Blood or Bone Marrow Transplant for the Treatment of Bone Marrow Failure Diseases (BMT CTN 1904)
NCT00025415	Phase 1	COMPLETED	Imatinib Mesylate in Treating Patients With Advanced Cancer and Liver Dysfunction
NCT00357305	Phase 1	COMPLETED	Vorinostat, Cytarabine, and Etoposide in Treating Patients With Relapsed and/or Refractory Acute Leukemia or Myelodysplastic Syndromes or Myeloproliferative Disorders
NCT00588991	Phase 1	COMPLETED	Veliparib and Topotecan With or Without Carboplatin in Treating Patients With Relapsed or Refractory Acute Leukemia, High-Risk Myelodysplasia, or Aggressive Myeloproliferative Disorders
NCT00718159	Phase 1	COMPLETED	Study of LY573636-sodium in Essential Thrombocythemia and Acute Myeloid Leukemia
NCT00890747	Phase 1	COMPLETED	Sunitinib Malate in Treating HIV-Positive Patients With Cancer Receiving Antiretroviral Therapy
NCT01014546	Phase 1	TERMINATED	Arsenic Trioxide With or Without Ascorbic Acid in Treating Patients With Myelofibrosis
NCT01520220	Phase 1	COMPLETED	Study of LY2784544 Testing Alternative Dosing in Participants With Myeloproliferative Neoplasms
NCT01588015	Phase 1	COMPLETED	Vaccine Therapy in Preventing Cytomegalovirus Infection in Patients With Hematological Malignancies Undergoing Donor Stem Cell Transplant
NCT02129101	Phase 1	COMPLETED	Azacitidine and Sonidegib or Decitabine in Treating Patients With Myeloid Malignancies
NCT02407080	Phase 1	COMPLETED	Open Label Study of Single Agent Oral RG7388 in Patients With Polycythemia Vera and Essential Thrombocythemia
NCT03566446	Phase 1	COMPLETED	CALR Exon 9 Mutant Peptide Vaccine to Patients With CALR-mutant Myeloproliferative Neoplasms
NCT04279847	Phase 1	ACTIVE_NOT_RECRUITING	Safety and Tolerability Study of INCB057643 in Participants With Myelofibrosis and Other Advanced Myeloid Neoplasms
NCT05025488	Phase 1	RECRUITING	Mutant CALR-peptide Based Vaccine in Patients With Mutated CALR Myeloproliferative Neoplasm
NCT06218628	Phase 1	RECRUITING	Pacritinib w/ Talazoparib in Pts w/ Myeloproliferative Neoplasms Unresponsive to JAK2 Inhibition
NCT06378437	Phase 1	RECRUITING	A Study of GLB-001 in Patients With Myeloid Malignancies
NCT00295971	Phase 1	COMPLETED	Donor Stem Cell Transplant in Treating Young Patients With Myelodysplastic Syndrome, Leukemia, Bone Marrow Failure Syndrome, or Severe Immunodeficiency Disease
NCT02962388	Phase 2/3	TERMINATED	The Ruxolitinib Versus Best Available Therapy Trial in Patients With High Risk ET in Second Line

Predicted chemistry — Sugi Predict

The predicted patent-compound landscape for MPL across ~30M SureChEMBL compounds — explore on Sugi Predict.