Loading
ACVR1 (ALK2) is the receptor that raises hepcidin, the hormone that hides iron from the bone marrow. Momelotinib and pacritinib block it as well as JAK2, which is why they improve, rather than worsen, the low red-cell counts of myelofibrosis.
ACVR1 (chromosome 2q24.1) encodes ALK2, a bone morphogenetic protein type I receptor that forms heterotetrameric complexes with the type II receptors AMHR2, ACVR2A or ACVR2B; on binding of ligands such as BMP7 or BMP9 the type II receptors transphosphorylate it, and its kinase domain then phosphorylates SMAD1, SMAD5 and SMAD8; it acts across bone, heart, cartilage, nervous and reproductive development and also suppresses TGF-beta/activin signalling by competing for the type II receptor (UniProt Q04771). In OnCo, ACVR1 is the receptor that drives hepcidin production and that momelotinib and pacritinib inhibit in addition to JAK2, lowering hepcidin, freeing iron for red-cell production and improving the anaemia of myelofibrosis.
In plain words · ACVR1 (ALK2) is the receptor that raises hepcidin, the hormone that hides iron from the bone marrow. Momelotinib and pacritinib block it as well as JAK2, which is why they improve, rather than worsen, the low red-cell counts of myelofibrosis.
ACVR1 (ALK2) is the receptor that raises hepcidin, the hormone that hides iron from the bone marrow. Momelotinib and pacritinib block it as well as JAK2, which is why they improve, rather than worsen, the low red-cell counts of myelofibrosis.
In myelofibrosis the target is ACVR1 in the hepcidin pathway rather than in the malignant clone: the pacritinib record notes that sparing JAK1 while blocking JAK2, FLT3, IRAK1 and ACVR1 lets it be used with very low platelet counts, and the momelotinib record credits ACVR1 inhibition for its effect on anaemia.
2 products aim at ACVR1 (ALK2): small molecules. Kinases are switched on by binding ATP inside the cell, so most drugs are small molecules shaped to plug that ATP pocket.
Broadly expressed or essential: HPA finds the RNA at low tissue specificity; the 2 medicines aimed at it (Momelotinib, Pacritinib) act on the wild-type protein, so normal tissue is exposed and the therapeutic window comes from the tumour's faster division or its dependence on the protein. HPA ACVR1: RNA low tissue specificity; high antibody staining in 2 normal tissues. Distribution: 1 cancer family in the corpus carries a prevalence row, label threshold or catalogue link for it (Myeloid neoplasms); Open Targets associates it with 2 specific cancer types at or above 0.5 (myelofibrosis, primary myelofibrosis); the corpus evidence decides and the Open Targets list is quoted for comparison. (Rule 7 of scripts/fetch-target-specificity.ts.)
Sources: Human Protein Atlas ACVR1 tissue; Open Targets ENSG00000115170 associations
First described 1993. Earliest sequence paper UniProt cites for the protein: Matsuzaki et al, J. Biol. Chem, 1993, "A widely expressed transmembrane serine/threonine kinase that does not bind activin, inhibin, transforming growth factor beta, or bone morphogenic factor". Source.
In myelofibrosis the target is ACVR1 in the hepcidin pathway rather than in the malignant clone: the pacritinib record notes that sparing JAK1 while blocking JAK2, FLT3, IRAK1 and ACVR1 lets it be used with very low platelet counts, and the momelotinib record credits ACVR1 inhibition for its effect on anaemia.
RNA: low tissue specificity, detected in all normal tissues.
Medium: Breast, Bronchus, Endometrium, Epididymis, Fallopian tube, Heart muscle, Kidney, Placenta.
No cancer stained high; medium in breast cancer, glioma, liver cancer, lung cancer.
Human Protein Atlas version 25.1, antibody staining at reliability approved, enhanced or supported; used under CC BY-SA 3.0. Staining counts are patients per level in the atlas cohort, not population prevalence.
Momelotinib is the JAK inhibitor designed for anaemic myelofibrosis patients: it can improve haemoglobin while shrinking the spleen.
The JAK inhibitor for myelofibrosis patients whose platelet counts are too low for ruxolitinib.
Query for this target: (TITLE:"ACVR1" OR ABSTRACT:"ACVR1" OR TITLE:"ALK2" OR ABSTRACT:"ALK2") AND (cancer OR tumor OR tumour OR oncology OR carcinoma OR lymphoma OR leukemia OR leukaemia OR myeloma OR sarcoma OR melanoma OR glioma). Results are unfiltered search hits about ACVR1 (ALK2), not a curated reading list.
Shares Pacritinib, Momelotinib, JAK-STAT signalling, JAK2 and the tag wave5-target.
Shares JAK-STAT signalling, JAK2, Myeloproliferative neoplasms (PV, ET, myelofibrosis) and the tag wave5-target.
Shares JAK2, Primary myelofibrosis and the tag wave5-target.
Shares JAK-STAT signalling, JAK2 and the tag wave5-target.
Shares Small-molecule kinase inhibitors and the tag wave5-target.
Shares Small-molecule kinase inhibitors and the tag wave5-target.
Shares Small-molecule kinase inhibitors and the tag wave5-target.
Shares Small-molecule kinase inhibitors and the tag wave5-target.