ACVR1 (ALK2)
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.
Overview
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.
- Target · the protein and the cell it sits on
- Drug · antibody, small molecule, cell or radioligand
- Effect · signal, damage or kill
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.
- 1 · What it is
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.
- 2 · What goes wrong in cancer
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.
- 3 · How drugs use it
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.
External identifiers
Biology
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.
- Hepcidin regulation (anaemia of myelofibrosis)
- Bone morphogenetic protein signalling in normal development
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.
Notes
top- Prevalence not recorded in this wave: HGNC and UniProt carry no positivity rates and no other source was consulted.
Latest papers
topQuery 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.
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