Details of the Drug Therapeutic Target (DTT)

General Information of Drug Therapeutic Target (DTT) (ID: TTPKHTZ)

• DTT Name: Activin receptor type IB (ACVR1B)
• Synonyms: Serine/threonine-protein kinase receptor R2; SKR2; Activin receptor-like kinase 4; Activin receptor type-1B; ALK4; ALK-4; ACVRLK4; ACTR-IB
• Gene Name: ACVR1B
• DTT Type: Patented-recorded target; [1]
• BioChemical Class: Kinase
• UniProt ID: ACV1B_HUMAN
• TTD ID: T47594
• EC Number: EC 2.7.11.30
• Sequence:
  MAESAGASSFFPLVVLLLAGSGGSGPRGVQALLCACTSCLQANYTCETDGACMVSIFNLD
  GMEHHVRTCIPKVELVPAGKPFYCLSSEDLRNTHCCYTDYCNRIDLRVPSGHLKEPEHPS
  MWGPVELVGIIAGPVFLLFLIIIIVFLVINYHQRVYHNRQRLDMEDPSCEMCLSKDKTLQ
  DLVYDLSTSGSGSGLPLFVQRTVARTIVLQEIIGKGRFGEVWRGRWRGGDVAVKIFSSRE
  ERSWFREAEIYQTVMLRHENILGFIAADNKDNGTWTQLWLVSDYHEHGSLFDYLNRYTVT
  IEGMIKLALSAASGLAHLHMEIVGTQGKPGIAHRDLKSKNILVKKNGMCAIADLGLAVRH
  DAVTDTIDIAPNQRVGTKRYMAPEVLDETINMKHFDSFKCADIYALGLVYWEIARRCNSG
  GVHEEYQLPYYDLVPSDPSIEEMRKVVCDQKLRPNIPNWWQSYEALRVMGKMMRECWYAN
  GAARLTALRIKKTLSQLSVQEDVKI
• Function: Transduces the activin signal from the cell surface to the cytoplasm and is thus regulating a many physiological and pathological processes including neuronal differentiation and neuronal survival, hair follicle development and cycling, FSH production by the pituitary gland, wound healing, extracellular matrix production, immunosuppression and carcinogenesis. Activin is also thought to have a paracrine or autocrine role in follicular development in the ovary. Within the receptor complex, type-2 receptors (ACVR2A and/or ACVR2B) act as a primary activin receptors whereas the type-1 receptors like ACVR1B act as downstream transducers of activin signals. Activin binds to type-2 receptor at the plasma membrane and activates its serine-threonine kinase. The activated receptor type-2 then phosphorylates and activates the type-1 receptor such as ACVR1B. Once activated, the type-1 receptor binds and phosphorylates the SMAD proteins SMAD2 and SMAD3, on serine residues of the C-terminal tail. Soon after their association with the activin receptor and subsequent phosphorylation, SMAD2 and SMAD3 are released into the cytoplasm where they interact with the common partner SMAD4. This SMAD complex translocates into the nucleus where it mediates activin-induced transcription. Inhibitory SMAD7, which is recruited to ACVR1B through FKBP1A, can prevent the association of SMAD2 and SMAD3 with the activin receptor complex, thereby blocking the activin signal. Activin signal transduction is also antagonized by the binding to the receptor of inhibin-B via the IGSF1 inhibin coreceptor. ACVR1B also phosphorylates TDP2. Transmembrane serine/threonine kinase activin type-1 receptor forming an activin receptor complex with activin receptor type-2 (ACVR2A or ACVR2B).
• KEGG Pathway:
  Cytokine-cytokine receptor interaction (hsa04060)
  TGF-beta signaling pathway (hsa04350)
  Signaling pathways regulating pluripotency of stem cells (hsa04550)
• Reactome Pathway:
  Regulation of signaling by NODAL (R-HSA-1433617)
  Signaling by Activin (R-HSA-1502540)
  Signaling by NODAL (R-HSA-1181150)

Molecular Interaction Atlas (MIA) of This DTT

6 Patented Agent(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
BDBM108945	DMZD6IJ	N. A.	N. A.	Patented	[2]
US10030004, Compound 11a	DMG4T13	N. A.	N. A.	Patented	[3]
US10030004, Compound 19	DM0RAPC	N. A.	N. A.	Patented	[3]
US10030004, Compound 33	DMD0GN6	N. A.	N. A.	Patented	[3]
US9682983, 1	DM6EQVT	N. A.	N. A.	Patented	[2]
US9682983, 33	DM6R1YP	N. A.	N. A.	Patented	[2]

2 Investigative Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
PMID23639540C13d	DMSTQGH	Discovery agent	N.A.	Investigative	[1]
PMID23639540C13r	DMHBZ0N	Discovery agent	N.A.	Investigative	[1]

References

• [1] Synthesis and structure-activity relationships of a novel and selective bone morphogenetic protein receptor (BMP) inhibitor derived from the pyrazolo[1.5-a]pyrimidine scaffold of dorsomorphin: the discovery of ML347 as an ALK2 versus ALK3 selective MLPCN probe. Bioorg Med Chem Lett. 2013 Jun 1;23(11):3248-52.
• [2] BMP inhibitors and methods of use thereof. US9682983.
• [3] Compounds and methods of use. US10030004.