Details of the Drug Therapeutic Target (DTT)

General Information of Drug Therapeutic Target (DTT) (ID: TT7MRDV)

• DTT Name: Macrophage colony-stimulating factor 1 receptor (CSF1R)
• Synonyms: Proto-oncogene c-Fms; M-CSF-R; FMS; CSF-1R; CSF-1-R; CSF-1 receptor; CD115
• Gene Name: CSF1R
• DTT Type: Successful target; [1]
• Related Disease: Bone/articular cartilage neoplasm [ICD-11: 2F7B]
• BioChemical Class: Kinase
• UniProt ID: CSF1R_HUMAN
• TTD ID: T20333
• EC Number: EC 2.7.10.1
• Sequence:
  MGPGVLLLLLVATAWHGQGIPVIEPSVPELVVKPGATVTLRCVGNGSVEWDGPPSPHWTL
  YSDGSSSILSTNNATFQNTGTYRCTEPGDPLGGSAAIHLYVKDPARPWNVLAQEVVVFED
  QDALLPCLLTDPVLEAGVSLVRVRGRPLMRHTNYSFSPWHGFTIHRAKFIQSQDYQCSAL
  MGGRKVMSISIRLKVQKVIPGPPALTLVPAELVRIRGEAAQIVCSASSVDVNFDVFLQHN
  NTKLAIPQQSDFHNNRYQKVLTLNLDQVDFQHAGNYSCVASNVQGKHSTSMFFRVVESAY
  LNLSSEQNLIQEVTVGEGLNLKVMVEAYPGLQGFNWTYLGPFSDHQPEPKLANATTKDTY
  RHTFTLSLPRLKPSEAGRYSFLARNPGGWRALTFELTLRYPPEVSVIWTFINGSGTLLCA
  ASGYPQPNVTWLQCSGHTDRCDEAQVLQVWDDPYPEVLSQEPFHKVTVQSLLTVETLEHN
  QTYECRAHNSVGSGSWAFIPISAGAHTHPPDEFLFTPVVVACMSIMALLLLLLLLLLYKY
  KQKPKYQVRWKIIESYEGNSYTFIDPTQLPYNEKWEFPRNNLQFGKTLGAGAFGKVVEAT
  AFGLGKEDAVLKVAVKMLKSTAHADEKEALMSELKIMSHLGQHENIVNLLGACTHGGPVL
  VITEYCCYGDLLNFLRRKAEAMLGPSLSPGQDPEGGVDYKNIHLEKKYVRRDSGFSSQGV
  DTYVEMRPVSTSSNDSFSEQDLDKEDGRPLELRDLLHFSSQVAQGMAFLASKNCIHRDVA
  ARNVLLTNGHVAKIGDFGLARDIMNDSNYIVKGNARLPVKWMAPESIFDCVYTVQSDVWS
  YGILLWEIFSLGLNPYPGILVNSKFYKLVKDGYQMAQPAFAPKNIYSIMQACWALEPTHR
  PTFQQICSFLQEQAQEDRRERDYTNLPSSSRSGGSGSSSSELEEESSSEHLTCCEQGDIA
  QPLLQPNNYQFC
• Function: Promotes the release of proinflammatory chemokines in response to IL34 and CSF1, and thereby plays an important role in innate immunity and in inflammatory processes. Plays an important role in the regulation of osteoclast proliferation and differentiation, the regulation of bone resorption, and is required for normal bone and tooth development. Required for normal male and female fertility, and for normal development of milk ducts and acinar structures in the mammary gland during pregnancy. Promotes reorganization of the actin cytoskeleton, regulates formation of membrane ruffles, cell adhesion and cell migration, and promotes cancer cell invasion. Activates several signaling pathways in response to ligand binding. Phosphorylates PIK3R1, PLCG2, GRB2, SLA2 and CBL. Activation of PLCG2 leads to the production of the cellular signaling molecules diacylglycerol and inositol 1,4,5-trisphosphate, that then lead to the activation of protein kinase C family members, especially PRKCD. Phosphorylation of PIK3R1, the regulatory subunit of phosphatidylinositol 3-kinase, leads to activation of the AKT1 signaling pathway. Activated CSF1R also mediates activation of the MAP kinases MAPK1/ERK2 and/or MAPK3/ERK1, and of the SRC family kinases SRC, FYN and YES1. Activated CSF1R transmits signals both via proteins that directly interact with phosphorylated tyrosine residues in its intracellular domain, or via adapter proteins, such as GRB2. Promotes activation of STAT family members STAT3, STAT5A and/or STAT5B. Promotes tyrosine phosphorylation of SHC1 and INPP5D/SHIP-1. Receptor signaling is down-regulated by protein phosphatases, such as INPP5D/SHIP-1, that dephosphorylate the receptor and its downstream effectors, and by rapid internalization of the activated receptor. Tyrosine-protein kinase that acts as cell-surface receptor for CSF1 and IL34 and plays an essential role in the regulation of survival, proliferation and differentiation of hematopoietic precursor cells, especially mononuclear phagocytes, such as macrophages and monocytes.
• KEGG Pathway:
  MAPK signaling pathway (hsa04010)
  Ras signaling pathway (hsa04014)
  Rap1 signaling pathway (hsa04015)
  Cytokine-cytokine receptor interaction (hsa04060)
  Viral protein interaction with cytokine and cytokine receptor (hsa04061)
  PI3K-Akt signaling pathway (hsa04151)
  Osteoclast differentiation (hsa04380)
  Hematopoietic cell lineage (hsa04640)
  Pathways in cancer (hsa05200)
  Transcriptional misregulation in cancer (hsa05202)
  Acute myeloid leukemia (hsa05221)
• Reactome Pathway:
  Transcriptional Regulation by VENTX (R-HSA-8853884)
  Other interleukin signaling (R-HSA-449836)

Molecular Interaction Atlas (MIA) of This DTT

1 Approved Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Pexidartinib	DMS2J0Z	Tenosynovial giant cell tumour	2F7B	Approved	[2]

13 Clinical Trial Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Sulfatinib	DMPOTM4	Neuroendocrine cancer	2B72.1	Phase 3	[1]
ARRY-382	DM0VGDC	Solid tumour/cancer	2A00-2F9Z	Phase 2	[1]
BLZ-945	DMG1LVA	Amyotrophic lateral sclerosis	8B60.0	Phase 2	[1]
Cabiralizumab	DMGE058	Pancreatic cancer	2C10	Phase 2	[3]
DCC-3014	DMHW289	Solid tumour/cancer	2A00-2F9Z	Phase 1/2	[4]
FPA-008	DM3ZN6Y	Autoimmune diabetes	5A10	Phase 1/2	[5]
ABSK021	DMA4WEO	Solid tumour/cancer	2A00-2F9Z	Phase 1	[6]
Axatilamab	DMFBMU7	Solid tumour/cancer	2A00-2F9Z	Phase 1	[7]
DCC-3014	DMLVG9D	Haematological malignancy	2B33.Y	Phase 1	[1]
EI1071	DMXAUB7	Solid tumour/cancer	2A00-2F9Z	Phase 1	[8]
PLX7486	DM0IVGU	Pancreatic cancer	2C10	Phase 1	[1]
SNDX-6352	DM8ZROW	Solid tumour/cancer	2A00-2F9Z	Phase 1	[1]
TPX-0022	DMC2IJN	Solid tumour/cancer	2A00-2F9Z	Phase 1	[9]

6 Patented Agent(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
PMID28270010-Compound-Figure24-a	DMNTQL5	N. A.	N. A.	Patented	[10]
Pyridine derivative 18	DMBZMYT	N. A.	N. A.	Patented	[11]
Pyridine derivative 19	DMXYT40	N. A.	N. A.	Patented	[11]
Pyridine derivative 20	DMAOF0W	N. A.	N. A.	Patented	[11]
Pyridine derivative 21	DMF3907	N. A.	N. A.	Patented	[11]
Pyridine derivative 22	DMSIERF	N. A.	N. A.	Patented	[11]

References

• [1] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
• [2] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health Human Services. 2019
• [3] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
• [4] Clinical pipeline report, company report or official report of Deciphera Pharmaceuticals.
• [5] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
• [6] Clinical pipeline report, company report or official report of Abbisko Therapeutics.
• [7] Clinical pipeline report, company report or official report of Syndax Pharmaceuticals.
• [8] Clinical pipeline report, company report or official report of Elixiron Immunotherapeutics.
• [9] Clinical pipeline report, company report or official report of Turning Point Therapeutics.
• [10] Tropomyosin receptor kinase inhibitors: an updated patent review for 2010-2016 - Part I.Expert Opin Ther Pat. 2017 Jun;27(6):733-751.
• [11] RET kinase inhibitors: a review of recent patents (2012-2015).Expert Opin Ther Pat. 2017 Jan;27(1):91-99.