Details of the Drug Therapeutic Target (DTT)

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

• DTT Name: Fibroblast growth factor receptor 2 (FGFR2)
• Synonyms: Keratinocyte growth factor receptor 2; Keratinocyte growth factor receptor; KSAM; KGFR; K-sam; FGFR-2; FGF-2 receptor; CD332; BEK
• Gene Name: FGFR2
• DTT Type: Successful target; [1]
• BioChemical Class: Kinase
• UniProt ID: FGFR2_HUMAN
• TTD ID: T58454
• EC Number: EC 2.7.10.1
• Sequence:
  MVSWGRFICLVVVTMATLSLARPSFSLVEDTTLEPEEPPTKYQISQPEVYVAAPGESLEV
  RCLLKDAAVISWTKDGVHLGPNNRTVLIGEYLQIKGATPRDSGLYACTASRTVDSETWYF
  MVNVTDAISSGDDEDDTDGAEDFVSENSNNKRAPYWTNTEKMEKRLHAVPAANTVKFRCP
  AGGNPMPTMRWLKNGKEFKQEHRIGGYKVRNQHWSLIMESVVPSDKGNYTCVVENEYGSI
  NHTYHLDVVERSPHRPILQAGLPANASTVVGGDVEFVCKVYSDAQPHIQWIKHVEKNGSK
  YGPDGLPYLKVLKAAGVNTTDKEIEVLYIRNVTFEDAGEYTCLAGNSIGISFHSAWLTVL
  PAPGREKEITASPDYLEIAIYCIGVFLIACMVVTVILCRMKNTTKKPDFSSQPAVHKLTK
  RIPLRRQVTVSAESSSSMNSNTPLVRITTRLSSTADTPMLAGVSEYELPEDPKWEFPRDK
  LTLGKPLGEGCFGQVVMAEAVGIDKDKPKEAVTVAVKMLKDDATEKDLSDLVSEMEMMKM
  IGKHKNIINLLGACTQDGPLYVIVEYASKGNLREYLRARRPPGMEYSYDINRVPEEQMTF
  KDLVSCTYQLARGMEYLASQKCIHRDLAARNVLVTENNVMKIADFGLARDINNIDYYKKT
  TNGRLPVKWMAPEALFDRVYTHQSDVWSFGVLMWEIFTLGGSPYPGIPVEELFKLLKEGH
  RMDKPANCTNELYMMMRDCWHAVPSQRPTFKQLVEDLDRILTLTTNEEYLDLSQPLEQYS
  PSYPDTRSSCSSGDDSVFSPDPMPYEPCLPQYPHINGSVKT
• Function: Required for normal embryonic patterning, trophoblast function, limb bud development, lung morphogenesis, osteogenesis and skin development. Plays an essential role in the regulation of osteoblast differentiation, proliferation and apoptosis, and is required for normal skeleton development. Promotes cell proliferation in keratinocytes and immature osteoblasts, but promotes apoptosis in differentiated osteoblasts. Phosphorylates PLCG1, FRS2 and PAK4. Ligand binding leads to the activation of several signaling cascades. Activation of PLCG1 leads to the production of the cellular signaling molecules diacylglycerol and inositol 1,4,5-trisphosphate. Phosphorylation of FRS2 triggers recruitment of GRB2, GAB1, PIK3R1 and SOS1, and mediates activation of RAS, MAPK1/ERK2, MAPK3/ERK1 and the MAP kinase signaling pathway, as well as of the AKT1 signaling pathway. FGFR2 signaling is down-regulated by ubiquitination, internalization and degradation. Mutations that lead to constitutive kinase activation or impair normal FGFR2 maturation, internalization and degradation lead to aberrant signaling. Over-expressed FGFR2 promotes activation of STAT1. Tyrosine-protein kinase that acts as cell-surface receptor for fibroblast growth factors and plays an essential role in the regulation of cell proliferation, differentiation, migration and apoptosis, and in the regulation of embryonic development.
• KEGG Pathway:
  MAPK signaling pathway (hsa04010)
  Ras signaling pathway (hsa04014)
  Rap1 signaling pathway (hsa04015)
  Endocytosis (hsa04144)
  PI3K-Akt signaling pathway (hsa04151)
  Signaling pathways regulating pluripotency of stem cells (hsa04550)
  Regulation of actin cytoskeleton (hsa04810)
  Pathways in cancer (hsa05200)
  Prostate cancer (hsa05215)
  Central carbon metabolism in cancer (hsa05230)
• Reactome Pathway: Activated point mutants of FGFR2 (R-HSA-2033519)

Molecular Interaction Atlas (MIA) of This DTT

3 Approved Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Interferon Alfa-2a, Recombinant	DMUTZ8S	Chronic HCV-1 infection	1E51.1	Approved	[2]
Palifermin	DM9JOYP	Oral mucositis	DA01.11	Approved	[1]
Pemigatinib	DM819JF	Cholangiocarcinoma	2C12.10	Approved	[3]

9 Clinical Trial Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
E-3810	DM42PFT	Solid tumour/cancer	2A00-2F9Z	Phase 3	[4]
Trafermin	DMLKI2B	Periodontitis	DA0C	Phase 3	[5]
Debio 1347	DMZW50O	Solid tumour/cancer	2A00-2F9Z	Phase 2	[6]
LY2874455	DMZ0DMY	Solid tumour/cancer	2A00-2F9Z	Phase 2	[7]
AEE-788	DMEOS5K	Solid tumour/cancer	2A00-2F9Z	Phase 1/2	[8]
MK-2461	DM21WBH	Alzheimer disease	8A20	Phase 1/2	[9]
Alofanib	DMIEKTF	Gastric adenocarcinoma	2B72	Phase 1	[10]
BAY1179470	DM7L91K	Solid tumour/cancer	2A00-2F9Z	Phase 1	[11]
RLY-4008	DM3O52N	Solid tumour/cancer	2A00-2F9Z	Phase 1	[12]

1 Discontinued Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
PD-0183812	DMWYP86	Retinoblastoma	2D02.2	Terminated	[13]

6 Investigative Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
ACTB-1003	DMPHSU8	Solid tumour/cancer	2A00-2F9Z	Investigative	[14]
Anti-FGFR2 humanized mab	DMMQ3WX	Solid tumour/cancer	2A00-2F9Z	Investigative	[14]
PK 11195	DMDOZPU	Discovery agent	N.A.	Investigative	[2]
Platelet factor 4 (PF-4)	DMV34O2	Discovery agent	N.A.	Investigative	[15]
Ro-4396686	DM5DMCH	Discovery agent	N.A.	Investigative	[16]
TG-100435	DMIR3X2	Discovery agent	N.A.	Investigative	[17]

Molecular Expression Atlas (MEA) of This DTT

Disease Name	ICD 11	Studied Tissue	p-value	Fold-Change	Z-score
Alzheimer's disease	8A00.0	Entorhinal cortex	4.82E-01	-0.03	-0.2
Retinoblastoma	2C82	Uvea	9.74E-01	1.08E-03	6.61E-03
Interstitial cystitis	GA10	Bladder tissue	6.15E-01	-0.05	-0.39

References

• [1] Keratinocyte growth factor. Expert Opin Biol Ther. 2009 Jun;9(6):779-87.
• [2] DrugBank: a knowledgebase for drugs, drug actions and drug targets. Nucleic Acids Res. 2008 Jan;36(Database issue):D901-6.
• [3] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health Human Services. 2020
• [4] E-3810 is a potent dual inhibitor of VEGFR and FGFR that exerts antitumor activity in multiple preclinical models. Cancer Res. 2011 Feb 15;71(4):1396-405.
• [5] Emerging drugs for diabetic foot ulcers. Expert Opin Emerg Drugs. 2006 Nov;11(4):709-24.
• [6] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
• [7] Company report (Eli Lilly) (drug: LY2874455)
• [8] A comparison of physicochemical property profiles of marketed oral drugs and orally bioavailable anti-cancer protein kinase inhibitors in clinical development. Curr Top Med Chem. 2007;7(14):1408-22.
• [9] MK-2461, a novel multitargeted kinase inhibitor, preferentially inhibits the activated c-Met receptor. Cancer Res. 2010 Feb 15;70(4):1524-33.
• [10] Corrigendum to 'Targeting FGFR2 with alofanib (RPT835) shows potent activity in tumour models' [Eur J Cancer 61 (2016) 20-28]. Eur J Cancer. 2017 Jan;70:156.
• [11] National Cancer Institute Drug Dictionary (drug id 751593).
• [12] Clinical pipeline report, company report or official report of Relay Therapeutics.
• [13] Pyrido[2,3-d]pyrimidin-7-one inhibitors of cyclin-dependent kinases. J Med Chem. 2000 Nov 30;43(24):4606-16.
• [14] URL: http://www.guidetopharmacology.org Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Target id: 1809).
• [15] A short peptide domain of platelet factor 4 blocks angiogenic key events induced by FGF-2. FASEB J. 2001 Mar;15(3):550-2.
• [16] Biological evaluation of a multi-targeted small molecule inhibitor of tumor-induced angiogenesis. Bioorg Med Chem Lett. 2006 Apr 1;16(7):1950-3.
• [17] Discovery of [7-(2,6-dichlorophenyl)-5-methylbenzo [1,2,4]triazin-3-yl]-[4-(2-pyrrolidin-1-ylethoxy)phenyl]amine--a potent, orally active Src kinas... Bioorg Med Chem Lett. 2007 Feb 1;17(3):602-8.