Details of the Drug Therapeutic Target (DTT)

General Information of Drug Therapeutic Target (DTT) (ID: TTRLW2X)

• DTT Name: Fibroblast growth factor receptor 1 (FGFR1)
• Synonyms: c-fgr; bFGF-R-1; bFGF-R; N-sam; HBGFR; Fms-like tyrosine kinase 2; FLT2; FLT-2; FLG; FGFR-1; FGFBR; CEK; CD331 antigen; CD331; Basic fibroblast growth factor receptor 1; BFGFR
• Gene Name: FGFR1
• DTT Type: Successful target; [1]
• BioChemical Class: Kinase
• UniProt ID: FGFR1_HUMAN
• TTD ID: T47101
• EC Number: EC 2.7.10.1
• Sequence:
  MWSWKCLLFWAVLVTATLCTARPSPTLPEQAQPWGAPVEVESFLVHPGDLLQLRCRLRDD
  VQSINWLRDGVQLAESNRTRITGEEVEVQDSVPADSGLYACVTSSPSGSDTTYFSVNVSD
  ALPSSEDDDDDDDSSSEEKETDNTKPNRMPVAPYWTSPEKMEKKLHAVPAAKTVKFKCPS
  SGTPNPTLRWLKNGKEFKPDHRIGGYKVRYATWSIIMDSVVPSDKGNYTCIVENEYGSIN
  HTYQLDVVERSPHRPILQAGLPANKTVALGSNVEFMCKVYSDPQPHIQWLKHIEVNGSKI
  GPDNLPYVQILKTAGVNTTDKEMEVLHLRNVSFEDAGEYTCLAGNSIGLSHHSAWLTVLE
  ALEERPAVMTSPLYLEIIIYCTGAFLISCMVGSVIVYKMKSGTKKSDFHSQMAVHKLAKS
  IPLRRQVTVSADSSASMNSGVLLVRPSRLSSSGTPMLAGVSEYELPEDPRWELPRDRLVL
  GKPLGEGCFGQVVLAEAIGLDKDKPNRVTKVAVKMLKSDATEKDLSDLISEMEMMKMIGK
  HKNIINLLGACTQDGPLYVIVEYASKGNLREYLQARRPPGLEYCYNPSHNPEEQLSSKDL
  VSCAYQVARGMEYLASKKCIHRDLAARNVLVTEDNVMKIADFGLARDIHHIDYYKKTTNG
  RLPVKWMAPEALFDRIYTHQSDVWSFGVLLWEIFTLGGSPYPGVPVEELFKLLKEGHRMD
  KPSNCTNELYMMMRDCWHAVPSQRPTFKQLVEDLDRIVALTSNQEYLDLSMPLDQYSPSF
  PDTRSSTCSSGEDSVFSHEPLPEEPCLPRHPAQLANGGLKRR
• Function: Required for normal mesoderm patterning and correct axial organization during embryonic development, normal skeletogenesis and normal development of the gonadotropin-releasing hormone (GnRH) neuronal system. Phosphorylates PLCG1, FRS2, GAB1 and SHB. 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. Promotes phosphorylation of SHC1, STAT1 and PTPN11/SHP2. In the nucleus, enhances RPS6KA1 and CREB1 activity and contributes to the regulation of transcription. FGFR1 signaling is down-regulated by IL17RD/SEF, and by FGFR1 ubiquitination, internalization and degradation. Tyrosine-protein kinase that acts as cell-surface receptor for fibroblast growth factors and plays an essential role in the regulation of embryonic development, cell proliferation, differentiation and migration.
• KEGG Pathway:
  MAPK signaling pathway (hsa04010)
  Ras signaling pathway (hsa04014)
  Rap1 signaling pathway (hsa04015)
  PI3K-Akt signaling pathway (hsa04151)
  Adherens junction (hsa04520)
  Signaling pathways regulating pluripotency of stem cells (hsa04550)
  Regulation of actin cytoskeleton (hsa04810)
  Pathways in cancer (hsa05200)
  Proteoglycans in cancer (hsa05205)
  Prostate cancer (hsa05215)
  Melanoma (hsa05218)
  Central carbon metabolism in cancer (hsa05230)
• Reactome Pathway:
  PIP3 activates AKT signaling (R-HSA-1257604)
  Signaling by FGFR1 amplification mutants (R-HSA-1839120)
  Signaling by activated point mutants of FGFR1 (R-HSA-1839122)
  FGFR1b ligand binding and activation (R-HSA-190370)
  FGFR1c ligand binding and activation (R-HSA-190373)
  FGFR1c and Klotho ligand binding and activation (R-HSA-190374)
  Constitutive Signaling by Aberrant PI3K in Cancer (R-HSA-2219530)
  NCAM signaling for neurite out-growth (R-HSA-375165)
  Signal transduction by L1 (R-HSA-445144)
  Phospholipase C-mediated cascade (R-HSA-5654219)
  Downstream signaling of activated FGFR1 (R-HSA-5654687)
  SHC-mediated cascade (R-HSA-5654688)
  PI-3K cascade (R-HSA-5654689)
  FRS-mediated FGFR1 signaling (R-HSA-5654693)
  Negative regulation of FGFR1 signaling (R-HSA-5654726)
  Signaling by FGFR1 in disease (R-HSA-5655302)
  RAF/MAP kinase cascade (R-HSA-5673001)
  PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling (R-HSA-6811558)
  Signaling by plasma membrane FGFR1 fusions (R-HSA-8853336)
  PI3K Cascade (R-HSA-109704)

Molecular Interaction Atlas (MIA) of This DTT

4 Approved Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Infigratinib	DMNKBEC	Cholangiocarcinoma	2C12.10	Approved	[2]
Intedanib	DMSTA36	Colorectal cancer	2B91.Z	Approved	[3]
Pemigatinib	DM819JF	Cholangiocarcinoma	2C12.10	Approved	[4]
Romiplostim	DM3U7SZ	Thrombocytopenia	3B64	Approved	[1]

12 Clinical Trial Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
ARQ-087	DM02BVQ	Intrahepatic cholangiocarcinoma	2C12.10	Phase 3	[5]
E-3810	DM42PFT	Solid tumour/cancer	2A00-2F9Z	Phase 3	[6]
Sulfatinib	DMPOTM4	Neuroendocrine cancer	2B72.1	Phase 3	[7]
AZD4547	DM3827C	Solid tumour/cancer	2A00-2F9Z	Phase 2/3	[8]
AM-001	DMGVQI8	Actinic keratosis	EK90.0	Phase 2	[9]
Debio 1347	DMZW50O	Solid tumour/cancer	2A00-2F9Z	Phase 2	[10]
FGF-1	DMXMC8I	Coronary heart disease	BA80.Z	Phase 2	[11]
FP-1039	DMUAXS5	Endometrial cancer	2C76	Phase 2	[12]
MK-3655	DMM5SVL	Non-alcoholic steatohepatitis	DB92.1	Phase 2	[13]
MK-2461	DM21WBH	Alzheimer disease	8A20	Phase 1/2	[14]
KW-2449	DMFO7RP	Acute myeloid leukaemia	2A60	Phase 1	[15]
NGM313	DMYNSRH	Type-2 diabetes	5A11	Phase 1	[16]

1 Preclinical Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
BMS-695735	DMQG39T	Solid tumour/cancer	2A00-2F9Z	Preclinical	[17]

1 Discontinued Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
PD-0183812	DMWYP86	Retinoblastoma	2D02.2	Terminated	[18]

19 Investigative Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
2-(1H-indazol-3-yl)-1H-benzo[d]imidazole	DM0CSH8	Discovery agent	N.A.	Investigative	[19]
3-(3-methoxybenzyl)-1H-pyrrolo[2,3-b]pyridine	DMU53NZ	Discovery agent	N.A.	Investigative	[20]
3-Benzimidazol-2-ylhydroquinolin-2-one	DMQXJA1	Discovery agent	N.A.	Investigative	[21]
AAL-993	DM35RFH	Discovery agent	N.A.	Investigative	[1]
ACTB-1003	DMPHSU8	Solid tumour/cancer	2A00-2F9Z	Investigative	[5]
Anti-FGFR1 mab program	DMP5VZQ	Solid tumour/cancer	2A00-2F9Z	Investigative	[5]
HKI-9924129	DM5LR2B	Gram-positive bacterial infection	1B74-1G40	Investigative	[22]
NP-506	DMVPIF8	Discovery agent	N.A.	Investigative	[23]
PD-0166326	DMD2CG9	Discovery agent	N.A.	Investigative	[22]
PD-0173952	DMSCQ9U	Discovery agent	N.A.	Investigative	[22]
PD-0173955	DMOZEW9	Discovery agent	N.A.	Investigative	[22]
PD-0173956	DM8RW92	Discovery agent	N.A.	Investigative	[22]
PD-0173958	DMZQ8YV	Discovery agent	N.A.	Investigative	[22]
PD-0179483	DMKO8LE	Discovery agent	N.A.	Investigative	[22]
PMID22765894C8h	DMH5RFU	Discovery agent	N.A.	Investigative	[24]
PMID24900538C2c	DM5PATM	Discovery agent	N.A.	Investigative	[25]
PMID26080733C7r	DM8D6ZL	Discovery agent	N.A.	Investigative	[26]
Ro-4396686	DM5DMCH	Discovery agent	N.A.	Investigative	[27]
SAR-106881	DM2J0UN	Peripheral arterial disease	BD4Z	Investigative	[5]

Molecular Expression Atlas (MEA) of This DTT

Disease Name	ICD 11	Studied Tissue	p-value	Fold-Change	Z-score
Uterine cancer	2C82	Endometrium tissue	1.04E-02	-0.2	-0.38
Atopic dermatitis	EA90	Skin	1.06E-01	-0.12	-0.72
Alzheimer's disease	8A00.0	Entorhinal cortex	4.79E-02	-0.03	-0.15
Acute myelocytic leukaemia	2C82	Bone marrow	5.16E-02	1.24E-03	4.64E-03
Ovarian cancer	2C82	Ovarian tissue	3.31E-03	-0.74	-1.73
Retinoblastoma	2C82	Uvea	3.33E-03	-0.58	-2.4
Liver cancer	2C82	Liver tissue	1.18E-03	-0.12	-0.59
Renal cancer	2C82	Kidney	2.92E-01	0.07	0.28
Parkinson's disease	8A00.0	Substantia nigra tissue	7.85E-01	-0.02	-0.16

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