Target Information
| Target General Information | Top | |||||
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| Target ID |
T91331
(Former ID: TTDC00131)
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| Target Name |
Fibroblast growth factor receptor 3 (FGFR3)
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| Synonyms |
JTK4; FGFR-3; CD333
Click to Show/Hide
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| Gene Name |
FGFR3
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| Target Type |
Successful target
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[1] | ||||
| Disease | [+] 3 Target-related Diseases | + | ||||
| 1 | Liver cancer [ICD-11: 2C12] | |||||
| 2 | Coronary atherosclerosis [ICD-11: BA80] | |||||
| 3 | Myocardial infarction [ICD-11: BA41-BA43] | |||||
| Function |
Plays an essential role in the regulation of chondrocyte differentiation, proliferation and apoptosis, and is required for normal skeleton development. Regulates both osteogenesis and postnatal bone mineralization by osteoblasts. Promotes apoptosis in chondrocytes, but can also promote cancer cell proliferation. Required for normal development of the inner ear. Phosphorylates PLCG1, CBL and FRS2. 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. Plays a role in the regulation of vitamin D metabolism. Mutations that lead to constitutive kinase activation or impair normal FGFR3 maturation, internalization and degradation lead to aberrant signaling. Over-expressed or constitutively activated FGFR3 promotes activation of PTPN11/SHP2, STAT1, STAT5A and STAT5B. Secreted isoform 3 retains its capacity to bind FGF1 and FGF2 and hence may interfere with FGF signaling. 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 and apoptosis.
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| BioChemical Class |
Kinase
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| UniProt ID | ||||||
| EC Number |
EC 2.7.10.1
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| Sequence |
MGAPACALALCVAVAIVAGASSESLGTEQRVVGRAAEVPGPEPGQQEQLVFGSGDAVELS
CPPPGGGPMGPTVWVKDGTGLVPSERVLVGPQRLQVLNASHEDSGAYSCRQRLTQRVLCH FSVRVTDAPSSGDDEDGEDEAEDTGVDTGAPYWTRPERMDKKLLAVPAANTVRFRCPAAG NPTPSISWLKNGREFRGEHRIGGIKLRHQQWSLVMESVVPSDRGNYTCVVENKFGSIRQT YTLDVLERSPHRPILQAGLPANQTAVLGSDVEFHCKVYSDAQPHIQWLKHVEVNGSKVGP DGTPYVTVLKTAGANTTDKELEVLSLHNVTFEDAGEYTCLAGNSIGFSHHSAWLVVLPAE EELVEADEAGSVYAGILSYGVGFFLFILVVAAVTLCRLRSPPKKGLGSPTVHKISRFPLK RQVSLESNASMSSNTPLVRIARLSSGEGPTLANVSELELPADPKWELSRARLTLGKPLGE GCFGQVVMAEAIGIDKDRAAKPVTVAVKMLKDDATDKDLSDLVSEMEMMKMIGKHKNIIN LLGACTQGGPLYVLVEYAAKGNLREFLRARRPPGLDYSFDTCKPPEEQLTFKDLVSCAYQ VARGMEYLASQKCIHRDLAARNVLVTEDNVMKIADFGLARDVHNLDYYKKTTNGRLPVKW MAPEALFDRVYTHQSDVWSFGVLLWEIFTLGGSPYPGIPVEELFKLLKEGHRMDKPANCT HDLYMIMRECWHAAPSQRPTFKQLVEDLDRVLTVTSTDEYLDLSAPFEQYSPGGQDTPSS SSSGDDSVFAHDLLPPAPPSSGGSRT Click to Show/Hide
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| 3D Structure | Click to Show 3D Structure of This Target | AlphaFold | ||||
| Drugs and Modes of Action | Top | |||||
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| Approved Drug(s) | [+] 1 Approved Drugs | + | ||||
| 1 | Pemigatinib | Drug Info | Approved | Cholangiocarcinoma | [2] | |
| Clinical Trial Drug(s) | [+] 6 Clinical Trial Drugs | + | ||||
| 1 | BMS-582664 | Drug Info | Phase 3 | Hepatocellular carcinoma | [4], [5] | |
| 2 | E-3810 | Drug Info | Phase 3 | Solid tumour/cancer | [6], [7] | |
| 3 | TKI258 | Drug Info | Phase 3 | Renal cell carcinoma | [8] | |
| 4 | B-701 | Drug Info | Phase 2 | Bladder cancer | [11], [12] | |
| 5 | AEE-788 | Drug Info | Phase 1/2 | Solid tumour/cancer | [13], [14] | |
| 6 | MK-2461 | Drug Info | Phase 1/2 | Alzheimer disease | [15] | |
| Mode of Action | [+] 2 Modes of Action | + | ||||
| Inhibitor | [+] 11 Inhibitor drugs | + | ||||
| 1 | Pemigatinib | Drug Info | [2] | |||
| 2 | BMS-582664 | Drug Info | [19] | |||
| 3 | E-3810 | Drug Info | [20] | |||
| 4 | TKI258 | Drug Info | [19] | |||
| 5 | AEE-788 | Drug Info | [19] | |||
| 6 | MK-2461 | Drug Info | [15] | |||
| 7 | 5,11-Dimethyl-6H-pyrido[4,3-b]carbazol-9-ol | Drug Info | [21] | |||
| 8 | ACTB-1003 | Drug Info | [22] | |||
| 9 | PMID21493067C1d | Drug Info | [23] | |||
| 10 | Ro-4396686 | Drug Info | [24] | |||
| 11 | SU5402 | Drug Info | [1] | |||
| Antagonist | [+] 1 Antagonist drugs | + | ||||
| 1 | B-701 | Drug Info | [12] | |||
| Cell-based Target Expression Variations | Top | |||||
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| Cell-based Target Expression Variations | ||||||
| Drug Binding Sites of Target | Top | |||||
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| Ligand Name: L-betagamma-meATP | Ligand Info | |||||
| Structure Description | Crystal Structure of an Asymmetric Dimer of FGF Receptor 3 Kinases Trapped in A-loop Tyrosine Transphosphorylation Reaction | PDB:6PNX | ||||
| Method | X-ray diffraction | Resolution | 2.20 Å | Mutation | Yes | [25] |
| PDB Sequence |
ELELPADPKW
465 ELSRARLTLG475 KPLGEGAFGQ485 VVMAEAIGID495 KDRAAKPVTV505 AVKMLKDDAT 515 DKDLSDLVSE525 MEMMKMIGKH535 KNIINLLGAC545 TQGGPLYVLV555 EYAAKGNLRE 565 FLRARRPPPE586 EQLTFKDLVS596 CAYQVARGME606 YLASQKCIHR616 DLAARNVLVT 626 EDNVMKIADF636 GLARDVHNLD646 YYKKTTNGRL656 PVKWMAPEAL666 FDEVYTHQSD 676 VWSFGVLLWE686 IFTLGGSPYP696 GIPVEELFKL706 LKEGHRMDKP716 ANCTHDLYMI 726 MRECWHAAPS736 QRPTFKQLVE746 DLDRVLTVTS756 T
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| Click to View More Binding Site Information of This Target and Ligand Pair | ||||||
| Ligand Name: Phosphonotyrosine | Ligand Info | |||||
| Structure Description | Crystal structure of FGFR3 in complex with pyrimidine derivative | PDB:6LVM | ||||
| Method | X-ray diffraction | Resolution | 2.53 Å | Mutation | No | [26] |
| PDB Sequence |
PEDPKWEFPR
469 DKLTLGKPLG479 EGCFGQVVMA489 EAIGIDKDRA499 AKPVTVAVKM509 LKDDATDKDL 519 SDLVSEMEMM529 KMIGKHKNII539 NLLGACTQGG549 PLYVLVEYAA559 KGNLREFLRA 569 RRPPGLDSEQ588 LTFKDLVSCA598 YQVARGMEYL608 ASQKCIHRDL618 AARNVLVTED 628 NVMKIADFGL638 ARDVHNLDKK650 TTNGRLPVKW660 MAPEALFDRV670 YTHQSDVWSF 680 GVLLWEIFTL690 GGSPYPGIPV700 EELFKLLKEG710 HRMDKPANCT720 HDLYMIMREC 730 WHAAPSQRPT740 FKQLVEDLDR750 VLTVT
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| Click to View More Binding Site Information of This Target and Ligand Pair | ||||||
| Click to View More Binding Site Information of This Target with Different Ligands | ||||||
| Different Human System Profiles of Target | Top |
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Human Similarity Proteins
of target is determined by comparing the sequence similarity of all human proteins with the target based on BLAST. The similarity proteins for a target are defined as the proteins with E-value < 0.005 and outside the protein families of the target.
A target that has fewer human similarity proteins outside its family is commonly regarded to possess a greater capacity to avoid undesired interactions and thus increase the possibility of finding successful drugs
(Brief Bioinform, 21: 649-662, 2020).
Human Tissue Distribution
of target is determined from a proteomics study that quantified more than 12,000 genes across 32 normal human tissues. Tissue Specificity (TS) score was used to define the enrichment of target across tissues.
The distribution of targets among different tissues or organs need to be taken into consideration when assessing the target druggability, as it is generally accepted that the wider the target distribution, the greater the concern over potential adverse effects
(Nat Rev Drug Discov, 20: 64-81, 2021).
Human Pathway Affiliation
of target is determined by the life-essential pathways provided on KEGG database. The target-affiliated pathways were defined based on the following two criteria (a) the pathways of the studied target should be life-essential for both healthy individuals and patients, and (b) the studied target should occupy an upstream position in the pathways and therefore had the ability to regulate biological function.
Targets involved in a fewer pathways have greater likelihood to be successfully developed, while those associated with more human pathways increase the chance of undesirable interferences with other human processes
(Pharmacol Rev, 58: 259-279, 2006).
Biological Network Descriptors
of target is determined based on a human protein-protein interactions (PPI) network consisting of 9,309 proteins and 52,713 PPIs, which were with a high confidence score of ≥ 0.95 collected from STRING database.
The network properties of targets based on protein-protein interactions (PPIs) have been widely adopted for the assessment of target’s druggability. Proteins with high node degree tend to have a high impact on network function through multiple interactions, while proteins with high betweenness centrality are regarded to be central for communication in interaction networks and regulate the flow of signaling information
(Front Pharmacol, 9, 1245, 2018;
Curr Opin Struct Biol. 44:134-142, 2017).
Human Similarity Proteins
Human Tissue Distribution
Human Pathway Affiliation
Biological Network Descriptors
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Note:
If a protein has TS (tissue specficity) scores at least in one tissue >= 2.5, this protein is called tissue-enriched (including tissue-enriched-but-not-specific and tissue-specific). In the plots, the vertical lines are at thresholds 2.5 and 4.
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| KEGG Pathway | Pathway ID | Affiliated Target | Pathway Map |
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| MAPK signaling pathway | hsa04010 | Affiliated Target |
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| Class: Environmental Information Processing => Signal transduction | Pathway Hierarchy | ||
| Ras signaling pathway | hsa04014 | Affiliated Target |
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| Class: Environmental Information Processing => Signal transduction | Pathway Hierarchy | ||
| Rap1 signaling pathway | hsa04015 | Affiliated Target |
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| Class: Environmental Information Processing => Signal transduction | Pathway Hierarchy | ||
| Calcium signaling pathway | hsa04020 | Affiliated Target |
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| Class: Environmental Information Processing => Signal transduction | Pathway Hierarchy | ||
| Endocytosis | hsa04144 | Affiliated Target |
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| Class: Cellular Processes => Transport and catabolism | Pathway Hierarchy | ||
| PI3K-Akt signaling pathway | hsa04151 | Affiliated Target |
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| Class: Environmental Information Processing => Signal transduction | Pathway Hierarchy | ||
| Signaling pathways regulating pluripotency of stem cells | hsa04550 | Affiliated Target |
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| Class: Cellular Processes => Cellular community - eukaryotes | Pathway Hierarchy | ||
| Regulation of actin cytoskeleton | hsa04810 | Affiliated Target |
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| Class: Cellular Processes => Cell motility | Pathway Hierarchy | ||
| Click to Show/Hide the Information of Affiliated Human Pathways | |||
| Degree | 20 | Degree centrality | 2.15E-03 | Betweenness centrality | 6.13E-04 |
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| Closeness centrality | 2.35E-01 | Radiality | 1.41E+01 | Clustering coefficient | 2.74E-01 |
| Neighborhood connectivity | 4.63E+01 | Topological coefficient | 1.12E-01 | Eccentricity | 12 |
| Download | Click to Download the Full PPI Network of This Target | ||||
| Chemical Structure based Activity Landscape of Target | Top |
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| Drug Property Profile of Target | Top | |
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| (1) Molecular Weight (mw) based Drug Clustering | (2) Octanol/Water Partition Coefficient (xlogp) based Drug Clustering | |
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| (3) Hydrogen Bond Donor Count (hbonddonor) based Drug Clustering | (4) Hydrogen Bond Acceptor Count (hbondacc) based Drug Clustering | |
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| (5) Rotatable Bond Count (rotbonds) based Drug Clustering | (6) Topological Polar Surface Area (polararea) based Drug Clustering | |
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| "RO5" indicates the cutoff set by lipinski's rule of five; "D123AB" colored in GREEN denotes the no violation of any cutoff in lipinski's rule of five; "D123AB" colored in PURPLE refers to the violation of only one cutoff in lipinski's rule of five; "D123AB" colored in BLACK represents the violation of more than one cutoffs in lipinski's rule of five | ||
| Co-Targets | Top | |||||
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| Co-Targets | ||||||
| Target Poor or Non Binders | Top | |||||
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| Target Poor or Non Binders | ||||||
| Target Regulators | Top | |||||
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| Target-regulating microRNAs | ||||||
| Target-interacting Proteins | ||||||
| Target Profiles in Patients | Top | |||||
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| Target Expression Profile (TEP) | ||||||
| Drug Resistance Mutation (DRM) | ||||||
| Target Affiliated Biological Pathways | Top | |||||
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| KEGG Pathway | [+] 11 KEGG Pathways | + | ||||
| 1 | MAPK signaling pathway | |||||
| 2 | Ras signaling pathway | |||||
| 3 | Rap1 signaling pathway | |||||
| 4 | Endocytosis | |||||
| 5 | PI3K-Akt signaling pathway | |||||
| 6 | Signaling pathways regulating pluripotency of stem cells | |||||
| 7 | Regulation of actin cytoskeleton | |||||
| 8 | Pathways in cancer | |||||
| 9 | MicroRNAs in cancer | |||||
| 10 | Bladder cancer | |||||
| 11 | Central carbon metabolism in cancer | |||||
| Panther Pathway | [+] 1 Panther Pathways | + | ||||
| 1 | FGF signaling pathway | |||||
| Reactome | [+] 1 Reactome Pathways | + | ||||
| 1 | FGFR3 mutant receptor activation | |||||
| WikiPathways | [+] 5 WikiPathways | + | ||||
| 1 | Regulation of Actin Cytoskeleton | |||||
| 2 | Endochondral Ossification | |||||
| 3 | Bladder Cancer | |||||
| 4 | Neural Crest Differentiation | |||||
| 5 | Signaling by FGFR | |||||
| Target-Related Models and Studies | Top | |||||
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| Target Validation | ||||||
| References | Top | |||||
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| REF 1 | Emerging therapies for multiple myeloma. Expert Opin Emerg Drugs. 2009 Mar;14(1):99-127. | |||||
| REF 2 | Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health Human Services. 2020 | |||||
| REF 3 | ClinicalTrials.gov (NCT00914420) Optical Coherence Tomography (OCT) Evaluation of Re-endothelization: A Comparison of the Intrepide Stent Versus Taxus . U.S. National Institutes of Health. | |||||
| REF 4 | 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. (Ligand id: 8097). | |||||
| REF 5 | ClinicalTrials.gov (NCT00908752) Phase III Trans-Arterial Chemo-Embolization (TACE) Adjuvant HCC. U.S. National Institutes of Health. | |||||
| REF 6 | 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. (Ligand id: 7649). | |||||
| REF 7 | ClinicalTrials.gov (NCT02135107) A Double-blind Comparative Study of the Efficacy and Safety of E3810 10mg Once and Twice Daily in Maintenance Therapy for PPI Resistant Gastroesophageal Reflux Disease Patients. U.S. National Institutes of Health. | |||||
| REF 8 | ClinicalTrials.gov (NCT01223027) Study of Dovitinib Versus Sorafenib in Patients With Metastatic Renal Cell Carcinoma. U.S. National Institutes of Health. | |||||
| REF 9 | ClinicalTrials.gov (NCT03834220) Basket Trial in Solid Tumors Harboring a Fusion of FGFR1, FGFR2 or FGFR3- (FUZE Clinical Trial). U.S. National Institutes of Health. | |||||
| REF 10 | ClinicalTrials.gov (NCT04638153) A Study Of Safety, Tolerability And Effectiveness Of Recifercept In Children With Achondroplasia. U.S. National Institutes of Health. | |||||
| REF 11 | Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA) | |||||
| REF 12 | Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA) | |||||
| REF 13 | 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. (Ligand id: 7643). | |||||
| REF 14 | ClinicalTrials.gov (NCT00107237) AEE788 and Everolimus in Treating Patients With Recurrent or Relapsed Glioblastoma Multiforme. U.S. National Institutes of Health. | |||||
| REF 15 | MK-2461, a novel multitargeted kinase inhibitor, preferentially inhibits the activated c-Met receptor. Cancer Res. 2010 Feb 15;70(4):1524-33. | |||||
| REF 16 | Clinical pipeline report, company report or official report of Genentech (2011). | |||||
| REF 17 | Clinical pipeline report, company report or official report of Sanofi | |||||
| REF 18 | Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800014130) | |||||
| REF 19 | 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. | |||||
| REF 20 | 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. | |||||
| REF 21 | Molecular modeling of wild-type and D816V c-Kit inhibition based on ATP-competitive binding of ellipticine derivatives to tyrosine kinases. J Med Chem. 2005 Oct 6;48(20):6194-201. | |||||
| REF 22 | 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: 1810). | |||||
| REF 23 | In vitro and in vivo evaluation of 6-aminopyrazolyl-pyridine-3-carbonitriles as JAK2 kinase inhibitors. Bioorg Med Chem Lett. 2011 May 15;21(10):2958-61. | |||||
| REF 24 | Biological evaluation of a multi-targeted small molecule inhibitor of tumor-induced angiogenesis. Bioorg Med Chem Lett. 2006 Apr 1;16(7):1950-3. | |||||
| REF 25 | Molecular basis for receptor tyrosine kinase A-loop tyrosine transphosphorylation. Nat Chem Biol. 2020 Mar;16(3):267-277. | |||||
| REF 26 | Structure-based drug design of 1,3,5-triazine and pyrimidine derivatives as novel FGFR3 inhibitors with high selectivity over VEGFR2. Bioorg Med Chem. 2020 May 15;28(10):115453. | |||||
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