IUPHAR/BPS Guide to Pharmacology CITE
https://doi.org/10.2218/gtopdb/F324/2025.3
Type IV RTKs: VEGF (vascular endothelial growth factor) receptor family in GtoPdb v.2025.3
Laura E. Kilpatrick1
- University of Nottingham, UK
Abstract
VEGF receptors are homo- and heterodimeric proteins, which are characterized by seven Ig-like loops in their extracellular domains and a split kinase domain in the cytoplasmic region. They are key regulators of angiogenesis and lymphangiogenesis; as such, they have been the focus of drug discovery for conditions such as metastatic cancer. Splice variants of VEGFR1 and VEGFR2 generate truncated proteins limited to the extracellular domains, capable of homodimerisation and binding VEGF ligands as a soluble, non-signalling entity. Ligands at VEGF receptors are typically homodimeric. VEGFA is able to activate VEGFR1 and VEGFR2 homodimers, VEGFR1/2 heterodimers and VEGFR2/3 heterodimers. VEGFB and placental growth factor activate VEGFR1 homodimers, while VEGFC and VEGFD activate VEGFR2/3 heterodimers and VEGFR3 homodimers, and, following proteolysis, VEGFR2 homodimers.
Contents
This is a citation summary for Type IV RTKs: VEGF (vascular endothelial growth factor) receptor family in the
Guide to Pharmacology
database (GtoPdb). It exists purely as an adjunct to the database to
facilitate the recognition of citations to and from the database by
citation analyzers. Readers will almost certainly want to visit the
relevant sections of the database which are given here under database
links.
GtoPdb is an expert-driven
guide to pharmacological targets and the substances that act on them.
GtoPdb is a reference work which is most usefully represented as an
on-line database. As in any publication this work should be
appropriately cited, and the papers it cites should also be
recognized. This document provides a citation for the relevant parts
of the database, and also provides a reference list for the research
cited by those parts. For further details see [13].
Please note that the database version for the citations given in
GtoPdb are to the most recent preceding version
in which the family or its subfamilies and targets were substantially
changed. The links below are to the current version. If you
need to consult the cited version, rather than the most recent version, please contact
the GtoPdb curators.
Database links
Type IV RTKs: VEGF (vascular endothelial growth factor) receptor family
https://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=324
Receptors
VEGFR-1(fms related receptor tyrosine kinase 1)
https://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=1812
VEGFR-2(kinase insert domain receptor)
https://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=1813
VEGFR-3(fms related receptor tyrosine kinase 4)
https://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=1814
References
- Adams CM, Anderson K, Artman 3rd G, Bizec JC, Cepeda R, Elliott J, Fassbender E, Ghosh M, Hanks S and Hardegger LA et al.. (2018) The Discovery of N-(1-Methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)-5-((6- ((methylamino)methyl)pyrimidin-4-yl)oxy)-1H-indole-1-carboxamide (Acrizanib), a VEGFR-2 Inhibitor Specifically Designed for Topical Ocular Delivery, as a Therapy for Neovascular Age-Related Macular Degeneration. J Med Chem 61: 1622-1635 [PMID:29400470]
- Akeno-Stuart N, Croyle M, Knauf JA, Malaguarnera R, Vitagliano D, Santoro M, Stephan C, Grosios K, Wartmann M and Cozens R et al.. (2007) The RET kinase inhibitor NVP-AST487 blocks growth and calcitonin gene expression through distinct mechanisms in medullary thyroid cancer cells. Cancer Res 67: 6956-64 [PMID:17638907]
- Albert DH, Tapang P, Magoc TJ, Pease LJ, Reuter DR, Wei RQ, Li J, Guo J, Bousquet PF and Ghoreishi-Haack NS et al.. (2006) Preclinical activity of ABT-869, a multitargeted receptor tyrosine kinase inhibitor. Mol Cancer Ther 5: 995-1006 [PMID:16648571]
- Anastassiadis T, Deacon SW, Devarajan K, Ma H and Peterson JR. (2011) Comprehensive assay of kinase catalytic activity reveals features of kinase inhibitor selectivity. Nat Biotechnol 29: 1039-45 [PMID:22037377]
- Antczak C, Mahida JP, Bhinder B, Calder PA and Djaballah H. (2012) A high-content biosensor-based screen identifies cell-permeable activators and inhibitors of EGFR function: implications in drug discovery. J Biomol Screen 17: 885-99 [PMID:22573732]
- Apsel B, Blair JA, Gonzalez B, Nazif TM, Feldman ME, Aizenstein B, Hoffman R, Williams RL, Shokat KM and Knight ZA. (2008) Targeted polypharmacology: discovery of dual inhibitors of tyrosine and phosphoinositide kinases. Nat Chem Biol 4: 691-9 [PMID:18849971]
- AstraZeneca. AZD4547. http://openinnovation.astrazeneca.com/what-we-offer/compound/azd4547/. Accessed on 11/09/2014.
- Bachegowda L, Morrone K, Winski SL, Mantzaris I, Bartenstein M, Ramachandra N, Giricz O, Sukrithan V, Nwankwo G and Shahnaz S et al.. (2016) Pexmetinib: A Novel Dual Inhibitor of Tie2 and p38 MAPK with Efficacy in Preclinical Models of Myelodysplastic Syndromes and Acute Myeloid Leukemia. Cancer Res 76: 4841-4849 [PMID:27287719]
- Barker MD, Liddle J, Atkinson FL, Wilson DM, Dickson MC, Ramirez-Molina C, Lewis H, Davis RP, Somers DO and Neu M et al.. (2018) Discovery of potent and selective Spleen Tyrosine Kinase inhibitors for the topical treatment of inflammatory skin disease. Bioorg Med Chem Lett 28: 3458-3462 [PMID:30249354]
- Beebe JS, Jani JP, Knauth E, Goodwin P, Higdon C, Rossi AM, Emerson E, Finkelstein M, Floyd E and Harriman S et al.. (2003) Pharmacological characterization of CP-547,632, a novel vascular endothelial growth factor receptor-2 tyrosine kinase inhibitor for cancer therapy. Cancer Res 63: 7301-9 [PMID:14612527]
- Bhide RS, Cai ZW, Zhang YZ, Qian L, Wei D, Barbosa S, Lombardo LJ, Borzilleri RM, Zheng X and Wu LI et al.. (2006) Discovery and preclinical studies of (R)-1-(4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-5- methylpyrrolo[2,1-f][1,2,4]triazin-6-yloxy)propan- 2-ol (BMS-540215), an in vivo active potent VEGFR-2 inhibitor. J Med Chem 49: 2143-6 [PMID:16570908]
- Bold G, Altmann KH, Frei J, Lang M, Manley PW, Traxler P, Wietfeld B, Brüggen J, Buchdunger E and Cozens R et al.. (2000) New anilinophthalazines as potent and orally well absorbed inhibitors of the VEGF receptor tyrosine kinases useful as antagonists of tumor-driven angiogenesis. J Med Chem 43: 2310-23 [PMID:10882357]
- Buneman P, Christie G, Davies JA, Dimitrellou R, Harding SD, Pawson AJ, Sharman JL and Wu Y. (2020) Why data citation isn't working, and what to do about it Database 2020 [PMID:32367113]
- Chen GP. (2008) Spiro substituted compounds as angiogenesis inhibitors Patent number: WO2008112407 A1. Assignee: Advenchen Laboratories, Llc. Priority date: 14/03/2007. Publication date: 18/09/2008.
- Cho TP, Dong SY, Jun F, Hong FJ, Liang YJ, Lu X, Hua PJ, Li LY, Lei Z and Bing H et al.. (2010) Novel potent orally active multitargeted receptor tyrosine kinase inhibitors: synthesis, structure-activity relationships, and antitumor activities of 2-indolinone derivatives. J Med Chem 53: 8140-9 [PMID:21028894]
- Claridge S, Raeppel F, Granger MC, Bernstein N, Saavedra O, Zhan L, Llewellyn D, Wahhab A, Deziel R and Rahil J et al.. (2008) Discovery of a novel and potent series of thieno[3,2-b]pyridine-based inhibitors of c-Met and VEGFR2 tyrosine kinases. Bioorg Med Chem Lett 18: 2793-8 [PMID:18434145]
- Conesa-Milián L, Falomir E, Murga J, Carda M and Marco JA. (2019) Novel multitarget inhibitors with antiangiogenic and immunomodulator properties. Eur J Med Chem 170: 87-98 [PMID:30878834]
- Curtin ML, Heyman HR, Frey RR, Marcotte PA, Glaser KB, Jankowski JR, Magoc TJ, Albert DH, Olson AM and Reuter DR et al.. (2012) Pyrazole diaminopyrimidines as dual inhibitors of KDR and Aurora B kinases. Bioorg Med Chem Lett 22: 4750-5 [PMID:22695126]
- Davis MI, Hunt JP, Herrgard S, Ciceri P, Wodicka LM, Pallares G, Hocker M, Treiber DK and Zarrinkar PP. (2011) Comprehensive analysis of kinase inhibitor selectivity. Nat Biotechnol 29: 1046-51 [PMID:22037378]
- Dominguez C, Smith L, Huang Q, Yuan C, Ouyang X, Cai L, Chen P, Kim J, Harvey T and Syed R et al.. (2007) Discovery of N-phenyl nicotinamides as potent inhibitors of Kdr. Bioorg Med Chem Lett 17: 6003-8 [PMID:17869515]
- Dumas JP, Joe TK, Kluender HCE, Lee W, Nagarantham D, Sibley RN, Su S, Boyer SJ and Dixon JA. (2001) Substituted pyridines and pyridazines with angiogenesis inhibiting activity Patent number: WO2001023375A2. Assignee: Bayer Corporation. Priority date: 28/09/1999. Publication date: 05/04/2001.
- Engers DW, Frist AY, Lindsley CW, Hong CC and Hopkins CR. (2013) 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 23: 3248-52 [PMID:23639540]
- Fedorov O, Marsden B, Pogacic V, Rellos P, Müller S, Bullock AN, Schwaller J, Sundström M and Knapp S. (2007) A systematic interaction map of validated kinase inhibitors with Ser/Thr kinases. Proc Natl Acad Sci USA 104: 20523-8 [PMID:18077363]
- Feldman RI, Wu JM, Polokoff MA, Kochanny MJ, Dinter H, Zhu D, Biroc SL, Alicke B, Bryant J and Yuan S et al.. (2005) Novel small molecule inhibitors of 3-phosphoinositide-dependent kinase-1. J Biol Chem 280: 19867-74 [PMID:15772071]
- Flynn DL, Kaufman MD and Smith BD. (2016) Inhibition of tumor cell interactions with the microenvironment resulting in a reduction in tumor growth and disease progression Patent number: WO2016061231. Assignee: Deciphera Pharmaceuticals, Llc. Priority date: 14/10/2014. Publication date: 21/04/2016.
- Fraley ME, Rubino RS, Hoffman WF, Hambaugh SR, Arrington KL, Hungate RW, Bilodeau MT, Tebben AJ, Rutledge RZ and Kendall RL et al.. (2002) Optimization of a pyrazolo[1,5-a]pyrimidine class of KDR kinase inhibitors: improvements in physical properties enhance cellular activity and pharmacokinetics. Bioorg Med Chem Lett 12: 3537-41 [PMID:12443771]
- Fujita H, Miyadera K, Kato M, Fujioka Y, Ochiiwa H, Huang J, Ito K, Aoyagi Y, Takenaka T and Suzuki T et al.. (2013) The novel VEGF receptor/MET-targeted kinase inhibitor TAS-115 has marked in vivo antitumor properties and a favorable tolerability profile. Mol Cancer Ther 12: 2685-96 [PMID:24140932]
- Gao Y, Davies SP, Augustin M, Woodward A, Patel UA, Kovelman R and Harvey KJ. (2013) A broad activity screen in support of a chemogenomic map for kinase signalling research and drug discovery. Biochem J 451: 313-28 [PMID:23398362]
- Garton AJ, Crew AP, Franklin M, Cooke AR, Wynne GM, Castaldo L, Kahler J, Winski SL, Franks A and Brown EN et al.. (2006) OSI-930: a novel selective inhibitor of Kit and kinase insert domain receptor tyrosine kinases with antitumor activity in mouse xenograft models. Cancer Res 66: 1015-24 [PMID:16424037]
- Gendreau SB, Ventura R, Keast P, Laird AD, Yakes FM, Zhang W, Bentzien F, Cancilla B, Lutman J and Chu F et al.. (2007) Inhibition of the T790M gatekeeper mutant of the epidermal growth factor receptor by EXEL-7647. Clin Cancer Res 13: 3713-23 [PMID:17575237]
- Getmanova EV, Chen Y, Bloom L, Gokemeijer J, Shamah S, Warikoo V, Wang J, Ling V and Sun L. (2006) Antagonists to human and mouse vascular endothelial growth factor receptor 2 generated by directed protein evolution in vitro. Chem Biol 13: 549-56 [PMID:16720276]
- Glaser KB, Li J, Marcotte PA, Magoc TJ, Guo J, Reuter DR, Tapang P, Wei RQ, Pease LJ and Bui MH et al.. (2012) Preclinical characterization of ABT-348, a kinase inhibitor targeting the aurora, vascular endothelial growth factor receptor/platelet-derived growth factor receptor, and Src kinase families. J Pharmacol Exp Ther 343: 617-27 [PMID:22935731]
- Guagnano V, Furet P, Spanka C, Bordas V, Le Douget M, Stamm C, Brueggen J, Jensen MR, Schnell C and Schmid H et al.. (2011) Discovery of 3-(2,6-dichloro-3,5-dimethoxy-phenyl)-1-{6-[4-(4-ethyl-piperazin-1-yl)-phenylamino]-pyrimidin-4-yl}-1-methyl-urea (NVP-BGJ398), a potent and selective inhibitor of the fibroblast growth factor receptor family of receptor tyrosine kinase. J Med Chem 54: 7066-83 [PMID:21936542]
- Harris PA, Boloor A, Cheung M, Kumar R, Crosby RM, Davis-Ward RG, Epperly AH, Hinkle KW, Hunter 3rd RN and Johnson JH et al.. (2008) Discovery of 5-[[4-[(2,3-dimethyl-2H-indazol-6-yl)methylamino]-2-pyrimidinyl]amino]-2-methyl-benzenesulfonamide (Pazopanib), a novel and potent vascular endothelial growth factor receptor inhibitor. J Med Chem 51: 4632-40 [PMID:18620382]
- Harris PA, Cheung M, Hunter 3rd RN, Brown ML, Veal JM, Nolte RT, Wang L, Liu W, Crosby RM and Johnson JH et al.. (2005) Discovery and evaluation of 2-anilino-5-aryloxazoles as a novel class of VEGFR2 kinase inhibitors. J Med Chem 48: 1610-9 [PMID:15743202]
- Hennequin LF, Thomas AP, Johnstone C, Stokes ES, Plé PA, Lohmann JJ, Ogilvie DJ, Dukes M, Wedge SR and Curwen JO et al.. (1999) Design and structure-activity relationship of a new class of potent VEGF receptor tyrosine kinase inhibitors. J Med Chem 42: 5369-89 [PMID:10639280]
- Hilberg F, Roth GJ, Krssak M, Kautschitsch S, Sommergruber W, Tontsch-Grunt U, Garin-Chesa P, Bader G, Zoephel A and Quant J et al.. (2008) BIBF 1120: triple angiokinase inhibitor with sustained receptor blockade and good antitumor efficacy. Cancer Res 68: 4774-82 [PMID:18559524]
- Hudkins RL, Becknell NC, Zulli AL, Underiner TL, Angeles TS, Aimone LD, Albom MS, Chang H, Miknyoczki SJ and Hunter K et al.. (2012) Synthesis and biological profile of the pan-vascular endothelial growth factor receptor/tyrosine kinase with immunoglobulin and epidermal growth factor-like homology domains 2 (VEGF-R/TIE-2) inhibitor 11-(2-methylpropyl)-12,13-dihydro-2-methyl-8-(pyrimidin-2-ylamino)-4H-indazolo[5,4-a]pyrrolo[3,4-c]carbazol-4-one (CEP-11981): a novel oncology therapeutic agent. J Med Chem 55: 903-13 [PMID:22148921]
- Kammasud N, Boonyarat C, Sanphanya K, Utsintong M, Tsunoda S, Sakurai H, Saiki I, André I, Grierson DS and Vajragupta O. (2009) 5-Substituted pyrido[2,3-d]pyrimidine, an inhibitor against three receptor tyrosine kinases. Bioorg Med Chem Lett 19: 745-50 [PMID:19110422]
- Khanwelkar RR, Chen GS, Wang HC, Yu CW, Huang CH, Lee O, Chen CH, Hwang CS, Ko CH and Chou NT et al.. (2010) Synthesis and structure-activity relationship of 6-arylureido-3-pyrrol-2-ylmethylideneindolin-2-one derivatives as potent receptor tyrosine kinase inhibitors. Bioorg Med Chem 18: 4674-86 [PMID:20570526]
- Kim MH, Tsuhako AL, Co EW, Aftab DT, Bentzien F, Chen J, Cheng W, Engst S, Goon L and Klein RR et al.. (2012) The design, synthesis, and biological evaluation of potent receptor tyrosine kinase inhibitors. Bioorg Med Chem Lett 22: 4979-85 [PMID:22765894]
- King C and Hristova K. (2019) Direct measurements of VEGF-VEGFR2 binding affinities reveal the coupling between ligand binding and receptor dimerization. J Biol Chem 294: 9064-9075 [PMID:31023826]
- Kiselyov AS, Semenova M, Semenov VV, Piatnitski E and Ouyang S. (2006) Hetaryl imidazoles: a novel dual inhibitors of VEGF receptors I and II. Bioorg Med Chem Lett 16: 1440-4 [PMID:16321531]
- Kubo K, Shimizu T, Ohyama S, Murooka H, Iwai A, Nakamura K, Hasegawa K, Kobayashi Y, Takahashi N and Takahashi K et al.. (2005) Novel potent orally active selective VEGFR-2 tyrosine kinase inhibitors: synthesis, structure-activity relationships, and antitumor activities of N-phenyl-N'-{4-(4-quinolyloxy)phenyl}ureas. J Med Chem 48: 1359-66 [PMID:15743179]
- Lam B, Arikawa Y, Cramlett J, Dong Q, de Jong R, Feher V, Grimshaw CE, Farrell PJ, Hoffman ID and Jennings A et al.. (2016) Discovery of TAK-659 an orally available investigational inhibitor of Spleen Tyrosine Kinase (SYK). Bioorg Med Chem Lett 26: 5947-5950 [PMID:27839918]
- Lee K, Jeong KW, Lee Y, Song JY, Kim MS, Lee GS and Kim Y. (2010) Pharmacophore modeling and virtual screening studies for new VEGFR-2 kinase inhibitors. Eur J Med Chem 45: 5420-7 [PMID:20869793]
- Li Y, Liu Y, Zhang D, Chen J, Yang G, Tang P, Yang C, Liu J, Zhang J and Ouyang L. (2023) Discovery, Synthesis, and Evaluation of Novel Dual Inhibitors of a Vascular Endothelial Growth Factor Receptor and Poly(ADP-Ribose) Polymerase for BRCA Wild-Type Breast Cancer Therapy. J Med Chem 66: 12069-12100 [PMID:37616488]
- Li Y, Xiong Y, Zhang G, Zhang L, Yang W, Yang J, Huang L, Qiao Z, Miao Z and Lin G et al.. (2018) Identification of 5-(2,3-Dihydro-1 H-indol-5-yl)-7 H-pyrrolo[2,3- d]pyrimidin-4-amine Derivatives as a New Class of Receptor-Interacting Protein Kinase 1 (RIPK1) Inhibitors, Which Showed Potent Activity in a Tumor Metastasis Model. J Med Chem 61: 11398-11414 [PMID:30480444]
- Li Y, Yang G, Zhang J, Tang P, Yang C, Wang G, Chen J, Liu J, Zhang L and Ouyang L. (2021) Discovery, Synthesis, and Evaluation of Highly Selective Vascular Endothelial Growth Factor Receptor 3 (VEGFR3) Inhibitor for the Potential Treatment of Metastatic Triple-Negative Breast Cancer. J Med Chem 64: 12022-12048 [PMID:34351741]
- Liao AT, Chien MB, Shenoy N, Mendel DB, McMahon G, Cherrington JM and London CA. (2002) Inhibition of constitutively active forms of mutant kit by multitargeted indolinone tyrosine kinase inhibitors. Blood 100: 585-93 [PMID:12091352]
- Lin R, Connolly PJ, Huang S, Wetter SK, Lu Y, Murray WV, Emanuel SL, Gruninger RH, Fuentes-Pesquera AR and Rugg CA et al.. (2005) 1-Acyl-1H-[1,2,4]triazole-3,5-diamine analogues as novel and potent anticancer cyclin-dependent kinase inhibitors: synthesis and evaluation of biological activities. J Med Chem 48: 4208-11 [PMID:15974571]
- Lu D, Shen J, Vil MD, Zhang H, Jimenez X, Bohlen P, Witte L and Zhu Z. (2003) Tailoring in vitro selection for a picomolar affinity human antibody directed against vascular endothelial growth factor receptor 2 for enhanced neutralizing activity. J Biol Chem 278: 43496-507 [PMID:12917408]
- Machrouhi F, Ouhamou N, Laderoute K, Calaoagan J, Bukhtiyarova M, Ehrlich PJ and Klon AE. (2010) The rational design of a novel potent analogue of the 5'-AMP-activated protein kinase inhibitor compound C with improved selectivity and cellular activity. Bioorg Med Chem Lett 20: 6394-9 [PMID:20932747]
- Manley PW, Furet P, Bold G, Brüggen J, Mestan J, Meyer T, Schnell CR, Wood J, Haberey M and Huth A et al.. (2002) Anthranilic acid amides: a novel class of antiangiogenic VEGF receptor kinase inhibitors. J Med Chem 45: 5687-93 [PMID:12477352]
- Marathe P, Tang Y, Sleczka B, Rodrigues D, Gavai A, Wong T, Christopher L and Zhang H. (2010) Preclinical pharmacokinetics and in vitro metabolism of BMS-690514, a potent inhibitor of EGFR and VEGFR2. J Pharm Sci 99: 3579-93 [PMID:20166197]
- McTigue M, Murray BW, Chen JH, Deng YL, Solowiej J and Kania RS. (2012) Molecular conformations, interactions, and properties associated with drug efficiency and clinical performance among VEGFR TK inhibitors. Proc Natl Acad Sci USA 109: 18281-9 [PMID:22988103]
- McTigue MA, Wickersham JA, Pinko C, Showalter RE, Parast CV, Tempczyk-Russell A, Gehring MR, Mroczkowski B, Kan CC and Villafranca JE et al.. (1999) Crystal structure of the kinase domain of human vascular endothelial growth factor receptor 2: a key enzyme in angiogenesis. Structure 7: 319-30 [PMID:10368301]
- Mendel DB, Laird AD, Xin X, Louie SG, Christensen JG, Li G, Schreck RE, Abrams TJ, Ngai TJ and Lee LB et al.. (2003) In vivo antitumor activity of SU11248, a novel tyrosine kinase inhibitor targeting vascular endothelial growth factor and platelet-derived growth factor receptors: determination of a pharmacokinetic/pharmacodynamic relationship. Clin Cancer Res 9: 327-37 [PMID:12538485]
- Mortensen DS, Perrin-Ninkovic SM, Shevlin G, Zhao J, Packard G, Bahmanyar S, Correa M, Elsner J, Harris R and Lee BG et al.. (2015) Discovery of mammalian target of rapamycin (mTOR) kinase inhibitor CC-223. J Med Chem 58: 5323-33 [PMID:26083478]
- Musumeci F, Radi M, Brullo C and Schenone S. (2012) Vascular endothelial growth factor (VEGF) receptors: drugs and new inhibitors. J Med Chem 55: 10797-822 [PMID:23098265]
- Nakagawa T, Tohyama O, Yamaguchi A, Matsushima T, Takahashi K, Funasaka S, Shirotori S, Asada M and Obaishi H. (2010) E7050: a dual c-Met and VEGFR-2 tyrosine kinase inhibitor promotes tumor regression and prolongs survival in mouse xenograft models. Cancer Sci 101: 210-5 [PMID:19832844]
- Ohno H, Kubo K, Murooka H, Kobayashi Y, Nishitoba T, Shibuya M, Yoneda T and Isoe T. (2006) A c-fms tyrosine kinase inhibitor, Ki20227, suppresses osteoclast differentiation and osteolytic bone destruction in a bone metastasis model. Mol Cancer Ther 5: 2634-43 [PMID:17121910]
- Pan BS, Chan GK, Chenard M, Chi A, Davis LJ, Deshmukh SV, Gibbs JB, Gil S, Hang G and Hatch H et al.. (2010) MK-2461, a novel multitargeted kinase inhibitor, preferentially inhibits the activated c-Met receptor. Cancer Res 70: 1524-33 [PMID:20145145]
- Patwardhan PP, Ivy KS, Musi E, de Stanchina E and Schwartz GK. (2016) Significant blockade of multiple receptor tyrosine kinases by MGCD516 (Sitravatinib), a novel small molecule inhibitor, shows potent anti-tumor activity in preclinical models of sarcoma. Oncotarget 7: 4093-109 [PMID:26675259]
- Patyna S, Laird AD, Mendel DB, O'farrell AM, Liang C, Guan H, Vojkovsky T, Vasile S, Wang X and Chen J et al.. (2006) SU14813: a novel multiple receptor tyrosine kinase inhibitor with potent antiangiogenic and antitumor activity. Mol Cancer Ther 5: 1774-82 [PMID:16891463]
- Pollard JR and Mortimore M. (2009) Discovery and development of aurora kinase inhibitors as anticancer agents. J Med Chem 52: 2629-51 [PMID:19320489]
- Qi B, Yang Y, Gong G, He H, Yue X, Xu X, Hu Y, Li J, Chen T and Wan X et al.. (2019) Discovery of N1-(4-((7-(3-(4-ethylpiperazin-1-yl)propoxy)-6-methoxyquinolin-4-yl)oxy)-3,5-difluorophenyl)-N3-(2-(2,6-difluorophenyl)-4-oxothiazolidin-3-yl)urea as a multi-tyrosine kinase inhibitor for drug-sensitive and drug-resistant cancers treatment. Eur J Med Chem 163: 10-27 [PMID:30503936]
- Renhowe PA, Pecchi S, Shafer CM, Machajewski TD, Jazan EM, Taylor C, Antonios-McCrea W, McBride CM, Frazier K and Wiesmann M et al.. (2009) Design, structure-activity relationships and in vivo characterization of 4-amino-3-benzimidazol-2-ylhydroquinolin-2-ones: a novel class of receptor tyrosine kinase inhibitors. J Med Chem 52: 278-92 [PMID:19113866]
- Sammond DM, Nailor KE, Veal JM, Nolte RT, Wang L, Knick VB, Rudolph SK, Truesdale AT, Nartey EN and Stafford JA et al.. (2005) Discovery of a novel and potent series of dianilinopyrimidineurea and urea isostere inhibitors of VEGFR2 tyrosine kinase. Bioorg Med Chem Lett 15: 3519-23 [PMID:15990302]
- Saxty G, Murray CW, Berdini V, Besong GE, Hamlett CCF, Johnson CN, Woodhead SJ, Reader M, Rees DC and Mevellec LA et al.. (2011) Pyrazolyl quinazoline kinase inhibitors. Patent number: WO2011135376 A1. Assignee: Astex Therapeutics Limited. Priority date: 30/04/2010. Publication date: 03/11/2011.
- Shuai W, Bu F, Zhu Y, Wu Y, Xiao H, Pan X, Zhang J, Sun Q, Wang G and Ouyang L. (2023) Discovery of Novel Indazole Chemotypes as Isoform-Selective JNK3 Inhibitors for the Treatment of Parkinson's Disease. J Med Chem 66: 1273-1300 [PMID:36649216]
- Su W-G, Zhang W, Jia H, Cui Y, Ren Y, Sai Y, Wu Z, Li W and Shao J. (2011) Compound, certain novel forms thereof, pharmaceutical compositions thereof and methods for preparation and use Patent number: WO2011060746. Assignee: Hutchison Medipharma Limited. Priority date: 23/11/2009. Publication date: 26/05/2011.
- Su Y, Wang J and Bao R. (2020) Inhibitor containing bicyclic derivative, preparation method therefor and use thereof Patent number: WO2020228756A1. Assignee: Shanghai Hansoh Biomedical Technology Co., Ltd., Jiangsu Hansoh Pharmaceutical Group Co., Ltd.. Priority date: 14/05/2020. Publication date: 19/11/2020.
- Subbiah V, Gainor JF, Rahal R, Brubaker JD, Kim JL, Maynard M, Hu W, Cao Q, Sheets MP and Wilson D et al.. (2018) Precision Targeted Therapy with BLU-667 for RET-Driven Cancers. Cancer Discov 8: 836-849 [PMID:29657135]
- Suh B-C, Salgaonkar PD, Lee J, Koh JS, Song H-J, Lee IY, Lee J, Jung DS, Kim J-H and Kim S-W. (2016) Compounds and compositions for modulating EGFR mutant kinase activities. Patent number: WO2016060443A2. Assignee: Yuhan Corporation. Priority date: 13/10/2014. Publication date: 21/04/2016.
- Sun L, Liang C, Shirazian S, Zhou Y, Miller T, Cui J, Fukuda JY, Chu JY, Nematalla A and Wang X et al.. (2003) Discovery of 5-[5-fluoro-2-oxo-1,2- dihydroindol-(3Z)-ylidenemethyl]-2,4- dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylaminoethyl)amide, a novel tyrosine kinase inhibitor targeting vascular endothelial and platelet-derived growth factor receptor tyrosine kinase. J Med Chem 46: 1116-9 [PMID:12646019]
- Sun L, Tran N, Liang C, Hubbard S, Tang F, Lipson K, Schreck R, Zhou Y, McMahon G and Tang C. (2000) Identification of substituted 3-[(4,5,6, 7-tetrahydro-1H-indol-2-yl)methylene]-1,3-dihydroindol-2-ones as growth factor receptor inhibitors for VEGF-R2 (Flk-1/KDR), FGF-R1, and PDGF-Rbeta tyrosine kinases. J Med Chem 43: 2655-63 [PMID:10893303]
- Sun L, Tran N, Liang C, Tang F, Rice A, Schreck R, Waltz K, Shawver LK, McMahon G and Tang C. (1999) Design, synthesis, and evaluations of substituted 3-[(3- or 4-carboxyethylpyrrol-2-yl)methylidenyl]indolin-2-ones as inhibitors of VEGF, FGF, and PDGF receptor tyrosine kinases. J Med Chem 42: 5120-30 [PMID:10602697]
- Sun L, Tran N, Tang F, App H, Hirth P, McMahon G and Tang C. (1998) Synthesis and biological evaluations of 3-substituted indolin-2-ones: a novel class of tyrosine kinase inhibitors that exhibit selectivity toward particular receptor tyrosine kinases. J Med Chem 41: 2588-603 [PMID:9651163]
- Sun Q, Zhou J, Zhang Z, Guo M, Liang J, Zhou F, Long J, Zhang W, Yin F and Cai H et al.. (2014) Discovery of fruquintinib, a potent and highly selective small molecule inhibitor of VEGFR 1, 2, 3 tyrosine kinases for cancer therapy. Cancer Biol Ther 15: 1635-45 [PMID:25482937]
- Sun X, Wang L, Yang H and Hu H. (2020) Crystal forms of compound, preparation method therefor, pharmaceutical composition and application thereof Patent number: WO2020216188. Assignee: Beijing Kangchen Pharmaceutical Co., Ltd.. Priority date: 20/04/2020. Publication date: 29/10/2020.
- Tao ZF, Chen Z, Bui MH, Kovar P, Johnson E, Bouska J, Zhang H, Rosenberg S, Sowin T and Lin NH. (2007) Macrocyclic ureas as potent and selective Chk1 inhibitors: an improved synthesis, kinome profiling, structure-activity relationships, and preliminary pharmacokinetics. Bioorg Med Chem Lett 17: 6593-601 [PMID:17935989]
- Tap WD, Wainberg ZA, Anthony SP, Ibrahim PN, Zhang C, Healey JH, Chmielowski B, Staddon AP, Cohn AL and Shapiro GI et al.. (2015) Structure-Guided Blockade of CSF1R Kinase in Tenosynovial Giant-Cell Tumor. N Engl J Med 373: 428-37 [PMID:26222558]
- Tian S, Quan H, Xie C, Guo H, Lü F, Xu Y, Li J and Lou L. (2011) YN968D1 is a novel and selective inhibitor of vascular endothelial growth factor receptor-2 tyrosine kinase with potent activity in vitro and in vivo. Cancer Sci 102: 1374-80 [PMID:21443688]
- Tovar C, Higgins B, Deo D, Kolinsky K, Liu JJ, Heimbrook DC and Vassilev LT. (2010) Small-molecule inducer of cancer cell polyploidy promotes apoptosis or senescence: Implications for therapy. Cell Cycle 9: 3364-75 [PMID:20814247]
- Traxler P, Allegrini PR, Brandt R, Brueggen J, Cozens R, Fabbro D, Grosios K, Lane HA, McSheehy P and Mestan J et al.. (2004) AEE788: a dual family epidermal growth factor receptor/ErbB2 and vascular endothelial growth factor receptor tyrosine kinase inhibitor with antitumor and antiangiogenic activity. Cancer Res 64: 4931-41 [PMID:15256466]
- Trudel S, Li ZH, Wei E, Wiesmann M, Chang H, Chen C, Reece D, Heise C and Stewart AK. (2005) CHIR-258, a novel, multitargeted tyrosine kinase inhibitor for the potential treatment of t(4;14) multiple myeloma. Blood 105: 2941-8 [PMID:15598814]
- Vieth M and Cummins DJ. (2000) DoMCoSAR: a novel approach for establishing the docking mode that is consistent with the structure-activity relationship. Application to HIV-1 protease inhibitors and VEGF receptor tyrosine kinase inhibitors. J Med Chem 43: 3020-32 [PMID:10956210]
- Wang D, Tang F, Wang S, Jiang Z and Zhang L. (2012) Preclinical anti-angiogenesis and anti-tumor activity of SIM010603, an oral, multi-targets receptor tyrosine kinases inhibitor. Cancer Chemother Pharmacol 69: 173-83 [PMID:21638122]
- Wedge SR, Kendrew J, Hennequin LF, Valentine PJ, Barry ST, Brave SR, Smith NR, James NH, Dukes M and Curwen JO et al.. (2005) AZD2171: a highly potent, orally bioavailable, vascular endothelial growth factor receptor-2 tyrosine kinase inhibitor for the treatment of cancer. Cancer Res 65: 4389-400 [PMID:15899831]
- Whittles CE, Pocock TM, Wedge SR, Kendrew J, Hennequin LF, Harper SJ and Bates DO. (2002) ZM323881, a novel inhibitor of vascular endothelial growth factor-receptor-2 tyrosine kinase activity. Microcirculation 9: 513-22 [PMID:12483548]
- Wilhelm SM, Carter C, Tang L, Wilkie D, McNabola A, Rong H, Chen C, Zhang X, Vincent P and McHugh M et al.. (2004) BAY 43-9006 exhibits broad spectrum oral antitumor activity and targets the RAF/MEK/ERK pathway and receptor tyrosine kinases involved in tumor progression and angiogenesis. Cancer Res 64: 7099-109 [PMID:15466206]
- Wilhelm SM, Dumas J, Adnane L, Lynch M, Carter CA, Schütz G, Thierauch KH and Zopf D. (2011) Regorafenib (BAY 73-4506): a new oral multikinase inhibitor of angiogenic, stromal and oncogenic receptor tyrosine kinases with potent preclinical antitumor activity. Int J Cancer 129: 245-55 [PMID:21170960]
- Wodicka LM, Ciceri P, Davis MI, Hunt JP, Floyd M, Salerno S, Hua XH, Ford JM, Armstrong RC and Zarrinkar PP et al.. (2010) Activation state-dependent binding of small molecule kinase inhibitors: structural insights from biochemistry. Chem Biol 17: 1241-9 [PMID:21095574]
- Wu F. (2021) Multi-kinase inhibitor compound, and crystal form and use thereof Patent number: US10889586B2. Assignee: Nanjing Transthera Biosciences Co Ltd. Priority date: 13/12/2016. Publication date: 12/01/2021.
- Wu Y, Wang B, Wang J, Qi S, Zou F, Qi Z, Liu F, Liu Q, Chen C and Hu C et al.. (2019) Discovery of 2-(4-Chloro-3-(trifluoromethyl)phenyl)-N-(4-((6,7-dimethoxyquinolin-4-yl)oxy)phenyl)acetamide (CHMFL-KIT-64) as a Novel Orally Available Potent Inhibitor against Broad-Spectrum Mutants of c-KIT Kinase for Gastrointestinal Stromal Tumors. J Med Chem 62: 6083-6101 [PMID:31250638]
- Xi N. (2015) Substituted quinoline compounds and methods of use Patent number: US9133162B2. Assignee: Sunshine Lake Pharma Co Ltd, Calitor Sciences LLC. Priority date: 28/02/2011. Publication date: 15/09/2015.
- Yakes FM, Chen J, Tan J, Yamaguchi K, Shi Y, Yu P, Qian F, Chu F, Bentzien F and Cancilla B et al.. (2011) Cabozantinib (XL184), a novel MET and VEGFR2 inhibitor, simultaneously suppresses metastasis, angiogenesis, and tumor growth. Mol Cancer Ther 10: 2298-308 [PMID:21926191]
- You WK, Sennino B, Williamson CW, Falcón B, Hashizume H, Yao LC, Aftab DT and McDonald DM. (2011) VEGF and c-Met blockade amplify angiogenesis inhibition in pancreatic islet cancer. Cancer Res 71: 4758-68 [PMID:21613405]
- Zhao G, Li WY, Chen D, Henry JR, Li HY, Chen Z, Zia-Ebrahimi M, Bloem L, Zhai Y and Huss K et al.. (2011) A novel, selective inhibitor of fibroblast growth factor receptors that shows a potent broad spectrum of antitumor activity in several tumor xenograft models. Mol Cancer Ther 10: 2200-10 [PMID:21900693]
- Zhou Y, Chen Y, Tong L, Xie H, Wen W, Zhang J, Xi Y, Shen Y, Geng M and Wang Y et al.. (2012) AL3810, a multi-tyrosine kinase inhibitor, exhibits potent anti-angiogenic and anti-tumour activity via targeting VEGFR, FGFR and PDGFR. J Cell Mol Med 16: 2321-30 [PMID:22304225]
- Zhou Y, Shan S, Li ZB, Xin LJ, Pan DS, Yang QJ, Liu YP, Yue XP, Liu XR and Gao JZ et al.. (2017) CS2164, a novel multi-target inhibitor against tumor angiogenesis, mitosis and chronic inflammation with anti-tumor potency. Cancer Sci 108: 469-477 [PMID:28004478]
- Zhu Z. (2003) Human antibodies specific to kdr and uses thereof Patent number: WO2003075840A2. Assignee: Imclone Systems Incorporated. Priority date: 04/03/2003. Publication date: 18/09/2003.