Discovery of fruquintinib, a potent and highly selective small molecule inhibitor of VEGFR 1, 2, 3 tyrosine kinases for cancer therapy

References

• Karkkainen MJ, Petrova TV. Vascular endothelial growth factor receptors in the regulation of angiogenesis and lymphangiogenesis. Oncogene 2000; 19:5598-605; PMID:11114740; http://dx.doi.org/10.1038/sj.onc.1203855
   PubMed Web of Science ®Google Scholar
• Bergers G, Benjamin LE. Tumorigenesis and the angiogenic switch. Nat Rev Cancer 2003; 3:401-10; PMID:12778130; http://dx.doi.org/10.1038/nrc1093
   PubMed Web of Science ®Google Scholar
• Ricci-Vitiani L, Pallini R, Biffoni M, Todaro M, Invernici G, Cenci T, Maira G, Parati EA, Stassi G, Larocca LM, et al. Tumour vascularization via endothelial differentiation of glioblastoma stem-like cells. Nature 2010; 468:824-8; PMID:21102434; http://dx.doi.org/10.1038/nature09557
   PubMed Web of Science ®Google Scholar
• Kerbel RS. Tumor angiogenesis. N Engl J Med 2008; 358:2039-49; PMID:18463380; http://dx.doi.org/10.1056/NEJMra0706596
   PubMed Web of Science ®Google Scholar
• Dvorak HF. Vascular permeability factor/vascular endothelial growth factor: a critical cytokine in tumor angiogenesis and a potential target for diagnosis and therapy. J Clin Oncol 2002; 20:4368-80; PMID:12409337; http://dx.doi.org/10.1200/JCO.2002.10.088
   PubMed Web of Science ®Google Scholar
• Rak J, Mitsuhashi Y, Bayko L, Filmus J, Shirasawa S, Sasazuki T, Kerbel RS. Mutant ras oncogenes upregulate VEGF/VPF expression: Implications for induction and inhibition of tumor angiogenesis. Cancer Res 1995; 55:4575-80; PMID:7553632
   PubMed Web of Science ®Google Scholar
• Farhang Ghahremani M, Goossens S, Nittner D, Bisteau X, Bartunkova S, Zwolinska A, Hulpiau P, Haigh K, Haenebalcke L, Drogat B, et al. p53 promotes VEGF expression and angiogenesis in the absence of an intact p21-Rb pathway. Cell Death Differ 2013; 20:888-97; PMID:23449391; http://dx.doi.org/10.1038/cdd.2013.12
   PubMed Web of Science ®Google Scholar
• Raja R, Kale S, Thorat D, Soundararajan G, Lohite K, Mane A, Karnik S, Kundu GC. Hypoxia-driven osteopontin contributes to breast tumor growth through modulation of HIF1α-mediated VEGF-dependent angiogenesis. Oncogene 2014; 33:2053-64; PMID:23728336; http://dx.doi.org/10.1038/onc.2013.171
   PubMed Web of Science ®Google Scholar
• Chatterjee S, Heukamp LC, Siobal M, Schöttle J, Wieczorek C, Peifer M, Frasca D, Koker M, König K, Meder L, et al. Tumor VEGF:VEGFR2 autocrine feed-forward loop triggers angiogenesis in lung cancer. J Clin Invest 2013; 123:1732-40; PMID:23454747; http://dx.doi.org/10.1172/JCI65385
   PubMed Web of Science ®Google Scholar
• Wang X, Chen X, Fang J, Yang C. Overexpression of both VEGF-A and VEGF-C in gastric cancer correlates with prognosis, and silencing of both is effective to inhibit cancer growth. Int J Clin Exp Pathol 2013; 6:586-97; PMID:23573305
   PubMed Web of Science ®Google Scholar
• Martins SF, Garcia EA, Luz MA, Pardal F, Rodrigues M, Filho AL. Clinicopathological correlation and prognostic significance of VEGF-A, VEGF-C, KDR and VEGFR-3 expression in colorectal cancer. Cancer Genomics Proteomics 2013; 10:55-67; PMID:23603341
   PubMed Web of Science ®Google Scholar
• Pan L, Baek S, Edmonds PR, Roach M, Wolkov H, Shah S, Pollack A, Hammond ME, Dicker AP. Vascular endothelial growth factor (VEGF) expression in locally advanced prostate cancer: secondary analysis of radiation therapy oncology group (RTOG) 8610. Radiat Oncol 2013; 8:100; PMID:23618468; http://dx.doi.org/10.1186/1748-717X-8-100
   PubMed Web of Science ®Google Scholar
• Engels K, du Bois A, Harter P, Fisseler-Eckhoff A, Kommoss F, Stauber R, Kaufmann M, Nekljudova V, Loibl S. VEGF-A and i-NOS expression are prognostic factors in serous epithelial ovarian carcinomas after complete surgical resection. J Clin Pathol 2009; 62:448-54; PMID:19126566; http://dx.doi.org/10.1136/jcp.2008.063859
   PubMed Web of Science ®Google Scholar
• Simonetti O, Lucarini G, Rubini C, Goteri G, Zizzi A, Staibano S, Campanati A, Ganzetti G, Di Primio R, Offidani A. Microvessel density and VEGF, HIF-1α expression in primary oral melanoma: correlation with prognosis. Oral Dis 2013; 19:620-7; PMID:23279259; http://dx.doi.org/10.1111/odi.12048
   PubMed Web of Science ®Google Scholar
• Shalaby F, Rossant J, Yamaguchi TP, Gertsenstein M, Wu XF, Breitman ML, Schuh AC. Failure of blood-islandformation and vasculogenesis in Flk-1-deficient mice. Nature 1995; 376:62-6; PMID:7596435; http://dx.doi.org/10.1038/376062a0
   PubMed Web of Science ®Google Scholar
• Shibuya M. Vascular endothelial growth factor (VEGF) and its receptor (VEGFR) signaling in angiogenesis: a crucial target for anti- and pro-angiogenic therapies. Genes Cancer 2011; 2:1097-105; PMID:22866201; http://dx.doi.org/10.1177/1947601911423031
   PubMedGoogle Scholar
• Ziche M, Donnini S, Morbidelli L. Development of new drugs in angiogenesis. Curr Drug Targets 2004; 5:485-93; PMID:15216914; http://dx.doi.org/10.2174/1389450043345371
   PubMed Web of Science ®Google Scholar
• Zhou CC, Bai CX, Guan ZZ, Jiang GL, Shi YK, Wang MZ, Wu YL, Zhang YP, Zhu YZ. Safety and efficacy of first-line bevacizumab combination therapy in Chinese population with advanced non-squamous NSCLC: data of subgroup analyses from MO19390 (SAiL) study. Clin Transl Oncol 2014; 16:463-8; PMID:24002945; http://dx.doi.org/10.1007/s12094-013-1102-5
   PubMed Web of Science ®Google Scholar
• Ciuleanu T, Tsai CM, Tsao CJ, Milanowski J, Amoroso D, Heo DS, Groen HJ, Szczesna A, Chung CY, Chao TY, et al. A phase II study of erlotinib in combination with bevacizumab versus chemotherapy plus bevacizumab in the first-line treatment of advanced non-squamous non-small cell lung cancer. Lung Cancer 2013; 82:276-81; PMID:23992877; http://dx.doi.org/10.1016/j.lungcan.2013.08.002
   PubMed Web of Science ®Google Scholar
• El-Rayes BF, Zalupski M, Bekai-Saab T, Heilbrun LK, Hammad N, Patel B, Urba S, Shields AF, Vaishampayan U, Dawson S, et al. A phase II study of bevacizumab, oxaliplatin, and docetaxel in locally advanced and metastatic gastric and gastroesophageal junction cancers. Ann Oncol 2010; 21:1999-2004; PMID:20332133; http://dx.doi.org/10.1093/annonc/mdq065
   PubMed Web of Science ®Google Scholar
• Moehler M, Sprinzl MF, Abdelfattah M, Schimanski CC, Adami B, Godderz W, Majer K, Flieger D, Teufel A, Siebler J, et al. Capecitabine and Irinotecan with and without bevacizumab for advanced colorectal cancer patients. World J Gastroenterol 2009; 15:449-56; PMID:19152449; http://dx.doi.org/10.3748/wjg.15.449
   PubMed Web of Science ®Google Scholar
• Grandinetti CA, Goldspiel BR. Sorafenib and sunitinib: novel targeted therapies for renal cell cancer. Pharmacotherapy 2007; 27:1125-44; PMID:17655513; http://dx.doi.org/10.1592/phco.27.8.1125
   PubMed Web of Science ®Google Scholar
• Keating GM, Santoro A. Sorafenib: a review of its use in advanced hepatocellular carcinoma. Drugs 2009; 69:223-40; PMID:19228077; http://dx.doi.org/10.2165/00003495-200969020-00006
   PubMed Web of Science ®Google Scholar
• Sartore-Bianchi A, Zeppellini A, Amatu A, Ricotta R, Bencardino K, Siena S. Regorafenib in metastatic colorectal cancer. Expert Rev Anticancer Ther 2014; 14:255-65; PMID:24559322; http://dx.doi.org/10.1586/14737140.2014.894887
   PubMed Web of Science ®Google Scholar
• van Geel RM, Beijnen JH, Schellens JH. Concise drug review: pazopanib and axitinib. Oncologist 2012; 17:1081-9; PMID:22733795; http://dx.doi.org/10.1634/theoncologist.2012-0055
   PubMed Web of Science ®Google Scholar
• Gu Y, Wang J, Li K, Zhang L, Ren HC, Guo LX, Sai Y, Zhang WH, Su WG. Preclinical pharmacokinetics and disposition of a novel selective VEGFR inhibitor fruquintinib (HMPL-013) and the prediction of its human pharmacokinetics. Cancer Chemoth Pharmacol 2014; 74:95-115; PMID:24817647; http://dx.doi.org/10.1007/s00280-014-2471-3
   PubMed Web of Science ®Google Scholar
• Huang L, Huang Z, Bai Z, Xie R, Sun L, Lin K. Development and strategies of KDR/KDR inhibitors. Future Med Chem 2012; 4:1839-52; PMID:23043480; http://dx.doi.org/10.4155/fmc.12.121
   PubMed Web of Science ®Google Scholar
• Takahashi S. Vascular endothelial growth factor (VEGF), VEGF receptors and their inhibitors for antiangiogenic tumor therapy. Biol Pharm Bull 2011; 34:1785-8; PMID:22130231; http://dx.doi.org/10.1248/bpb.34.1785
   PubMed Web of Science ®Google Scholar
• Koch S, Tugues S, Li X, Gualandi L, laesson-Welsh L. Signal transduction by vascular endothelial growth factor receptors. Biochem J 2011; 437:169-83; PMID:21711246; http://dx.doi.org/10.1042/BJ20110301
   PubMed Web of Science ®Google Scholar
• Witzenbichler B, Asahara T, Murohara T, Silver M, Spyridopoulos I, Magner M, Principe N, Kearney M, Hu JS, Isner JM. Vascular endothelial growth factor-C (VEGF-C/VEGF-2) promotes angiogenesis in the setting of tissue ischemia. Am J Pathol 1998; 153:381-94; PMID:9708799; http://dx.doi.org/10.1016/S0002-9440(10)65582-4
   PubMed Web of Science ®Google Scholar
• Karkkainen MJ, Petrova TV. Vascular endothelial growth factor receptors in the regulation of angiogenesis and lymphangiogenesis. Oncogene 2000; 19:5598-605; PMID:11114740; http://dx.doi.org/10.1038/sj.onc.1203855
   PubMed Web of Science ®Google Scholar
• Huang YW, Xu LQ, Luo RZ, Huang X, Hou T, Zhang YN. VEGF-c expression in an in vivo model of orthotopic endometrial cancer and retroperitoneal lymph node metastasis. Reprod Biol Endocrinol 2013; 11:49; PMID:23693075; http://dx.doi.org/10.1186/1477-7827-11-49
   PubMed Web of Science ®Google Scholar
• Kigure W, Fujii T, Sutoh T, Morita H, Katoh T, Yajima RN, Yamaguchi S, Tsutsumi S, Asao T, Kuwano H. The association of VEGF-C expression with tumor lymphatic vessel density and lymph node metastasis in patients with gastric cancer and gastrointestinal stromal tumor. Hepatogastroenterology 2013; 60:277-80; PMID:23574654
   PubMed Web of Science ®Google Scholar
• Yao G, He P, Chen L, Hu X, Gu F, Ye C. MT1-MMP in breast cancer: induction of VEGF-C correlates with metastasis and poor prognosis. Cancer Cell Int 2013; 13:98; PMID:24119788; http://dx.doi.org/10.1186/1475-2867-13-98
   PubMed Web of Science ®Google Scholar
• Wong SY, Haack H, Crowley D, Barry M, Bronson RT, Hynes RO. Tumor-secreted vascular endothelial growth factor-C is necessary for prostate cancer lymphangiogenesis, but lymphangiogenesis is unnecessary for lymph node metastasis. Cancer Res 2005; 65:9789-98; PMID:16267000; http://dx.doi.org/10.1158/0008-5472.CAN-05-0901
   PubMed Web of Science ®Google Scholar
• Martins SF, Garcia EA, Luz MA, Pardal F, Rodrigues M, Filho AL. Clinicopathological correlation and prognostic significance of VEGF-A, VEGF-C, VEGFR-2 and VEGFR-3 expression in colorectal cancer. Cancer Genomics Proteomics 2013; 10:55-67; PMID:23603341
   PubMed Web of Science ®Google Scholar
• Al-Rawi MA, Jiang WG. Lymphangiogenesis and cancer metastasis. Front Biosci 2011; 16:23-39; http://dx.doi.org/10.2741/3715
   Web of Science ®Google Scholar
• Jin Li, Junning Cao, Jian Zhang, Zhiyu Chen, Wei Peng, Songhua Fan, Charlie Qi, Yi Gu, Yang Sai, Hua Mu. Phase I study of safety and pharmacokinetics of fruquintinib, a selective inhibitor of VEGF receptor-1, -2, and -3 tyrosine kinases in patients with advanced solid tumors. [Abstract]. In: Proceedings of the 104th annual meeting of the American association for cancer research. 2013 Apr 6–10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73 (8 Suppl): Abstract nr 2413. doi:10.1158/1538-7445.AM2013-2413
   Google Scholar