Dovitinib (CHIR258, TKI258): Structure, development and preclinical and clinical activity

Future Oncology

Volumn 11, Issue 1, 2015, Pages 39-50

  Porta, Camillo ^a,b   Giglione, Palma ^a   Liguigli, Wanda ^b   Paglino, Chiara ^a,b  

^a Division of Urology   (Italy)

^b Italian Nephro Oncology Group Gruppo Italiano di Oncologia Nefrologica ^*  (Italy)

Author keywords

Dovitinib; drug development; FGFR inhibitor; renal cell carcinoma; VEGFR inhibitor

Indexed keywords

DOVITINIB; FIBROBLAST GROWTH FACTOR; FIBROBLAST GROWTH FACTOR RECEPTOR; MAMMALIAN TARGET OF RAPAMYCIN INHIBITOR; PROTEIN TYROSINE KINASE INHIBITOR; SORAFENIB; 4-AMINO-5-FLUORO-3-(5-(4-METHYLPIPERAZIN-1-YL)-1H-BENZIMIDAZOL-2-YL)QUINOLIN-2(1H)-ONE; BENZIMIDAZOLE DERIVATIVE; PLATELET DERIVED GROWTH FACTOR RECEPTOR; QUINOLONE DERIVATIVE; VASCULOTROPIN RECEPTOR;

ALOPECIA; ANTINEOPLASTIC ACTIVITY; ARTICLE; ASTHENIA; BREAST CANCER; DECREASED APPETITE; DIARRHEA; DRUG MECHANISM; DRUG SAFETY; DRUG SCREENING; DRUG STRUCTURE; DYSGEUSIA; ENDOMETRIUM CANCER; FATIGUE; GASTROINTESTINAL STROMAL TUMOR; HAND FOOT SYNDROME; HUMAN; HYPERTENSION; HYPERTRIGLYCERIDEMIA; KIDNEY CARCINOMA; LIVER CELL CARCINOMA; NAUSEA; PHARMACODYNAMICS; PHASE 1 CLINICAL TRIAL (TOPIC); PHASE 2 CLINICAL TRIAL (TOPIC); PHASE 3 CLINICAL TRIAL (TOPIC); PRIORITY JOURNAL; RASH; SKIN TOXICITY; STOMATITIS; VOMITING; ANTAGONISTS AND INHIBITORS; CHEMISTRY; CLINICAL TRIAL (TOPIC); GENETICS; NEOPLASMS; PATHOLOGY;

BENZIMIDAZOLES; CLINICAL TRIALS AS TOPIC; HUMANS; NEOPLASMS; QUINOLONES; RECEPTORS, FIBROBLAST GROWTH FACTOR; RECEPTORS, PLATELET-DERIVED GROWTH FACTOR; RECEPTORS, VASCULAR ENDOTHELIAL GROWTH FACTOR;

EID: 84921044642     PISSN: 14796694     EISSN: 17448301     Source Type: Journal    
DOI: 10.2217/fon.14.208     Document Type: Article

References (53)

1. Kaelin WG Jr. The von Hippel-Lindau tumour suppressor protein: O2 sensing and cancer. Nat. Rev. Cancer 8, 865-873 (2008).
2. Brugarolas J. Renal-cell carcinoma. Molecular pathways and therapies. N. Engl. J. Med. 356, 185-187 (2007).
3. Majmundar AJ, Wong WJ, Simon MC. Hypoxia-inducible factors and the response to hypoxic stress. Mol. Cell 40, 294-309 (2010).
4. Baldewijns MM, van Vlodrop IJ, Schouten LJ, Soetekouw PM, de Bruine AP, van Engeland M. Genetics and epigenetics of renal cell cancer. Biochim. Biophys. Acta 1785, 133-155 (2008).
5. Rini BI, Atkins MB. Resistance to targeted therapy in renal-cell carcinoma. Lancet Oncol. 10, 992-1000 (2009).
6. Casanovas O, Hicklin DJ, Bergers G, Hanahan D. Drug resistance by evasion of antiangiogenic targeting of VEGF signaling in late-stage pancreatic islet tumors. Cancer Cell 8, 299-309 (2005).
7. Wesche J, Haglund K, Haugsten EM. Fibroblast growth factors and their receptors in cancer. Biochem. J. 437, 199-213 (2011).
8. Lee JG, Ko MK, Kat EP. Endothelial mesenchymal transformation mediated by IL-1β-induced FGF-2 in corneal endothelial cells. Exp. Eye Res. 95, 35-39 (2012).
9. Masola V, Gambaro G, Tibaldi E et al. Heparanase and syndecan-1 interplay orchestrates fibroblast growth factor-2-induced epithelial-mesenchymal transition in renal tubular cells. J. Biol. Chem. 287, 1478-1488 (2012).
10. Shang Y, Cai X, Fan D. Roles of epithelial-mesenchymal transition in cancer drug resistance. Curr. Cancer Drug Targets 13, 915-929 (2013).
11. Katoh M, Nakagama H. FGF receptors: cancer biology and therapeutics. Med. Res. Rev. 34, 280-300 (2013).
12. Ornitz DM, Itoh N. Fibroblast growth factors. Genome Biol. 2(3), REVIEWS 3005 (2001).
13. Belov AA, Mohammadi M. Molecular mechanisms of fibroblast growth factor signaling in physiology and pathology. Cold Spring Harb. Perspect. Biol. 5(6), a015958 (2013).
14. Coleman SJ, Bruce C, Chioni AM, Kocher HM, Grose RP. The ins and outs of fibroblast growth factor receptor signalling. Clin. Sci. 127, 217-231 (2014).
15. Greenman C, Stephens P, Smith R et al. Patterns of somatic mutation in human cancer genomes. Nature 446, 153-158 (2007).
16. Katoh M. Cross-talk of WNT and FGF signaling pathways at GSK3β to regulate β-catenin and SNAIL signaling cascades. Cancer Biol. Ther. 5, 1059-1064 (2006).
17. Porta C, Paglino C, Imarisio I et al. Changes in circulating pro-angiogenic cytokines, other than VEGF, before progression to sunitinib therapy in advanced renal cell carcinoma patients. Oncology 84, 115-122 (2013).
18. Gyanchandani R, Ortega Alves MV, Myers JN, Kim S. A proangiogenic signature is revealed in FGF-mediated bevacizumab-resistant head and neck squamous cell carcinoma. Mol. Cancer Res. 11, 1585-1596 (2013).
19. Narayanan V, Pollyea DA, Gutman JA, Jimeno A. Ponatinib for the treatment of chronic myeloid leukemia and Philadelphia chromosome-positive acute lymphoblastic leukemia. Drugs Today (Barc.) 49, 261-269 (2013).
20. Diaz-Padilla I, Siu LL. Brivanib alaninate for cancer. Expert Opin. Investig. Drugs 20, 577-586 (2011).
21. Chou T, Finn RS. Brivanib: a review of development. Future Oncol. 8, 1083-1090 (2012).
22. Bhide RS, Cai Z-W, Zhang Y-Z et al. 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, 2143-2146 (2006).
23. Ayers M, Fargnoli J, Lewin A, Wu Q, Platero JS. Discovery and validation of biomarkers that respond to treatment with brivanib alaninate, a small-molecule VEGFR-2/FGFR-1 antagonist. Cancer Res. 67, 6899-6906 (2007).
24. Huynh H, Ngo VC, Fargnoli J et al. Brivanib alaninate, a dual inhibitor of vascular endothelial growth factor receptor and fibroblast growth factor receptor tyrosine kinases, induces growth inhibition in mouse models of human hepatocellular carcinoma. Clin. Cancer Res. 14, 6146-6153 (2008).
25. Cai Z-W, Zhang Y, Borzilleri RM et al. Discovery of brivanib alaninate ((S)-((R)-1-(4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-5-methylpyrrolo[2,1-f[[1,2,4]triazin-6-yloxy) propan-2-yl)2-aminopropanoate), a novel prodrug of dual vascular endothelial growth factor receptor-2 and fibroblast growth factor receptor-1 kinase iinhibitor (BMS-540215). J. Med. Chem. 51, 1976-1980 (2008).
26. Johnson PJ, Qin S, Park JW et al. Brivanib versus sorafenib as first-line therapy in patients with unresectable, advanced hepatocellular carcinoma: results from the randomized Phase III BRISK-FL study. J. Clin. Oncol. 31, 3517-3524 (2013).
27. Llovet JM, Decaens T, Raoul JL et al. Brivanib in patients with advanced hepatocellular carcinoma who were intolerant to sorafenib or for whom sorafenib failed: results from the randomized Phase III BRISK-PS study. J. Clin. Oncol. 31, 3509-3516 (2013).
28. Siu LL, Shapiro JD, Jonker DJ et al. Phase III randomized, placebo-controlled study of cetuximab plus brivanib alaninate versus cetuximab plus placebo in patients with metastatic, chemotherapy-refractory, wild-type K-RAS colorectal carcinoma: the NCIC Clinical Trials Group and AGITG CO.20 Trial. J. Clin. Oncol. 31, 2477-2484 (2013).
29. Dufies M, Cassuto O, Jacquel A, Robert G, Auberger P. Ponatinib circumvents all types of Imatinib resistance in chronic myelogenous leukemia cell lines. Cell Cycle 12, 1645-1646 (2013).
30. Cortes JE, Kim DW, Pinilla-Ibarz J et al. A Phase 2 trial of ponatinib in Philadelphia chromosome-positive leukemias. N. Engl. J. Med. 369, 1783-1796 (2013).
31. Wang X, Kay A, Anak O et al. Population pharmacokinetic/pharmacodynamic modeling to assist dosing schedule selection for dovitinib. J. Clin. Pharmacol. 53, 14-20 (2012).
32. Chen Z-Y, Shi M, Peng L-X et al. Dovitinib preferentially targets endothelial cells rather than cancer cells for the inhibition of hepatocellular carcinoma growth and metastasis. J. Transl. Med. 10, 245 (2012).
33. Hasinoff BB, Wu X, Nitiss JL, Kanagasabai R, Yalowich JC. The anticancer multi-kinase inhibitor dovitinib also targets topoisomerase I and topoisomerase II. Biochem. Pharmacol. 84, 1617-1626 (2012).
34. Dubbelman AC, Upthagrove A, Beijnen JH et al. Disposition and metabolism of 14C-dovitinib (TKI258), an inhibitor of FGFR and VEGFR, after oral administration in patients with advanced solid tumors. Cancer Chemother. Pharmacol. 70, 653-663 (2012).
35. Angevin E, Lopez-Martin JA, Lin C-C et al. Phase I study of dovitinib (TKI258), an oral FGFR, VEGFR, and PDGFR inhibitor, in advanced or metastatic renal cell carcinoma. Clin. Cancer Res. 19, 1257-1268 (2013).
36. Keyes KA, Mann L, Cox K et al. Circulating angiogenic growth factor levels in mice bearing human tumors using luminex multiplex technology. Cancer Chemother. Pharmacol. 51, 321-327 (2003).
37. Sivanand S, Penã-Llopis S, Zhao H et al. A validated tumorgraft model reveals activity of dovitinib against renal cell carcinoma. Sci. Transl. Med. 4, 137ra75 (2012).
38. Grisanzio C, Seeley A, Chang M et al. Orthotopic xenografts of RCC retain histological, immunophenotypic and genetic features of tumours in patients. J. Pathol. 225, 212-221 (2011).
39. Huynh H, Chow PKH, Tai WM et al. Dovitinib demonstrates antitumor and antimetastatic activities in xenograft models of hepatocellular carcinoma. J. Hepatol. 56, 595-601 (2012).
40. Tai WT, Cheng AL, Shiau CW et al. Dovitinib induces apoptosis and overcomes sorafenib resistance in hepatocellular carcinoma through SHP-1-mediated inhibition of STAT3. Mol. Cancer Ther. 11, 452-463 (2011).
41. Chen KF, Chen H-L, Liu C-Y et al. Dovitinib sensitizes hepatocellular carcinoma cells to TRAIL and tigatuzumab, a novel anti-DR5 antibody, through SHP-1-dependent inhibition of STAT3. Biochem. Pharmacol. 83, 769-777 (2012).
42. Pollock PM, Gartside MG, Dejeza LC et al. Frequent activating FGFR2 mutations in endometrial carcinomas parallel germline mutations associated with craniosynostosis and skeletal dysplasia syndromes. Oncogene 26, 7158-7162 (2007).
43. Dutt A, Salvesen HB, Chen TH et al. Drug-sensitive FGFR2 mutations in endometrial carcinoma. Proc. Natl Acad. Sci. USA 105, 8713-8717 (2008).
44. Byron SA, Gartside M, Powell MA et al. FGFR2 point mutations in 466 endometrioid endometrial tumors: relationship with MSI, KRAS, PIK3CA, CTNNB1 mutations and clinicopathological features. PLoS ONE 7, e30801 (2012).
45. Konecny GE, Kolarova T, O'Brien NA et al. Activity of the fibroblast growth factor receptor inhibitors dovitinib (TKI258) and NVP-BGJ398 in human endometrial cancer cells. Mol. Cancer Ther. 12, 632-642 (2013).
46. André F, Bachelot T, Campone M et al. Targeting FGFR with dovitinib (TKI258): preclinical and clinical data in breast cancer. Clin. Cancer Res. 19, 3693-3702 (2013).
47. Issa A, Gill JW, Heideman MR et al. Combinatorial targeting of FGF and ErbB receptors blocks growth and metastatic spread of breast cancer models. Breast Cancer Res. 15, R8 (2013).
48. Kim KB, Chesney J, Robinson D, Gardner H, Shi MM, Kirkwood JM. Phase I/II and pharmacodynamic study of Dovitinib (TKI258), an inhibitor of fibroblast growth factor receptors and VEGF receptors, in patients with advanced melanoma. Clin. Cancer Res. 17, 7451-7461 (2011).
49. Angevin E, Grünwald V, Ravaud A et al. A Phase II study of dovitinib (TKI258), an FGFR-and VEGFR inhibitor, in patients with advanced or metastatic renal cell cancer (mRCC). J. Clin. Oncol. 29(Suppl.), 4551 (2011).
50. Motzer RJ, Porta C, Vogelzang N et al. Phase 3 trial of dovitinib versus sorafenib for third-line targeted treatment of patients with metastatic renal cell carcinoma: an open-label, randomized Phase 3 trial. Lancet Oncol. 15, 286-296 (2014).
51. Kang YK, Yoo C, Ryoo BY et al. Phase II study of dovitinib in patients with metastatic and/or unresectable gastrointestinal stromal tumours after failure of imatinib and sunitinib. Br. J. Cancer 109, 2309-2315 (2013).
52. Sarker D, Molife R, Evans TR et al. A Phase I pharmacokinetic and pharmacodynamic study of TKI258, an oral, multitargeted receptor tyrosine kinase inhibitor in patients with advanced solid tumors. Clin. Cancer Res. 14, 2075-2081 (2008).
53. Byron SA, Chen H, Wortmann A et al. The N550K/H mutations in FGFR2 confer differential resistance to PD173074, dovitinib, and ponatinib ATP-competitive inhibitors. Neoplasia 15, 975-988 (2013).