Dovitinib lactate
Dovitinib, also known as TKI-258 or CHIR-258, is an orally bioavailable FGFR3 inhibitor, which strongly binds to fibroblast growth factor receptor 3 (FGFR3) and inhibits its phosphorylation, which may result in the inhibition of tumor cell proliferation and the induction of tumor cell death. In addition, this agent may inhibit other members of the RTK superfamily, including the vascular endothelial growth factor receptor; fibroblast growth factor receptor 1; platelet-derived growth factor receptor type 3; FMS-like tyrosine kinase 3; stem cell factor receptor (c-KIT); and colony-stimulating factor receptor 1; this may result in an additional reduction in cellular proliferation and angiogenesis, and the induction of tumor cell apoptosis.
1: Quintela-Fandino M, Bueno MJ, Lombardia L, Gil M, Gonzalez-Martin A, Marquez R, Bratos R, Guerra J, Tan E, Lopez A, Colomer R, Salazar R. Selective activity over a constitutively active RET-variant of the oral multikinase inhibitor dovitinib: Results of the CNIO-BR002 phase I-trial. Mol Oncol. 2014 Jul 17. pii: S1574-7891(14)00160-4. doi: 10.1016/j.molonc.2014.07.005. [Epub ahead of print] PubMed PMID: 25103625.
2: Galsky MD, Posner M, Holcombe RF, Lee KM, Misiukiewicz K, Tsao CK, Godbold J, Soto R, Gimpel-Tetra K, Lowe N, Oh WK. Phase Ib study of dovitinib in combination with gemcitabine plus cisplatin or gemcitabine plus carboplatin in patients with advanced solid tumors. Cancer Chemother Pharmacol. 2014 Jul 15. [Epub ahead of print] PubMed PMID: 25023489.
3: Powles T, Foreshew SJ, Shamash J, Sarwar N, Crabb S, Sahdev A, Nixon J, Lim L, Pungaliya A, Foreshaw A, Davies R, Greenwood M, Wilson P, Pacey S, Galazi M, Jones R, Chowdhury S. A phase Ib study investigating the combination of everolimus and dovitinib in vascular endothelial growth factor refractory clear cell renal cancer. Eur J Cancer. 2014 Aug;50(12):2057-64. doi: 10.1016/j.ejca.2014.04.021. Epub 2014 Jun 4. PubMed PMID: 24908540.
4: Escudier B, Grünwald V, Ravaud A, Ou YC, Castellano D, Lin CC, Gschwend JE, Harzstark A, Beall S, Pirotta N, Squires M, Shi M, Angevin E. Phase II results of Dovitinib (TKI258) in patients with metastatic renal cell cancer. Clin Cancer Res. 2014 Jun 1;20(11):3012-22. doi: 10.1158/1078-0432.CCR-13-3006. Epub 2014 Apr 1. PubMed PMID: 24691021.
5: Motzer RJ, Porta C, Vogelzang NJ, Sternberg CN, Szczylik C, Zolnierek J, Kollmannsberger C, Rha SY, Bjarnason GA, Melichar B, De Giorgi U, Grünwald V, Davis ID, Lee JL, Esteban E, Urbanowitz G, Cai C, Squires M, Marker M, Shi MM, Escudier B. Dovitinib versus sorafenib for third-line targeted treatment of patients with metastatic renal cell carcinoma: an open-label, randomised phase 3 trial. Lancet Oncol. 2014 Mar;15(3):286-96. doi: 10.1016/S1470-2045(14)70030-0. Epub 2014 Feb 17. PubMed PMID: 24556040.
6: Schmidinger M. Third-line dovitinib in metastatic renal cell carcinoma. Lancet Oncol. 2014 Mar;15(3):245-6. doi: 10.1016/S1470-2045(14)70082-8. Epub 2014 Feb 17. PubMed PMID: 24556039.
7: Gaur S, Chen L, Ann V, Lin WC, Wang Y, Chang VH, Hsu NY, Shia HS, Yen Y. Dovitinib synergizes with oxaliplatin in suppressing cell proliferation and inducing apoptosis in colorectal cancer cells regardless of RAS-RAF mutation status. Mol Cancer. 2014 Feb 4;13:21. doi: 10.1186/1476-4598-13-21. PubMed PMID: 24495750; PubMed Central PMCID: PMC3996163.
8: Eritja N, Domingo M, Dosil MA, Mirantes C, Santacana M, Valls J, Llombart-Cussac A, Matias-Guiu X, Dolcet X. Combinatorial therapy using dovitinib and ICI182.780 (fulvestrant) blocks tumoral activity of endometrial cancer cells. Mol Cancer Ther. 2014 Apr;13(4):776-87. doi: 10.1158/1535-7163.MCT-13-0794. Epub 2014 Jan 21. PubMed PMID: 24448819.
9: Hänze J, Henrici M, Hegele A, Hofmann R, Olbert PJ. Epithelial mesenchymal transition status is associated with anti-cancer responses towards receptor tyrosine-kinase inhibition by dovitinib in human bladder cancer cells. BMC Cancer. 2013 Dec 11;13:589. doi: 10.1186/1471-2407-13-589. PubMed PMID: 24325461; PubMed Central PMCID: PMC3866461.
10: Man WY, Mak JP, Poon RY. Dovitinib induces mitotic defects and activates the G2 DNA damage checkpoint. J Cell Mol Med. 2014 Jan;18(1):143-55. doi: 10.1111/jcmm.12176. Epub 2013 Nov 18. PubMed PMID: 24238094.
11: Kang YK, Yoo C, Ryoo BY, Lee JJ, Tan E, Park I, Park JH, Choi YJ, Jo J, Ryu JS, Ryu MH. Phase II study of dovitinib in patients with metastatic and/or unresectable gastrointestinal stromal tumours after failure of imatinib and sunitinib. Br J Cancer. 2013 Oct 29;109(9):2309-15. doi: 10.1038/bjc.2013.594. Epub 2013 Oct 1. PubMed PMID: 24084771; PubMed Central PMCID: PMC3817332.
12: Byron SA, Chen H, Wortmann A, Loch D, Gartside MG, Dehkhoda F, Blais SP, Neubert TA, Mohammadi M, Pollock PM. The N550K/H mutations in FGFR2 confer differential resistance to PD173074, dovitinib, and ponatinib ATP-competitive inhibitors. Neoplasia. 2013 Aug;15(8):975-88. PubMed PMID: 23908597; PubMed Central PMCID: PMC3730048.
13: André F, Bachelot T, Campone M, Dalenc F, Perez-Garcia JM, Hurvitz SA, Turner N, Rugo H, Smith JW, Deudon S, Shi M, Zhang Y, Kay A, Porta DG, Yovine A, Baselga J. Targeting FGFR with dovitinib (TKI258): preclinical and clinical data in breast cancer. Clin Cancer Res. 2013 Jul 1;19(13):3693-702. doi: 10.1158/1078-0432.CCR-13-0190. Epub 2013 May 8. PubMed PMID: 23658459.
14: Konecny GE, Kolarova T, O'Brien NA, Winterhoff B, Yang G, Qi J, Qi Z, Venkatesan N, Ayala R, Luo T, Finn RS, Kristof J, Galderisi C, Porta DG, Anderson L, Shi MM, Yovine A, Slamon DJ. Activity of the fibroblast growth factor receptor inhibitors dovitinib (TKI258) and NVP-BGJ398 in human endometrial cancer cells. Mol Cancer Ther. 2013 May;12(5):632-42. doi: 10.1158/1535-7163.MCT-12-0999. Epub 2013 Feb 26. PubMed PMID: 23443805.
15: Wang X, Kay A, Anak O, Angevin E, Escudier B, Zhou W, Feng Y, Dugan M, Schran H. Population pharmacokinetic/pharmacodynamic modeling to assist dosing schedule selection for dovitinib. J Clin Pharmacol. 2013 Jan;53(1):14-20. doi: 10.1177/0091270011433330. Epub 2013 Jan 24. PubMed PMID: 23400739.
16: Angevin E, Lopez-Martin JA, Lin CC, Gschwend JE, Harzstark A, Castellano D, Soria JC, Sen P, Chang J, Shi M, Kay A, Escudier B. Phase I study of dovitinib (TKI258), an oral FGFR, VEGFR, and PDGFR inhibitor, in advanced or metastatic renal cell carcinoma. Clin Cancer Res. 2013 Mar 1;19(5):1257-68. doi: 10.1158/1078-0432.CCR-12-2885. Epub 2013 Jan 21. PubMed PMID: 23339124.
17: Chen ZY, Shi M, Peng LX, Wei W, Li XJ, Guo ZX, Li SH, Zhong C, Qian CN, Guo RP. Dovitinib preferentially targets endothelial cells rather than cancer cells for the inhibition of hepatocellular carcinoma growth and metastasis. J Transl Med. 2012 Dec 10;10:245. doi: 10.1186/1479-5876-10-245. PubMed PMID: 23228017; PubMed Central PMCID: PMC3552726.
18: 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. 2012 Dec 15;84(12):1617-26. doi: 10.1016/j.bcp.2012.09.023. Epub 2012 Oct 5. PubMed PMID: 23041231; PubMed Central PMCID: PMC3501595.
19: Dubbelman AC, Upthagrove A, Beijnen JH, Marchetti S, Tan E, Krone K, Anand S, Schellens JH. 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. 2012 Nov;70(5):653-63. doi: 10.1007/s00280-012-1947-2. Epub 2012 Aug 22. PubMed PMID: 23010851.
20: Sivanand S, Peña-Llopis S, Zhao H, Kucejova B, Spence P, Pavia-Jimenez A, Yamasaki T, McBride DJ, Gillen J, Wolff NC, Morlock L, Lotan Y, Raj GV, Sagalowsky A, Margulis V, Cadeddu JA, Ross MT, Bentley DR, Kabbani W, Xie XJ, Kapur P, Williams NS, Brugarolas J. A validated tumorgraft model reveals activity of dovitinib against renal cell carcinoma. Sci Transl Med. 2012 Jun 6;4(137):137ra75. doi: 10.1126/scitranslmed.3003643. PubMed PMID: 22674553; PubMed Central PMCID: PMC3570965.
2: Galsky MD, Posner M, Holcombe RF, Lee KM, Misiukiewicz K, Tsao CK, Godbold J, Soto R, Gimpel-Tetra K, Lowe N, Oh WK. Phase Ib study of dovitinib in combination with gemcitabine plus cisplatin or gemcitabine plus carboplatin in patients with advanced solid tumors. Cancer Chemother Pharmacol. 2014 Jul 15. [Epub ahead of print] PubMed PMID: 25023489.
3: Powles T, Foreshew SJ, Shamash J, Sarwar N, Crabb S, Sahdev A, Nixon J, Lim L, Pungaliya A, Foreshaw A, Davies R, Greenwood M, Wilson P, Pacey S, Galazi M, Jones R, Chowdhury S. A phase Ib study investigating the combination of everolimus and dovitinib in vascular endothelial growth factor refractory clear cell renal cancer. Eur J Cancer. 2014 Aug;50(12):2057-64. doi: 10.1016/j.ejca.2014.04.021. Epub 2014 Jun 4. PubMed PMID: 24908540.
4: Escudier B, Grünwald V, Ravaud A, Ou YC, Castellano D, Lin CC, Gschwend JE, Harzstark A, Beall S, Pirotta N, Squires M, Shi M, Angevin E. Phase II results of Dovitinib (TKI258) in patients with metastatic renal cell cancer. Clin Cancer Res. 2014 Jun 1;20(11):3012-22. doi: 10.1158/1078-0432.CCR-13-3006. Epub 2014 Apr 1. PubMed PMID: 24691021.
5: Motzer RJ, Porta C, Vogelzang NJ, Sternberg CN, Szczylik C, Zolnierek J, Kollmannsberger C, Rha SY, Bjarnason GA, Melichar B, De Giorgi U, Grünwald V, Davis ID, Lee JL, Esteban E, Urbanowitz G, Cai C, Squires M, Marker M, Shi MM, Escudier B. Dovitinib versus sorafenib for third-line targeted treatment of patients with metastatic renal cell carcinoma: an open-label, randomised phase 3 trial. Lancet Oncol. 2014 Mar;15(3):286-96. doi: 10.1016/S1470-2045(14)70030-0. Epub 2014 Feb 17. PubMed PMID: 24556040.
6: Schmidinger M. Third-line dovitinib in metastatic renal cell carcinoma. Lancet Oncol. 2014 Mar;15(3):245-6. doi: 10.1016/S1470-2045(14)70082-8. Epub 2014 Feb 17. PubMed PMID: 24556039.
7: Gaur S, Chen L, Ann V, Lin WC, Wang Y, Chang VH, Hsu NY, Shia HS, Yen Y. Dovitinib synergizes with oxaliplatin in suppressing cell proliferation and inducing apoptosis in colorectal cancer cells regardless of RAS-RAF mutation status. Mol Cancer. 2014 Feb 4;13:21. doi: 10.1186/1476-4598-13-21. PubMed PMID: 24495750; PubMed Central PMCID: PMC3996163.
8: Eritja N, Domingo M, Dosil MA, Mirantes C, Santacana M, Valls J, Llombart-Cussac A, Matias-Guiu X, Dolcet X. Combinatorial therapy using dovitinib and ICI182.780 (fulvestrant) blocks tumoral activity of endometrial cancer cells. Mol Cancer Ther. 2014 Apr;13(4):776-87. doi: 10.1158/1535-7163.MCT-13-0794. Epub 2014 Jan 21. PubMed PMID: 24448819.
9: Hänze J, Henrici M, Hegele A, Hofmann R, Olbert PJ. Epithelial mesenchymal transition status is associated with anti-cancer responses towards receptor tyrosine-kinase inhibition by dovitinib in human bladder cancer cells. BMC Cancer. 2013 Dec 11;13:589. doi: 10.1186/1471-2407-13-589. PubMed PMID: 24325461; PubMed Central PMCID: PMC3866461.
10: Man WY, Mak JP, Poon RY. Dovitinib induces mitotic defects and activates the G2 DNA damage checkpoint. J Cell Mol Med. 2014 Jan;18(1):143-55. doi: 10.1111/jcmm.12176. Epub 2013 Nov 18. PubMed PMID: 24238094.
11: Kang YK, Yoo C, Ryoo BY, Lee JJ, Tan E, Park I, Park JH, Choi YJ, Jo J, Ryu JS, Ryu MH. Phase II study of dovitinib in patients with metastatic and/or unresectable gastrointestinal stromal tumours after failure of imatinib and sunitinib. Br J Cancer. 2013 Oct 29;109(9):2309-15. doi: 10.1038/bjc.2013.594. Epub 2013 Oct 1. PubMed PMID: 24084771; PubMed Central PMCID: PMC3817332.
12: Byron SA, Chen H, Wortmann A, Loch D, Gartside MG, Dehkhoda F, Blais SP, Neubert TA, Mohammadi M, Pollock PM. The N550K/H mutations in FGFR2 confer differential resistance to PD173074, dovitinib, and ponatinib ATP-competitive inhibitors. Neoplasia. 2013 Aug;15(8):975-88. PubMed PMID: 23908597; PubMed Central PMCID: PMC3730048.
13: André F, Bachelot T, Campone M, Dalenc F, Perez-Garcia JM, Hurvitz SA, Turner N, Rugo H, Smith JW, Deudon S, Shi M, Zhang Y, Kay A, Porta DG, Yovine A, Baselga J. Targeting FGFR with dovitinib (TKI258): preclinical and clinical data in breast cancer. Clin Cancer Res. 2013 Jul 1;19(13):3693-702. doi: 10.1158/1078-0432.CCR-13-0190. Epub 2013 May 8. PubMed PMID: 23658459.
14: Konecny GE, Kolarova T, O'Brien NA, Winterhoff B, Yang G, Qi J, Qi Z, Venkatesan N, Ayala R, Luo T, Finn RS, Kristof J, Galderisi C, Porta DG, Anderson L, Shi MM, Yovine A, Slamon DJ. Activity of the fibroblast growth factor receptor inhibitors dovitinib (TKI258) and NVP-BGJ398 in human endometrial cancer cells. Mol Cancer Ther. 2013 May;12(5):632-42. doi: 10.1158/1535-7163.MCT-12-0999. Epub 2013 Feb 26. PubMed PMID: 23443805.
15: Wang X, Kay A, Anak O, Angevin E, Escudier B, Zhou W, Feng Y, Dugan M, Schran H. Population pharmacokinetic/pharmacodynamic modeling to assist dosing schedule selection for dovitinib. J Clin Pharmacol. 2013 Jan;53(1):14-20. doi: 10.1177/0091270011433330. Epub 2013 Jan 24. PubMed PMID: 23400739.
16: Angevin E, Lopez-Martin JA, Lin CC, Gschwend JE, Harzstark A, Castellano D, Soria JC, Sen P, Chang J, Shi M, Kay A, Escudier B. Phase I study of dovitinib (TKI258), an oral FGFR, VEGFR, and PDGFR inhibitor, in advanced or metastatic renal cell carcinoma. Clin Cancer Res. 2013 Mar 1;19(5):1257-68. doi: 10.1158/1078-0432.CCR-12-2885. Epub 2013 Jan 21. PubMed PMID: 23339124.
17: Chen ZY, Shi M, Peng LX, Wei W, Li XJ, Guo ZX, Li SH, Zhong C, Qian CN, Guo RP. Dovitinib preferentially targets endothelial cells rather than cancer cells for the inhibition of hepatocellular carcinoma growth and metastasis. J Transl Med. 2012 Dec 10;10:245. doi: 10.1186/1479-5876-10-245. PubMed PMID: 23228017; PubMed Central PMCID: PMC3552726.
18: 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. 2012 Dec 15;84(12):1617-26. doi: 10.1016/j.bcp.2012.09.023. Epub 2012 Oct 5. PubMed PMID: 23041231; PubMed Central PMCID: PMC3501595.
19: Dubbelman AC, Upthagrove A, Beijnen JH, Marchetti S, Tan E, Krone K, Anand S, Schellens JH. 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. 2012 Nov;70(5):653-63. doi: 10.1007/s00280-012-1947-2. Epub 2012 Aug 22. PubMed PMID: 23010851.
20: Sivanand S, Peña-Llopis S, Zhao H, Kucejova B, Spence P, Pavia-Jimenez A, Yamasaki T, McBride DJ, Gillen J, Wolff NC, Morlock L, Lotan Y, Raj GV, Sagalowsky A, Margulis V, Cadeddu JA, Ross MT, Bentley DR, Kabbani W, Xie XJ, Kapur P, Williams NS, Brugarolas J. A validated tumorgraft model reveals activity of dovitinib against renal cell carcinoma. Sci Transl Med. 2012 Jun 6;4(137):137ra75. doi: 10.1126/scitranslmed.3003643. PubMed PMID: 22674553; PubMed Central PMCID: PMC3570965.
| Chemical | |
|---|---|
| CAS Num | 915769-50-5 (lactate); 405169-16-6 (free base) |
| Chemical Formula | C24H27FN6O4 |
| Molecular Weight | 482.51 |
| IUPAC Chemical Name | 4-Amino-5-fluoro-3-[6-(4-methyl-1-piperazinyl)-1H-benzimidazol-2-yl]-2(1H)-quinolinone 2-hydroxypropanoate |
| Elemental Analysis | C, 59.74; H, 5.64; F, 3.94; N, 17.42; O, 13.26 |
| Synonym | TKI258; TKI-258; TKI 258; CHIR258; CHIR-258; CHIR 258; Dovitinib lactate |
| Solubility | Soluble in DMSO, not in water |
| SMILES Code | O=C1NC2=C(C(F)=CC=C2)C(N)=C1C3=NC4=CC=C(N5CCN(C)CC5)C=C4N3.CC(O)C(O)=O |
| Biological | |
| Targets and Effects | FGFR3 inhibitor |
| Pathways | Apoptosis |
| Physical | |
| Appearance | white solid powder |
| Purity | >98% (or refer to the Certificate of Analysis) |
| Shipping Condition | Shipped under ambient temperature as non-hazardous chemical. This product is stable enough for a few weeks during ordinary shipping and time spent in Customs. |
| Storage Condition | Dry, dark and at 0 - 4 C for short term (days to weeks) or -20 C for long term (months to years). |
| Shelf Life | >2 years if stored properly |
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