Description: Tivozanib, also known as KRN951, is an orally bioavailable inhibitor of vascular endothelial growth factor receptors (VEGFRs) 1, 2 and 3 with potential antiangiogenic and antineoplastic activities. Tivozanib binds to and inhibits VEGFRs 1, 2 and 3, which may result in the inhibition of endothelial cell migration and proliferation, inhibition of tumor angiogenesis and tumor cell death. VEGFR tyrosine kinases, frequently overexpressed by a variety of tumor cell types, play a key role in angiogenesis.

Synonym: AV951; AV-951; AV 951; KRN951; KRN 951; KRN-951, Tivozanib

IUPAC/Chemical Name: 1-(2-chloro-4-((6,7-dimethoxyquinolin-4-yl)oxy)phenyl)-3-(5-methylisoxazol-3-yl)urea

THEORETICAL ANALYSIS

Name: Tivozanib
CAS#: 475108-18-0
Chemical Formula: C22H19ClN4O5
Exact Mass: 454.1044
Molecular Weight: 454.86306
Elemental Analysis: C, 58.09; H, 4.21; Cl, 7.79; N, 12.32; O, 17.59

TECHNICAL DATA

REFERENCES

1: Mehta A, Sonpavde G, Escudier B. Tivozanib for the treatment of renal cell carcinoma: results and implications of the TIVO-1 trial. Future Oncol. 2014 Aug;10(11):1819-26. doi: 10.2217/fon.14.120. PubMed PMID: 25325825.

2: Laguna MP. Re: Tivozanib versus Sorafenib as Initial Targeted Therapy for Patients with Metastatic Renal Cell Carcinoma: Results from a Phase III Trial. J Urol. 2014 Oct;192(4):1079. doi: 10.1016/j.juro.2014.07.054. Epub 2014 Jul 18. PubMed PMID: 25304551.

3: Yang D, Kathawala RJ, Chufan EE, Patel A, Ambudkar SV, Chen ZS, Chen X. Tivozanib reverses multidrug resistance mediated by ABCB1 (P-glycoprotein) and ABCG2 (BCRP). Future Oncol. 2014 Aug;10(11):1827-41. doi: 10.2217/fon.13.253. Epub 2013 Dec 3. PubMed PMID: 24295377.

4: Motzer RJ, Nosov D, Eisen T, Bondarenko I, Lesovoy V, Lipatov O, Tomczak P, Lyulko O, Alyasova A, Harza M, Kogan M, Alekseev BY, Sternberg CN, Szczylik C, Cella D, Ivanescu C, Krivoshik A, Strahs A, Esteves B, Berkenblit A, Hutson TE. Tivozanib versus sorafenib as initial targeted therapy for patients with metastatic renal cell carcinoma: results from a phase III trial. J Clin Oncol. 2013 Oct 20;31(30):3791-9. doi: 10.1200/JCO.2012.47.4940. Epub 2013 Sep 9. PubMed PMID: 24019545.

5: Garnick MB. Preserving the sanctity of overall survival for drugs approved on the basis of progression-free survival: tivozanib as a case study. J Clin Oncol. 2013 Oct 20;31(30):3746-8. doi: 10.1200/JCO.2013.51.4869. Epub 2013 Sep 9. Erratum in: J Clin Oncol. 2013 Dec 1;31(34):4383. PubMed PMID: 24019543.

6: Mayer EL, Scheulen ME, Beckman J, Richly H, Duarte A, Cotreau MM, Strahs AL, Agarwal S, Steelman L, Winer EP, Dickler MN. A Phase I dose-escalation study of the VEGFR inhibitor tivozanib hydrochloride with weekly paclitaxel in metastatic breast cancer. Breast Cancer Res Treat. 2013 Jul;140(2):331-9. doi: 10.1007/s10549-013-2632-9. Epub 2013 Jul 19. PubMed PMID: 23868188.

7: Cowey CL. Profile of tivozanib and its potential for the treatment of advanced renal cell carcinoma. Drug Des Devel Ther. 2013 Jun 21;7:519-27. doi: 10.2147/DDDT.S31442. Print 2013. Review. PubMed PMID: 23818763; PubMed Central PMCID: PMC3693745.

8: Hepgur M, Sadeghi S, Dorff TB, Quinn DI. Tivozanib in the treatment of renal cell carcinoma. Biologics. 2013;7:139-48. doi: 10.2147/BTT.S32958. Epub 2013 Jun 11. PubMed PMID: 23788831; PubMed Central PMCID: PMC3684142.

9: Wong HH, Eisen T. Tivozanib for the treatment of metastatic renal cancer. Expert Rev Anticancer Ther. 2013 Jun;13(6):649-60. doi: 10.1586/era.13.40. Review. PubMed PMID: 23773100.

10: Fishman MN, Srinivas S, Hauke RJ, Amato RJ, Esteves B, Cotreau MM, Strahs AL, Slichenmyer WJ, Bhargava P, Kabbinavar FF. Phase Ib study of tivozanib (AV-951) in combination with temsirolimus in patients with renal cell carcinoma. Eur J Cancer. 2013 Sep;49(13):2841-50. doi: 10.1016/j.ejca.2013.04.019. Epub 2013 May 28. PubMed PMID: 23726267.

11: Berge EM, Bowles DW, Flaig TW, Lam ET, Jimeno A. Tivozanib: practical implications for renal cell carcinoma and other solid tumors. Drugs Today (Barc). 2013 May;49(5):303-15. doi: 10.1358/dot.2013.49.5.1960218. Review. PubMed PMID: 23724410.

12: Kang S, Roh YJ, Kim IB. Antiangiogenic effects of tivozanib, an oral VEGF receptor tyrosine kinase inhibitor, on experimental choroidal neovascularization in mice. Exp Eye Res. 2013 Jul;112:125-33. doi: 10.1016/j.exer.2013.05.006. Epub 2013 May 20. PubMed PMID: 23701975.

13: Niwakawa M, Yamaguchi R, Onozawa Y, Yasui H, Taku K, Naito T, Akinaga S, Boku N, Yamamoto N. Phase I study of highly selective inhibitor of VEGFR tyrosine kinase, tivozanib, in Japanese patients with solid tumors. Cancer Sci. 2013 Aug;104(8):1039-44. doi: 10.1111/cas.12197. Epub 2013 Jun 21. PubMed PMID: 23679664.

14: Wolpin BM, Ng K, Zhu AX, Abrams T, Enzinger PC, McCleary NJ, Schrag D, Kwak EL, Allen JN, Bhargava P, Chan JA, Goessling W, Blaszkowsky LS, Supko JG, Elliot M, Sato K, Regan E, Meyerhardt JA, Fuchs CS. Multicenter phase II study of tivozanib (AV-951) and everolimus (RAD001) for patients with refractory, metastatic colorectal cancer. Oncologist. 2013;18(4):377-8. doi: 10.1634/theoncologist.2012-0378. Epub 2013 Apr 11. PubMed PMID: 23580238; PubMed Central PMCID: PMC3639523.

15: Figlin R. Tivozanib in renal cell carcinoma. Clin Adv Hematol Oncol. 2013 Jan;11(1):43-5. PubMed PMID: 23416862.

16: Haberkorn BC, Eskens FA. Structure, development, preclinical and clinical efficacy of tivozanib (KRN-951, AV-951). Future Oncol. 2013 Jan;9(1):13-20. doi: 10.2217/fon.12.167. Review. PubMed PMID: 23252559.

17: Taneja SS. Re: Antitumor activity and safety of tivozanib (AV-951) in a phase II randomized discontinuation trial in patients with renal cell carcinoma. J Urol. 2012 Dec;188(6):2149-50. doi: 10.1016/j.juro.2012.08.170. Epub 2012 Oct 18. PubMed PMID: 23141221.

18: Pal SK, Bergerot PG, Figlin RA. Tivozanib: current status and future directions in the treatment of solid tumors. Expert Opin Investig Drugs. 2012 Dec;21(12):1851-9. doi: 10.1517/13543784.2012.733695. Epub 2012 Sep 26. Review. PubMed PMID: 23013465; PubMed Central PMCID: PMC3934561.

19: Nosov DA, Esteves B, Lipatov ON, Lyulko AA, Anischenko AA, Chacko RT, Doval DC, Strahs A, Slichenmyer WJ, Bhargava P. Antitumor activity and safety of tivozanib (AV-951) in a phase II randomized discontinuation trial in patients with renal cell carcinoma. J Clin Oncol. 2012 May 10;30(14):1678-85. doi: 10.1200/JCO.2011.35.3524. Epub 2012 Apr 9. PubMed PMID: 22493422.

20: Gupta S, Fishman M. Progress and contrasts of the development of tivozanib for therapy of kidney cancer. Expert Opin Pharmacother. 2011 Dec;12(18):2915-22. doi: 10.1517/14656566.2011.636032. Review. Erratum in: Expert Opin Pharmacother. 2012 Feb;13(2):291. PubMed PMID: 22098229.