WARNING: This product is for research use only, not for human or veterinary use.
MedKoo CAT#: 205748
Description: Lexibulin, also known as CYT997, is a n orally bioavailable small-molecule with tubulin-inhibiting, vascular-disrupting, and potential antineoplastic activities. Lexibulin inhibits tubulin polymerization in tumor blood vessel endothelial cells and tumor cells, blocking the formation of the mitotic spindle and leading to cell cycle arrest at the G2/M phase; this may result in disruption of the tumor vasculature and tumor blood flow, and tumor cell death.
MedKoo Cat#: 205748
Chemical Formula: C24H30N6O2
Exact Mass: 434.24302
Molecular Weight: 434.534
Elemental Analysis: C, 66.34; H, 6.96; N, 19.34; O, 7.36
Synonym: CYT997; CYT-997; CYT 997. lexibulin.
IUPAC/Chemical Name: (S)-1-ethyl-3-(2-methoxy-4-(5-methyl-4-((1-(pyridin-3-yl)butyl)amino)pyrimidin-2-yl)phenyl)urea
InChi Key: MTJHLONVHHPNSI-IBGZPJMESA-N
InChi Code: InChI=1S/C24H30N6O2/c1-5-8-19(18-9-7-12-25-15-18)28-22-16(3)14-27-23(30-22)17-10-11-20(21(13-17)32-4)29-24(31)26-6-2/h7,9-15,19H,5-6,8H2,1-4H3,(H2,26,29,31)(H,27,28,30)/t19-/m0/s1
SMILES Code: O=C(NC1=CC=C(C2=NC=C(C)C(N[C@H](C3=CC=CN=C3)CCC)=N2)C=C1OC)NCC
Phase I study of Lexibulin (CYT997): Thirty-one patients received CYT997 over 12 dose levels (7-358 mg m(-2)). Doses up to 202 mg m(-2) were well tolerated. Dose-limiting toxicities were observed at 269 and 358 mg m(-2), consisting of grade 3 prolonged corrected QT interval in two patients and grade 3 hypoxia and grade 4 dyspnea in one patient. All toxicities were reversible. The pharmacokinetics of CYT997 were linear over the entire dose range. Dynamic contrast-enhanced magnetic resonance imaging scans showed significant changes in tumour K(trans) values consistent with vascular disruption in 7 out of 11 evaluable patients treated at CYT997 doses of >or=65 mg m(-2). Moreover, plasma levels of von Willebrand factor and caspase-cleaved cytokeratin-18 increased post-treatment at higher dose levels. Among 22 patients evaluable for response, 18 achieved stable disease for >2 cycles. CONCLUSIONS: CYT997 was well tolerated at doses that were associated with pharmacodynamic evidence of vascular disruption in tumours. (source: Br J Cancer. 2010 Aug 24;103(5):597-606.)
1: Chen X, Yang C, Xu Y, Zhou H, Liu H, Qian W. The microtubule depolymerizing agent CYT997 effectively kills acute myeloid leukemia cells via activation of caspases and inhibition of PI3K/Akt/mTOR pathway proteins. Exp Ther Med. 2013 Aug;6(2):299-304. Epub 2013 Jun 14. PubMed PMID: 24137178; PubMed Central PMCID: PMC3786882.
2: Burge M, Francesconi AB, Kotasek D, Fida R, Smith G, Wilks A, Vasey PA, Lickliter JD. Phase I, pharmacokinetic and pharmacodynamic evaluation of CYT997, an orally-bioavailable cytotoxic and vascular-disrupting agent. Invest New Drugs. 2013 Feb;31(1):126-35. doi: 10.1007/s10637-012-9813-y. Epub 2012 Mar 27. PubMed PMID: 22451157.
3: Burns CJ, Fantino E, Powell AK, Shnyder SD, Cooper PA, Nelson S, Christophi C, Malcontenti-Wilson C, Dubljevic V, Harte MF, Joffe M, Phillips ID, Segal D, Wilks AF, Smith GD. The microtubule depolymerizing agent CYT997 causes extensive ablation of tumor vasculature in vivo. J Pharmacol Exp Ther. 2011 Dec;339(3):799-806. doi: 10.1124/jpet.111.186965. Epub 2011 Sep 14. PubMed PMID: 21917561.
4: Lickliter JD, Francesconi AB, Smith G, Burge M, Coulthard A, Rose S, Griffin M, Milne R, McCarron J, Yeadon T, Wilks A, Cubitt A, Wyld DK, Vasey PA. Phase I trial of CYT997, a novel cytotoxic and vascular-disrupting agent. Br J Cancer. 2010 Aug 24;103(5):597-606. doi: 10.1038/sj.bjc.6605841. PubMed PMID: 20733579; PubMed Central PMCID: PMC2938266.
5: Monaghan K, Khong T, Smith G, Spencer A. CYT997 causes apoptosis in human multiple myeloma. Invest New Drugs. 2011 Apr;29(2):232-8. doi: 10.1007/s10637-009-9350-5. Epub 2009 Nov 12. PubMed PMID: 19907921.
6: Burns CJ, Fantino E, Phillips ID, Su S, Harte MF, Bukczynska PE, Frazzetto M, Joffe M, Kruszelnicki I, Wang B, Wang Y, Wilson N, Dilley RJ, Wan SS, Charman SA, Shackleford DM, Fida R, Malcontenti-Wilson C, Wilks AF. CYT997: a novel orally active tubulin polymerization inhibitor with potent cytotoxic and vascular disrupting activity in vitro and in vivo. Mol Cancer Ther. 2009 Nov;8(11):3036-45. doi: 10.1158/1535-7163.MCT-09-0076. Epub 2009 Nov 3. PubMed PMID: 19887548.
7: Burns CJ, Harte MF, Bu X, Fantino E, Joffe M, Sikanyika H, Su S, Tranberg CE, Wilson N, Charman SA, Shackleford DM, Wilks AF. Discovery of CYT997: a structurally novel orally active microtubule targeting agent. Bioorg Med Chem Lett. 2009 Aug 15;19(16):4639-42. doi: 10.1016/j.bmcl.2009.06.079. Epub 2009 Jun 25. PubMed PMID: 19616947.