Lexibulin
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MedKoo CAT#: 205748

CAS#: 917111-44-5

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.

Chemical Structure

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Lexibulin
CAS# 917111-44-5
Product data Instruction

Theoretical Analysis

MedKoo Cat#: 205748
Name: Lexibulin
CAS#: 917111-44-5
Chemical Formula: C24H30N6O2
Exact Mass: 434.24
Molecular Weight: 434.534
Elemental Analysis: C, 66.34; H, 6.96; N, 19.34; O, 7.36

Price and Availability

Size Price Availability Quantity
10mg USD 150 Ready to ship
25mg USD 250 Ready to ship
50mg USD 450 Ready to ship
100mg USD 750 Ready to ship
200mg USD 1150 Ready to ship
500mg USD 2050 Ready to ship
1g USD 3050 Ready to ship
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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

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).

Solubility: Soluble in DMSO, not in water

Shelf Life: >2 years if stored properly

Drug Formulation: This drug may be formulated in DMSO

Stock Solution Storage: 0 - 4 C for short term (days to weeks), or -20 C for long term (months).

HS Tariff Code: 2934.99.9001

More Info: 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.)      

Biological target: Lexibulin (CYT-997) is a potent and orally active tubulin polymerisation inhibitor with IC50s of 10-100 nM in cancer cell lines.
In vitro activity: It was next determined whether CYT997 can induce autophagy in OS cells. First, 143B and SJSA were transfected with GFP-LC3encoding plasmids to analyze the formation of autophagosomes, and LysoTracker Red dye was used to label cellular acidic vesicular organelles (AVOs) such as lysosomes. Cells treated with CYT997 exhibited more acidic compartments in the cytoplasm and significantly higher numbers of GFP-LC3 puncta than did control cells. Compared to those in the control group, large numbers of autophagosomes were observed in the CYT997-treated group (Fig.2b and Fig. 3a). Furthermore, expression of autophagy-related proteins, including LC3B and Beclin-1, was assesed by western blotting and found that CYT997 increased expression of LC3B-II and beclin-1 in a concentration-dependent manner. To determine whether CYT997-induced autophagy is prosurvival or prodeath, 3-MA, CQ and ATG5 and ATG7-targeted shRNA was used to inhibit autophagy before CYT997 treatment. CCK-8 analysis and PI/AnnexinFITC flow cytometry indicated that pretreatment with autophagy inhibitor enhanced the effect of CYT997 on cell viability and apoptosis (Fig 2d, e and f and Additional file 2: Figure S1, Additional file 1: S2E). In conclusion, CYT997 induces autophagy in OS cells, and the induced autophagy promotes cell survival. Reference: J Exp Clin Cancer Res. 2019; 38: 44. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6357486/
In vivo activity: To investigate the effect of CYT997 in tumor growth in vivo, mice bearing gastric cancer PDX xenografts were used. When tumors reached a volume of 50 mm3, mice were intraperitoneally injected with normal saline (NS) and CYT997 (15 mg/kg) respectively. Tumor size was measured every other day and tumors were excised after 10 days post injection. It was found that CYT997 significantly decreased tumor volume and tumor weight compared with control group (Fig. 7a-c). Furthermore, it was also found that the expressions of p-JAK2 and p-STAT3 were decreased after CYT997 treatment. And CYT997 increased the expression of cleaved caspase 3 and LC3B (Fig.7d-e;7d-e; Additional file 1: Fig. S9). In addition, it was found that there were no obvious changes in body weight and organ-related toxicities were scarce in mice (Fig.7f7f and g). Collectively, these results suggest that CYT997 inhibits tumor growth and cell proliferation in vivo. Reference: J Exp Clin Cancer Res. 2020; 39: 119. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7310559/

Solubility Data

Solvent Max Conc. mg/mL Max Conc. mM
Solubility
DMSO 69.0 158.79
Ethanol 51.0 117.37

Preparing Stock Solutions

The following data is based on the product molecular weight 434.53 Batch specific molecular weights may vary from batch to batch due to the degree of hydration, which will affect the solvent volumes required to prepare stock solutions.

Recalculate based on batch purity %
Concentration / Solvent Volume / Mass 1 mg 5 mg 10 mg
1 mM 1.15 mL 5.76 mL 11.51 mL
5 mM 0.23 mL 1.15 mL 2.3 mL
10 mM 0.12 mL 0.58 mL 1.15 mL
50 mM 0.02 mL 0.12 mL 0.23 mL
Formulation protocol: 1. Wang Z, Yin F, Xu J, Zhang T, Wang G, Mao M, Wang Z, Sun W, Han J, Yang M, Jiang Y, Hua Y, Cai Z. CYT997(Lexibulin) induces apoptosis and autophagy through the activation of mutually reinforced ER stress and ROS in osteosarcoma. J Exp Clin Cancer Res. 2019 Jan 31;38(1):44. doi: 10.1186/s13046-019-1047-9. PMID: 30704503; PMCID: PMC6357486. 2. Teng Y, Cai Y, Pi W, Gao L, Shay C. Augmentation of the anticancer activity of CYT997 in human prostate cancer by inhibiting Src activity. J Hematol Oncol. 2017 Jun 12;10(1):118. doi: 10.1186/s13045-017-0485-0. PMID: 28606127; PMCID: PMC5469135. 3. Cao Y, Wang J, Tian H, Fu GH. Mitochondrial ROS accumulation inhibiting JAK2/STAT3 pathway is a critical modulator of CYT997-induced autophagy and apoptosis in gastric cancer. J Exp Clin Cancer Res. 2020 Jun 23;39(1):119. doi: 10.1186/s13046-02001621-y. PMID: 32576206; PMCID: PMC7310559.
In vitro protocol: 1. Wang Z, Yin F, Xu J, Zhang T, Wang G, Mao M, Wang Z, Sun W, Han J, Yang M, Jiang Y, Hua Y, Cai Z. CYT997(Lexibulin) induces apoptosis and autophagy through the activation of mutually reinforced ER stress and ROS in osteosarcoma. J Exp Clin Cancer Res. 2019 Jan 31;38(1):44. doi: 10.1186/s13046-019-1047-9. PMID: 30704503; PMCID: PMC6357486. 2. Teng Y, Cai Y, Pi W, Gao L, Shay C. Augmentation of the anticancer activity of CYT997 in human prostate cancer by inhibiting Src activity. J Hematol Oncol. 2017 Jun 12;10(1):118. doi: 10.1186/s13045-017-0485-0. PMID: 28606127; PMCID: PMC5469135.
In vivo protocol: 1. Wang Z, Yin F, Xu J, Zhang T, Wang G, Mao M, Wang Z, Sun W, Han J, Yang M, Jiang Y, Hua Y, Cai Z. CYT997(Lexibulin) induces apoptosis and autophagy through the activation of mutually reinforced ER stress and ROS in osteosarcoma. J Exp Clin Cancer Res. 2019 Jan 31;38(1):44. doi: 10.1186/s13046-019-1047-9. PMID: 30704503; PMCID: PMC6357486. 2. Cao Y, Wang J, Tian H, Fu GH. Mitochondrial ROS accumulation inhibiting JAK2/STAT3 pathway is a critical modulator of CYT997-induced autophagy and apoptosis in gastric cancer. J Exp Clin Cancer Res. 2020 Jun 23;39(1):119. doi: 10.1186/s13046-02001621-y. PMID: 32576206; PMCID: PMC7310559.

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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.