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/
|
Solvent |
mg/mL |
mM |
| Solubility |
| DMSO |
69.0 |
158.79 |
| Ethanol |
51.0 |
117.37 |
Note: There can be variations in solubility for the same chemical from different vendors or different batches from the same vendor. The following factors can affect the solubility of the same chemical: solvent used for crystallization, residual solvent content, polymorphism, salt versus free form, degree of hydration, solvent temperature. Please use the solubility data as a reference only. Warming and sonication will facilitate dissolving. Still have questions? Please contact our Technical Support scientists.
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.
| 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.
1: Mahmoud EM, Shongwe M, Moghadam ES, Moghimi-Rad P, Stoll R, Abdel-Jalil R. Design, synthesis, and molecular docking study of novel cinnoline derivatives as potential inhibitors of tubulin polymerization. Z Naturforsch C J Biosci. 2022 Aug 23;78(3-4):123-131. doi: 10.1515/znc-2022-0087. PMID: 35993925.
2: Miller SR, Zhang X, Hau RK, Jilek JL, Jennings EQ, Galligan JJ, Foil DH, Zorn KM, Ekins S, Wright SH, Cherrington NJ. Predicting Drug Interactions with Human Equilibrative Nucleoside Transporters 1 and 2 Using Functional Knockout Cell Lines and Bayesian Modeling. Mol Pharmacol. 2021 Feb;99(2):147-162. doi: 10.1124/molpharm.120.000169. Epub 2020 Dec 1. PMID: 33262250; PMCID: PMC7816041.
3: 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.
4: Wang Y, Zhang H, Gigant B, Yu Y, Wu Y, Chen X, Lai Q, Yang Z, Chen Q, Yang J. Structures of a diverse set of colchicine binding site inhibitors in complex with tubulin provide a rationale for drug discovery. FEBS J. 2016 Jan;283(1):102-11. doi: 10.1111/febs.13555. Epub 2015 Nov 4. PMID: 26462166.
