CYT997, a synthetic small molecule optimized for antiproliferative activity in a panel of cell-based assays, in which the compound shows an IC50 of between 1 and 100 nmol/L across a panel of cancer cell lines. The compound inhibits the polymerization of tubulin with an IC50 of ～3 μmol/L.CYT997 causes a significant increase of cells in the G2-M phase of the cell cycle.Caspase-3 activation is also observed in cells treated with CYT997 along with the generation of poly (ADP-ribose) polymerase.CYT997 exhibits vascular disrupting activity as measured in vitro by effects on the permeability of human umbilical vein endothelial cell monolayers, and in vivo by effects on tumor blood flow. CYT997 possesses a useful combination of pharmacologic and pharmacokinetic properties and has considerable potential as a novel anticancer agent.
|Source||J Hematol Oncol (2017). Figure 1. CYT997|
|Cell Lines||DU145, PC3, LNCaP, and 22Rv1 cells|
|Concentrations||30, 60 nM|
|Incubation Time||48 h|
|Results||A sharp decrease in activated STAT3 was observed in DU145 cells when exposed to CYT997|
|Cell lines||DU145, A549, Ramos, KHOS/NP, A375, HCT-15, HT1376, BT-20, A431, PA-1, U937, HepG2, TF-1, Baf3/TelJAK2, PC3, and K562|
|Preparation method||Exposing the cells to various concentrations of CYT997 for ~72 hours. Assessing cell proliferation with either the Alamar blue or MTT assays. For MTT assays, adding 5 mg/mL of MTT to all wells, incubating plates for 6 hours at 37 °C, and then adding lysis buffer (10% SDS in 0.01 N HCl) and measuring absorbance at 620 nm in a BMG Technologies Lumistar or Polarstar plate reader. For Alamar blue assays, adding Alamar blue (10 μL/well) to each well and incubating the plates at 37 °C for 4 hours. Then measureing the fluorescence using a fluorescence plate reader with an excitation filter at 544 nm and an emission filter at 590 nm. For cell cycle analysis, cells are fixed and permeabilized with 70% ethanol in PBS and incubated at 4 °C overnight. RNase-treated samples (10 μg RNase/mL for 20 minutes at 37 °C) are stained with propidium iodide (5 μg/mL) at 4 °C for a minimum of 10 minutes. Cell cycle variables are determined by fluorescence-activated cell sorting (FACS) analysis using a Beckman-Coulter Quanta SC MPL system and analyzed using CXP Software. For apoptosis analysis, cells are detached and collected. Using the Vybrant Apoptosis Assay Kit to do Annexin staining . Storing cells on ice and analyzing on a Beckman Coulter Quanta MPL within 1 hour of preparation. Using two-channel analysis to determine Annexin V–positive cells .|
|Concentrations||Dissolved in DMSO, final concentrations ~1 μM|
|Incubation time||~72 hours|
|Animal models||Male nude mice inoculated s.c. with PC3 cells, and female BALB/c mice inoculated with 4T1 cells|
|Formulation||Formulated in NMP/PEG300/saline|
|Administration||Oral gavage thrice a day|
|Solubility (25°C)||DMSO 77 mg/mL|
Powder -20°C 3 years ; 4°C 2 years
In solvent -80°C 6 months ; -20°C 1 month
|Body Surface Area (m2)||0.007||0.025||0.15||0.05||0.02||0.5|
|Animal A (mg/kg) = Animal B (mg/kg) multiplied by||Animal B Km|
|Animal A Km|
For example, to modify the dose of Compound A used for a mouse (20 mg/kg) to a dose based on the BSA for a rat, multiply 20 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for Compound A of 10 mg/kg.
 Ya Cao, et al. Mitochondrial ROS accumulation inhibiting JAK2/STAT3 pathway is a critical modulator of CYT997-induced autophagy and apoptosis in gastric cancer
 Zongyi Wang, et al. CYT997(Lexibulin) induces apoptosis and autophagy through the activation of mutually reinforced ER stress and ROS in osteosarcoma
 Xiangdong Zhao, et al. Intracellular reduction in ATP levels contributes to CYT997-induced suppression of metastasis of head and neck squamous carcinoma
 Yong Teng, et al. Augmentation of the anticancer activity of CYT997 in human prostate cancer by inhibiting Src activity
 Katherine Monaghan, et al. CYT997 causes apoptosis in human multiple myeloma
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