Home Cytoskeletal Signaling Microtubule Associated inhibitor Lexibulin (CYT997)

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Lexibulin (CYT997) Microtubule Associated inhibitor

Cat.No.S2195

Lexibulin (CYT997, SRI-32007) is a potent microtubule polymerization inhibitor with IC50 of 10-100 nM in cancer cell lines. This compound is in Phase 2.
Lexibulin (CYT997) Microtubule Associated inhibitor Chemical Structure

Chemical Structure

Molecular Weight: 434.53

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Chemical Information, Storage & Stability

Molecular Weight 434.53 Formula

C24H30N6O2

 Storage (From the date of receipt)
CAS No. 917111-44-5 Download SDF Storage of Stock Solutions

Synonyms SRI-32007 Smiles CCCC(C1=CN=CC=C1)NC2=NC(=NC=C2C)C3=CC(=C(C=C3)NC(=O)NCC)OC

Solubility

In vitro
Batch:

DMSO : 86 mg/mL (197.91 mM)
(Moisture-contaminated DMSO may reduce solubility. Use fresh, anhydrous DMSO.)

Ethanol : 20 mg/mL

Water : Insoluble

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Mass Concentration Volume Molecular Weight

In vivo
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Mechanism of Action

Targets/IC50/Ki
Microtubules (cancer cell lines) [1]
10 nM-100 nM
In vitro
Lexibulin (CYT997) (1 μM) treatment for 24 hours in A549 cells induces rapid reorganization of microtubules including the destruction of the existing microtubule network and accumulation of tubulin in plaques within the cytoplasm of some cells, leading to significant cell morphology alterations including the loss of adhesion and cell rounding. It displays potent cytotoxic activity against a range of 16 cancer cells with IC50 ranging from 9 nM for HepG2 to 101 nM for KHOS/NP. Especially, this compound exhibits potent activity against HCT15 cells, known to possess the multidrug resistance mechanism Pgp (MDR+), with IC50 of 52 nM. Through inhibition of microtubule polymerization, it blocks the cell cycle at the G2-M boundary, and induces an increase in phosphorylated Bcl-2 and increased expression of cyclin B1, as well as caspase-3 activation and the generation of poly (ADP-ribose) polymerase. Its treatment causes a rapid and reversible increase in the permeability of HUVEC monolayers with IC50 of ~80 nM at 1 hour of exposure. [1] Consistent with the disruption of cellular tubulin, it potently inhibits proliferation, induces cell cycle arrest and most importantly apoptosis of both human myeloma cell lines (HMCLs) and primary MM cells. [2]
Kinase Assay
Turbidimetric assay for tubulin polymerization
The effect of Lexibulin (CYT997) on microtubule polymerization is determined using a conventional turbidimetric assay with bovine neuronal tubulin, in which microtubule assembly is monitored by an increase in absorbance at 340 nm. Increasing concentrations of this compound are added to 100 μL of tubulin/GTP/glycerol. Turbidimetric assays of microtubule assembly are performed by incubating bovine microtubule protein in cuvettes at 37 °C in a thermostatically controlled spectrophotometer, measuring the change in absorbance at 340 nm over time in PEM buffer [80 nM PIPES (pH 6.9), 2 mM MgCl2, 0.5 mM EGTA, and 5% glycerol].
In vivo
The half-life of Lexibulin (CYT997) for oral administration (2.5 hours) to rats is slightly longer than that for intravenous administration (1.5 hours), with the absolute oral bioavailability being 50% to 70%. Oral administration of this compound induces dose-dependent inhibition of tumor growth of PC3 xenografts in mice, more potently compared with paclitaxel. It is also effective in an orthotopic syngeneic model using the mouse breast cancer 4T1 cells, which are some refractory to Paclitaxel treatment. A single dose of CYT997 (7.5 mg/kg, i.p.) reduces tumor blood flow significantly at 6 hours in liver metastases, to a similar extent as the positive control CA4P dosed at 100 mg/kg. [1] Treatment with this compound (15 mg/kg/day) significantly prolongs the survival in a murine model of aggressive systemic myelomatosis. [2]
References

Clinical Trial Information

(data from https://clinicaltrials.gov, updated on 2024-05-22)

NCT Number Recruitment Conditions Sponsor/Collaborators Start Date Phases
NCT00650949 Terminated
Glioblastoma Multiforme
Gilead Sciences
 November 2009 Phase 1|Phase 2
NCT00664378 Terminated
Relapsed and Refractory Multiple Myeloma
Gilead Sciences
 January 2008 Phase 2

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