CYT997 (Lexibulin)

Definition

ChEBI: 1-ethyl-3-[2-methoxy-4-[5-methyl-4-[[(1S)-1-(3-pyridinyl)butyl]amino]-2-pyrimidinyl]phenyl]urea is a member of ureas.

Biological Activity

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

in vitro

Treatment of A549 cells with CYT997 (1 μM) for 24 hours induced rapid reorganization of microtubules, including disruption of the existing microtubule network and accumulation of some cytoplasmic tubulin in plaques, resulting in significant changes in cell morphology, including Adherent cells are lost and cells are reduced. CYT997 is toxic to 16 cancer cells with IC50 ranging from 9 nM in HepG2 cells to 101 nM in KHOS/NP cells. CYT997 effectively acts on HCT15 cells, has a multi-drug resistance mechanism Pgp (MDR consistent with CYT997 destroys cellular tubulin, CYT997 effectively inhibits proliferation, induces cell cycle arrest, and induces apoptosis in human myeloid cell lines (HMCLs) and primary MM cells die.

in vivo

The half-life of CYT997 in oral-treated rats (2.5 hours) was slightly longer than that of intravenous injection (1.5 hours), and the absolute oral bioavailability was 50% to 70%. Oral administration of CYT997 to mice bearing PC3 xenografts inhibited tumor growth more effectively than Paclitaxel in a dose-dependent manner. CYT997 was also effective in an orthotopic model of mouse breast cancer 4T1 cells, some of which were resistant to Paclitaxel treatment. Intraperitoneal injection of CYT997 at a dose of 7.5 mg/kg to liver metastases significantly reduced blood flow at the 6th hour, similar to the positive control effect of CA4P at a dose of 100 mg/kg. Consistent with in vitro anti-myeloma activity, CYT997 significantly extended lifespan in a mouse model of aggressive systemic myeloid leukemia at a dose of 15 mg/kg daily.