化合物信息

Description

Cancer

Description

HMN-214 (IVX-214) is a potent inhibitor of Polo-like kinase (Plk)1 with IC50 of 118 nM.

Targets

IC₅₀

In Vitro

HMN-214 is an oral prodrug that is rapidly converted to HMN-176. The in vitro data of HMN-214 are scarce. However, HMN-176, active metabolite of HMN-214, shows potent and broad-spectrumanti-tumor activity against various cancer cells, including HeLa, PC-3, DU-145, MIAPaCa-2, U937, MCF-7, A549, and WiDr, with a mean IC50 value of 118 nM. HMN-176 is also cytotoxic to drug-resistant human and murine cell lines, including P388/CDDP, P388/VCR, K2/CDDP, and K2/VP-16, with IC50 values ranging from 143 nM–265 nM. In HeLa cells, HMN-176 (3 μM) blocks cell cycle at G2/M phase. ^[1]In Doxorubicin-resistant K2/ARS cells, HMN-176 inhibits cell growth with an IC50 value of 2 μM. HMN-176 (3 μM) down-regulates the expression of the multidrug resistance gene (MDR1), due to the disturbance of NF-Y transcription factor binding to the MDR1 promoter. ^[2]In human RPE1 and CFPAC-1 cells, HMN-176 (2.5 μM) delays satisfaction of the spindle assembly checkpoint. HMN-176 (250 nM–2.5 μM) inhibits meiotic spindle assembly and aster formationin Spisula oocytes. HMN-176 (2.5 μM) also inhibits aster microtubule formation from human centrosomes. These results indicate that the anti-tumor activity of HMN-176 is at least partially via disrupting centrosome-mediated MT assembly during mitosis. ^[3]

In Vivo

HMN-214 is an oral pro-drug of HMN-176 with improved oral absorption. HMN-214 (30 mg/kg) triggers no obvious neurotoxicity in mice. In mouse xenograft model of PC-3, A549, and WiDr cells, HMN-214 (10 mg/kg–20 mg/kg) inhibits tumor growth. ^[1]In nude mice model bearing multidrug-resistant KB-A.1 cells, HMN-214 (10 mg/kg–20 mg/kg) significantly suppresses MDR1 mRNA expression. ^[2]

Clinical Trials

Features

Cell Lines

HeLa, PC-3, DU-145, MIAPaCa-2, U937, MCF-7, A549, and WiDr cells

Concentrations

0–10 μM, dissolved in DMSO

Incubation Time

72 hours

Methods

Cells are seeded into a 96-well microplate at a density of 3 × 10³–1 × 10⁴ cells/well. Dilutions of HMN-214 or HMN-176 are added the next day and the plate is incubated for 72 hours. The inhibition of growth is measured by the MTT assay and IC50 values are then obtained.

Animal Models

Male BALB/c nude mice bearing xenografts of PC-3, A549, and WiDr cells

Formulation

Dissolved in 0.5% methylcellulose

Doses

10 mg/kg–20 mg/kg

Administration

Oral gavage on a QD × 28 schedule