化合物信息

Description

Cancer

Description

MS-275 is an HDAC inhibitor of HDAC1 and HDAC3 with IC50 of 0.51 μM and 1.7 μM, respectively.

Targets

IC₅₀

In Vitro

MS-275 shows inhibitory to HDACs by 2′-amino group. MS-275 induces accumulation of p21 ^WAF1/CIP1 and gelsolin in K562 cell. MS-275 could reduce S-phase cells and induce G1-phase cells in A2780 cell. MS-275 inhibits the proliferation of human tumor cell lines including A2780, Calu-3, HL-60, K562, St-4, HT-29, KB-3-1, Capan-1, 4-1St and HCT-15 with IC50 from 41.5 nM to 4.71 μM, which due to HAD-inhibition. ^[1] MS-275 is not sensitive to other HDACs (4, 6, 8 and 10) with IC50 about/above 100 μM. ^[2] MS-275 shows great inhibition to human leukemia and lymphoma cells, including U937, HL-60, K562, and Jurkat. MS-275 also decreases expression of cyclin D1 and the antiapoptotic proteins Mcl-1 and XIAP. ^[3]

In Vivo

MS-275 exhibits great antitumor activity against human tumor xenografts except HCT-15 at 49 mg/kg. ^[1] MS-275 demonstrates promising therapeutic potential in both solid and hematologic malignancies, as well as regulation of physiologic and aberrant gene expression. ^[4] MS-275, combination with IL-2, has great antitumor activity to renal cell carcinoma xenograft model, which due to decreased T regulatory cells and increased splenocytes. ^[5]

Clinical Trials

MS-275 is currently in Phase I/II clinical trials in recurrent advanced non-small cell lung cancer, combining with 5-azacytidine.

Features

Standard HDAC Assays

Rat liver enzyme is diluted 1:6 with HDAC buffer. Recombinant human HDACs are diluted 1:4 in HDAC buffer. For standard HDAC assays, 60 μL of HDAC buffer is mixed with 10 μL of diluted enzyme solution at 30 °C. The HDAC reaction is started by adding 30 μL substrate solution in HDAC buffer followed by 30 min of incubation at 30 °C. The reaction is stopped by adding 100 μL trypsin solutions (10 mg/ml trypsin in 50 mM Tris-HCl [pH 8.0], 100 mM NaCl, 2 μM TSA). After a 20 min incubation period at 30 °C, the release of AMC is monitored by measuring the fluorescence at 460 nm (λ_ex = 390 nm). Fluorescence intensity is calibrated using free AMC. For standard time course experiments, 20 pmol of substrate is used in the initial 100 μL HDAC reaction. K_m and V_max values are determined by measuring the fluorescence AMC generated by enzymatic cleavage of 2–50 pmol of substrate. The experimental data are analyzed using a Hanes plot. The AMC signals are recorded against a blank with buffer and substrate but without the enzyme.

Cell Lines

A2780, Calu-3, HL-60, K562, St-4, HT-29, KB-3-1, Capan-1, 4-1St and HCT-15 cells

Concentrations

~ 10 μM

Incubation Time

3 days

Methods

Animal Models

A2780, HT-29, HTC-15, KB-3-1, 4-1St, St-4, Capan-1 and Calu-3 cells are injected subcutaneously into the flank of nude mice.

Formulation

Dissolved with 0.05 N HCl, 0.1% Tween 80

Doses

12.3, 24.5 and 49 mg/kg

Administration

Administered orally once daily 5 days per week for 4 weeks