ARS-1620

本公司产品仅用于科研实验，不得用于人体或动物的临床与诊断

ARS-1620 是一种有效的、特异性的共价 KRAS G12C 抑制剂。

ARS-1620 is a potent, specific and covalent KRAS G12C inhibitor with an observed rate of 1,100±200 M-1S-1, shows >10-fold improved potency over the initial ARS-853; inhibits RAS signaling with IC50 of 120 nM, exhibits a half maximal G12C target engagement (TE50) at 0.3 uM and near complete engagement at 3.0 uM across a panel of cell lines harboring the mutant allele; achieves rapid and sustained in vivo target occupancy to induce tumor regression, and is a novel generation of KRASG12C-specific inhibitor with promising therapeutic potential.

ARS-1620 is an atropisomeric selective KRASG12C inhibitor with desirable pharmacokinetics. ARS-1620 exhibits complete growth suppression of p.G12C cell lines (IC50=150 nM) with relatively benign effects on control cell lines. It is found that ARS-1620 significantly reduces expression of the gene set in p.G12C mutant cells in a time-dependent manner but not in the p.G12S mutant cells. Following a 5-day treatment period, only a minority of G12C mutant cell lines are sensitive to ARS-1620 under monolayer culture conditions, whereas in 3D-spheroid conditions, ARS-1620 elicits a robust response (p=0.0140).

Following a single oral dose or 5 consecutive daily doses, ARS-1620 yields average peak tumor concentrations of 1.5 μM (50 mg/kg) and 5.5 μM (200 mg/kg), respectively, that enables significant KRASG12C target occupancy (>=70% G12C-TE at 200 mg/kg) for >24 hr. In MIAPaCa2 xenografts (p.G12C), ARS-1620 significantly inhibits tumor growth (p<0.001) in a dose-dependent manner with marked regression at a dose of 200 mg/kg, given once daily. Across all tumor models employed, ARS-1620 is well tolerated over the entire 3-week treatment period. Moreover, there are no observed clinical signs or toxicity of ARS-1620 in CD-1 mice even at oral doses up to 1,000 mg/kg administered daily over a 7-day period.

ARS1620

MAPK/ERK Signaling

Ras

Ras

Cancer

——

1698055-85-4

430.84

C21H17ClF2N4O2

>98% (HPLC)

DMSO : ≥ 53 mg/mL 123.02 mM

C=CC(N1CCN(C2=C3C=C(Cl)[C@@]([C@@]4=C(O)C=CC=C4F)=C(F)C3=NC=N2)CC1)=O

(S)-1-(4-(6-chloro-8-fluoro-7-(2-fluoro-6-hydroxyphenyl)quinazolin-4-yl)piperazin-1-yl)prop-2-en-1-one

(-20℃)

With Ice Pack

≥ 2 years