產(chǎn)品名：MRTX1133

CAS 號(hào)：2621928-55-8

分子式：C33H31F3N6O2

分子量：600.63

純  度：99%

備  注：僅供科研

描述MRTX1133是一種非共價(jià)、有效和選擇性KRAS G12D抑制劑。MRTX1133以最佳方式填充開(kāi)關(guān)II口袋,并延伸三個(gè)取代基以與蛋白質(zhì)良好地相互作用,導(dǎo)致對(duì)KRASG12D的KD估計(jì)為0.2 pM。MRTX1133阻止SOS1催化的核苷酸交換和/或KRASG12D/GTP/RAF1復(fù)合物的形成,從而抑制突變體KRAS依賴性信號(hào)轉(zhuǎn)導(dǎo)。MRTX1133在細(xì)胞分析中具有皮摩爾結(jié)合親和力、一位數(shù)納摩爾活性,并且在含有KRASG12D突變的腫瘤模型中具有顯著的體內(nèi)療效[1]。

相關(guān)類別

研究領(lǐng)域 >> 癌癥

信號(hào)通路 >> G 蛋白偶聯(lián)受體/G 蛋白 >> 拉斯

靶點(diǎn)

KRas G12D

體外研究MRTX1133在IC50范圍為1-10nm的AGS細(xì)胞系中抑制ERK磷酸化(AsPC-1、Panc 04.03、Panc 02.03、SW1990、GP2D、Suit2、A427、SNU1033和HPAC細(xì)胞)。在2D活性測(cè)定中,MRTX1133對(duì)AGS細(xì)胞(KRAS G12D)的IC50為6 nM,同時(shí)顯示出對(duì)MKN1的500倍以上選擇性,MKN1是一種依賴KRAS生長(zhǎng)和存活的細(xì)胞系,由于野生型KRAS的擴(kuò)增[1]。

體內(nèi)研究MRTX1133在KRASG12D突變異種移植小鼠腫瘤模型中顯示有效性[1]。動(dòng)物模型：6-8周齡,雌性,裸鼠(Panc 04.03模型)[1]劑量：3、10或30mg/kg給藥：腹腔注射；每天兩次,共28天結(jié)果：該模型中的抗腫瘤療效研究產(chǎn)生MRTX1133劑量依賴性抗腫瘤活性,在3 mg/kg BID(IP)下觀察到94%的生長(zhǎng)抑制,腫瘤消退?62%及?在10 mg/kg BID(IP)和30 mg/kg BID(IP)下分別觀察到73%。

產(chǎn)品描述：

 MRTX1133 is a potent and selective KRAS G12D inhibitor. MRTX1133 targets the KRAS G12D protein in both active and inactive states. In preclinical studies, MRTX1133 exhibited a long half-life, an ability to bind the KRAS G12D protein in both active and inactive states, and selective inhibition of KRAS G12D mutant cancer cells. In G12D mutant tumor models, MRTX1133 showed dose-dependent selective inhibition of the KRAS pathway and tumor regression.

體外研究： MRTX1133 inhibits ERK phosphorylation in the AGS cell line with an IC50 ranging 1-10 nM (AsPC-1, Panc 04.03, Panc 02.03, SW1990, GP2D, Suit2, A427, SNU1033, and HPAC cells). In a 2D viability assay, the IC50 of MRTX1133 is 6 nM against AGS cells (KRAS G12D), while demonstrating more than 500-fold selectivity against MKN1, a cell line which is dependent on KRAS for its growth and survival due to the amplification of wild-type KRAS.

體內(nèi)研究： MRTX1133 displays efficacious in a KRAS G12D mutant xenograft mouse tumor model.