Structure-Guided Design and Initial Studies of a Bifunctional MEK/PI3K Inhibitor (ST-168),ACS Medicinal Chemistry Letters

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Structure-Guided Design and Initial Studies of a Bifunctional MEK/PI3K Inhibitor (ST-168)
ACS Medicinal Chemistry Letters ( IF 3.5 ) Pub Date : 2017-07-25 00:00:00 , DOI: 10.1021/acsmedchemlett.7b00111
Marcian E. Van Dort ₁ , Stefanie Galbán ₁ , Charles A. Nino ₁ , Hao Hong ₁ , April A. Apfelbaum ₁ , Gary D. Luker ₁ , Greg M. Thurber ₁ , Lydia Atangcho ₁ , Cagri G. Besirli ₁ , Brian D. Ross ₁

Affiliation

The structure-based design of a new single entity, MEK/PI3K bifunctional inhibitor (7, ST-168), which displays improved MEK1 and PI3K isoform inhibition, is described. ST-168 demonstrated a 2.2-fold improvement in MEK1 inhibition and a 2.8-, 2.7-, 23-, and 2.5-fold improved inhibition toward the PI3Kα, PI3Kβ, PI3Kδ, and PI3Kγ isoforms, respectively, as compared to a previous lead compound (4; ST-162) in in vitro enzymatic inhibition assays. ST-168 demonstrated superior tumoricidal efficacy over ST-162 in an A375 melanoma spheroid tumor model. ST-168 was comparatively more effective than ST-162 in promoting tumor control when administrated orally in a tumor therapy study conducted in an A375 melanoma mouse model confirming its bioavailability and efficacy toward combined in vivo MEK1/PI3K inhibition.

中文翻译：

双功能MEK / PI3K抑制剂的结构导向设计和初步研究（ST-168）

描述了一种新的单一实体MEK / PI3K双功能抑制剂（7，ST-168）的基于结构的设计，该抑制剂显示出改善的MEK1和PI3K同工型抑制作用。与以前的先导化合物相比，ST-168分别显示出对PI3Kα，PI3Kβ，PI3Kδ和PI3Kγ同工型的MEK1抑制作用提高了2.2倍，对PI3Kα，PI3Kβ，PI3Kδ和PI3Kγ的抑制作用分别提高了2.8、2.7、23和2.5倍。（4；ST-162）在体外酶抑制试验中。在A375黑色素瘤球状肿瘤模型中，ST-168表现出优于ST-162的杀癌效果。ST-168比ST-162更有效在A375黑色素瘤小鼠模型中进行的肿瘤治疗研究中口服给药时，具有促进肿瘤控制的作用，证实了其对体内MEK1 / PI3K联合抑制的生物利用度和功效。

更新日期：2017-07-26

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