基于卡博替尼的靶向c-Met激酶的PROTACs的设计、合成及体外研究

Design, Synthesis and In Vitro Investigation of Cabozantinib-Based PROTACs to Target c-Met Kinase.

作者信息

Sachkova Anastasia A, Andreeva Daria V, Tikhomirov Alexander S, Scherbakov Alexander M, Salnikova Diana I, Sorokin Danila V, Bogdanov Fedor B, Rysina Yulia D, Shchekotikhin Andrey E, Shchegravina Ekaterina S, Fedorov Alexey Yu

机构信息

Department of Organic Chemistry, Nizhny Novgorod State University, Gagarina Av. 23, 603950 Nizhny Novgorod, Russia.

Gause Institute of New Antibiotics, 11 B. Pirogovskaya Street, 119021 Moscow, Russia.

出版信息

Pharmaceutics. 2022 Dec 16;14(12):2829. doi: 10.3390/pharmaceutics14122829.

Abstract

(1) Background: This investigation aimed at developing a series of c-Met-targeting cabozantinib-based PROTACs. (2) Methods: Purification of intermediate and target compounds was performed using column chromatography, in vitro antiproliferation activity was measured using a standard MTT assay and a c-Met degradation assay was performed via the immunoblotting technique. (3) Results: Several compounds exhibited antiproliferative activity towards different cell lines of breast cancer (T47D, MDA-MB-231, SKBR3, HCC1954 and MCF7) at the same level as parent cabozantinib and 7-demethyl cabozantinib. Two target conjugates, bearing a VHL-ligand as an E3-ligase binding moiety and glycol-based linkers, exhibited the effective inhibition of c-Met phosphorylation and an ability to decrease the level of c-Met in HCC1954 cells at micromolar concentrations. (4) Conclusions: Two compounds exhibit c-Met inhibition activity in the nanomolar range and can be considered as PROTAC molecules due to their ability to decrease the total level of c-Met in HCC1954 cells. The structures of the offered compounds can be used as starting points for further evaluation of cabozantinib-based PROTACs.

摘要

(1) 背景:本研究旨在开发一系列以卡博替尼为基础、靶向c-Met的PROTAC。(2) 方法:采用柱色谱法对中间体和目标化合物进行纯化,使用标准MTT法测定体外抗增殖活性,并通过免疫印迹技术进行c-Met降解试验。(3) 结果:几种化合物对不同的乳腺癌细胞系(T47D、MDA-MB-231、SKBR3、HCC1954和MCF7)表现出与母体卡博替尼和7-去甲基卡博替尼相同水平的抗增殖活性。两种带有VHL配体作为E3连接酶结合部分和基于二醇的连接子的目标缀合物,在微摩尔浓度下对HCC1954细胞表现出对c-Met磷酸化的有效抑制作用以及降低c-Met水平的能力。(4) 结论:两种化合物在纳摩尔范围内表现出c-Met抑制活性,并且由于它们能够降低HCC1954细胞中c-Met的总水平,可被视为PROTAC分子。所提供化合物的结构可作为进一步评估基于卡博替尼的PROTAC的起点。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a919/9781691/99297b4ea624/pharmaceutics-14-02829-g001.jpg

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