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Structure-based design of 2,4-diaminopyrimidine derivatives bearing a pyrrolyl group as ALK and ROS1 inhibitors

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Abstract

In order to develop potent ALK and ROS1 dual inhibitors, twenty-eight 2,4-diaminopyrimidine derivatives (9a–9n and 10a–10n) bearing a pyrrolyl moiety were designed and synthesized based on the co-crystal structure of ceritinib with ALKwt protein. Most compounds displayed considerable activity against ALK and ROS1 addicted cells; meanwhile, compound 10d showed excellent activity against Karpas299, H2228 and HCC78 with IC50 values of 0.01, 0.08 and 0.042 μM. Subsequently, seven compounds were selected for kinase studies in vitro, resulting in the discovery of 10d with IC50 values of 1.8, 4.3 and 3.6 nM against ALK, ALKL1196M and ROS1, respectively. Furthermore, the biological assays revealed that compound 10d induced cell apoptosis in a dose-dependent manner. Ultimately, molecular docking studies presented reasonable and optimal binding interactions with ALKwt and ROS1.

Graphical abstract: Structure-based design of 2,4-diaminopyrimidine derivatives bearing a pyrrolyl group as ALK and ROS1 inhibitors

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Article information


Submitted
02 Dec 2019
Accepted
11 Mar 2020
First published
11 Mar 2020

New J. Chem., 2020, Advance Article
Article type
Paper

Structure-based design of 2,4-diaminopyrimidine derivatives bearing a pyrrolyl group as ALK and ROS1 inhibitors

J. Wang, S. Wei, T. Li, L. Xing, M. Cao, N. Jiang, M. Guo, D. Zuo and X. Zhai, New J. Chem., 2020, Advance Article , DOI: 10.1039/C9NJ05980F

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