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Structural modification of an EGFR inhibitor that showed weak off-target activity against RET leading to the discovery of a potent RET inhibitor

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Abstract

Here, we describe the structural optimization of a known EGFR inhibitor (compound 1) that showed weak off-target activity against RET. Twenty-six analogs of 1 were synthesized. SAR analysis led to the discovery of several compounds that showed considerable potency against the RET-dependent thyroid cancer cell line TT. Kinase inhibitory potency was then measured for the most active compound (2u) in the cellular assay. The results showed that 2u is a potent RET inhibitor with an \(\hbox {IC}_{50}\) value of 7 nM.

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Fig. 1
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Acknowledgments

This work was supported by the 863 Hi- Tech Program (Nos. 2012AA020301, 2012AA020308), the National Natural Science Foundation of China (81172987), and SRFDP (20100181110025)

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Authors and Affiliations

  1. State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University, Chengdu, 610041, Sichuan, China

    Qi-Zheng Sun, Yong Xu, Jing-Jing Liu, Chun-Hui Zhang, Wen-Jing Wang & Sheng-Yong Yang

  2. West China School of pharmacy, Sichuan University, No. 17, Renmin Road South, Chengdu, Sichuan, China

    Ze-Rong Wang & Lin-Li Li

  3. School of Life Science and Engineering, Southwest University of Science and Technology, Mianyang, 621010, China

    Ren-Lin Zheng

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  1. Qi-Zheng Sun
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  2. Yong Xu
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Corresponding authors

Correspondence to Lin-Li Li or Sheng-Yong Yang.

Additional information

Qi-Zheng Sun, Yong Xu, and Jing-Jing Liu have contributed equally to this study.

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Sun, QZ., Xu, Y., Liu, JJ. et al. Structural modification of an EGFR inhibitor that showed weak off-target activity against RET leading to the discovery of a potent RET inhibitor. Mol Divers 18, 403–409 (2014). https://doi.org/10.1007/s11030-014-9508-8

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  • DOI: https://doi.org/10.1007/s11030-014-9508-8

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