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Zhan Z, Ai J, Liu Q, et al. Discovery of Anilinopyrimidines as Dual Inhibitors of c-Met and VEGFR-2: Synthesis, SAR, and Cellular Activity. ACS Med Chem Lett. 2014;5(6):673-8doi: 10.1021/ml500066m.
Zhan, Z., Ai, J., Liu, Q., Ji, Y., Chen, T., Xu, Y., Geng, M., & Duan, W. (2014). Discovery of Anilinopyrimidines as Dual Inhibitors of c-Met and VEGFR-2: Synthesis, SAR, and Cellular Activity. ACS medicinal chemistry letters, 5(6), 673-8. https://doi.org/10.1021/ml500066m
Zhan, Zhengsheng, et al. "Discovery of Anilinopyrimidines as Dual Inhibitors of c-Met and VEGFR-2: Synthesis, SAR, and Cellular Activity." ACS medicinal chemistry letters vol. 5,6 (2014): 673-8. doi: https://doi.org/10.1021/ml500066m
Zhan Z, Ai J, Liu Q, Ji Y, Chen T, Xu Y, Geng M, Duan W. Discovery of Anilinopyrimidines as Dual Inhibitors of c-Met and VEGFR-2: Synthesis, SAR, and Cellular Activity. ACS Med Chem Lett. 2014 Mar 26;5(6):673-8. doi: 10.1021/ml500066m. eCollection 2014 Jun 12. PMID: 24944742; PMCID: PMC4060942.
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ACS Med Chem Lett. 2014 Mar 26;5(6):673-8. doi: 10.1021/ml500066m. eCollection 2014 Jun 12.

Discovery of Anilinopyrimidines as Dual Inhibitors of c-Met and VEGFR-2: Synthesis, SAR, and Cellular Activity.

ACS medicinal chemistry letters

Zhengsheng Zhan, Jing Ai, Qiufeng Liu, Yinchun Ji, Tiantian Chen, Yechun Xu, Meiyu Geng, Wenhu Duan

Affiliations

  1. Department of Medicinal Chemistry, Division of Antitumor Pharmacology, and Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences , 555 Zu Chong Zhi Road, Shanghai 201203, China.

PMID: 24944742 PMCID: PMC4060942 DOI: 10.1021/ml500066m

Abstract

Both c-Met and VEGFR-2 are important targets for cancer therapies. Here we report a series of potent dual c-Met and VEGFR-2 inhibitors bearing an anilinopyrimidine scaffold. Two novel synthetic protocols were employed for rapid analoguing of the designed molecules for structure-activity relationship (SAR) exploration. Some analogues displayed nanomolar potency against c-Met and VEGFR-2 at enzymatic level. Privileged compounds 3a, 3b, 3g, 3h, and 18a exhibited potent antiproliferative effect against c-Met addictive cell lines with IC50 values ranged from 0.33 to 1.7 μM. In addition, a cocrystal structure of c-Met in complex with 3h has been determined, which reveals the binding mode of c-Met to its inhibitor and helps to interpret the SAR of the analogues.

Keywords: Anilinopyrimidine; SAR; VEGFR-2; c-Met; dual inhibitor

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