2-Amino-2,3-dihydro-1 H-indene-5-carboxamide-Based Discoidin Domain Receptor 1 (DDR1) Inhibitors: Design, Synthesis, and in Vivo Antipancreatic Cancer Efficacy

Dongsheng Zhu; Huocong Huang; Daniel M. Pinkas; Jinfeng Luo; Debolina Ganguly; Alice E. Fox; Emily Arner; Qiuping Xiang; Zheng Chao Tu; Alex N. Bullock; Rolf A. Brekken; Ke Ding; Xiaoyun Lu

doi:10.1021/acs.jmedchem.9b00365

2-Amino-2,3-dihydro-1 H-indene-5-carboxamide-Based Discoidin Domain Receptor 1 (DDR1) Inhibitors: Design, Synthesis, and in Vivo Antipancreatic Cancer Efficacy

Dongsheng Zhu, Huocong Huang, Daniel M. Pinkas, Jinfeng Luo, Debolina Ganguly, Alice E. Fox, Emily Arner, Qiuping Xiang, Zheng Chao Tu, Alex N. Bullock, Rolf A. Brekken, Ke Ding, Xiaoyun Lu

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40 Scopus citations

Abstract

A series of 2-amino-2,3-dihydro-1H-indene-5-carboxamides were designed and synthesized as new selective discoidin domain receptor 1 (DDR1) inhibitors. One of the representative compounds, 7f, bound with DDR1 with a K_d value of 5.9 nM and suppressed the kinase activity with an half-maximal (50%) inhibitory concentration value of 14.9 nM. 7f potently inhibited collagen-induced DDR1 signaling and epithelial-mesenchymal transition, dose-dependently suppressed colony formation of pancreatic cancer cells, and exhibited promising in vivo therapeutic efficacy in orthotopic mouse models of pancreatic cancer.

Original language	English (US)
Pages (from-to)	7431-7444
Number of pages	14
Journal	Journal of Medicinal Chemistry
Volume	62
Issue number	16
DOIs	https://doi.org/10.1021/acs.jmedchem.9b00365
State	Published - Aug 22 2019

ASJC Scopus subject areas

Molecular Medicine
Drug Discovery

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Zhu, D., Huang, H., Pinkas, D. M., Luo, J., Ganguly, D., Fox, A. E., Arner, E., Xiang, Q., Tu, Z. C., Bullock, A. N., Brekken, R. A., Ding, K., & Lu, X. (2019). 2-Amino-2,3-dihydro-1 H-indene-5-carboxamide-Based Discoidin Domain Receptor 1 (DDR1) Inhibitors: Design, Synthesis, and in Vivo Antipancreatic Cancer Efficacy. Journal of Medicinal Chemistry, 62(16), 7431-7444. https://doi.org/10.1021/acs.jmedchem.9b00365

Zhu, D, Huang, H, Pinkas, DM, Luo, J, Ganguly, D, Fox, AE, Arner, E, Xiang, Q, Tu, ZC, Bullock, AN, Brekken, RA, Ding, K & Lu, X 2019, '2-Amino-2,3-dihydro-1 H-indene-5-carboxamide-Based Discoidin Domain Receptor 1 (DDR1) Inhibitors: Design, Synthesis, and in Vivo Antipancreatic Cancer Efficacy', Journal of Medicinal Chemistry, vol. 62, no. 16, pp. 7431-7444. https://doi.org/10.1021/acs.jmedchem.9b00365

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title = "2-Amino-2,3-dihydro-1 H-indene-5-carboxamide-Based Discoidin Domain Receptor 1 (DDR1) Inhibitors: Design, Synthesis, and in Vivo Antipancreatic Cancer Efficacy",

abstract = "A series of 2-amino-2,3-dihydro-1H-indene-5-carboxamides were designed and synthesized as new selective discoidin domain receptor 1 (DDR1) inhibitors. One of the representative compounds, 7f, bound with DDR1 with a Kd value of 5.9 nM and suppressed the kinase activity with an half-maximal (50%) inhibitory concentration value of 14.9 nM. 7f potently inhibited collagen-induced DDR1 signaling and epithelial-mesenchymal transition, dose-dependently suppressed colony formation of pancreatic cancer cells, and exhibited promising in vivo therapeutic efficacy in orthotopic mouse models of pancreatic cancer.",

author = "Dongsheng Zhu and Huocong Huang and Pinkas, {Daniel M.} and Jinfeng Luo and Debolina Ganguly and Fox, {Alice E.} and Emily Arner and Qiuping Xiang and Tu, {Zheng Chao} and Bullock, {Alex N.} and Brekken, {Rolf A.} and Ke Ding and Xiaoyun Lu",

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doi = "10.1021/acs.jmedchem.9b00365",

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AU - Zhu, Dongsheng

AU - Huang, Huocong

AU - Pinkas, Daniel M.

AU - Luo, Jinfeng

AU - Ganguly, Debolina

AU - Fox, Alice E.

AU - Arner, Emily

AU - Xiang, Qiuping

AU - Tu, Zheng Chao

AU - Bullock, Alex N.

AU - Brekken, Rolf A.

AU - Ding, Ke

AU - Lu, Xiaoyun

PY - 2019/8/22

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AB - A series of 2-amino-2,3-dihydro-1H-indene-5-carboxamides were designed and synthesized as new selective discoidin domain receptor 1 (DDR1) inhibitors. One of the representative compounds, 7f, bound with DDR1 with a Kd value of 5.9 nM and suppressed the kinase activity with an half-maximal (50%) inhibitory concentration value of 14.9 nM. 7f potently inhibited collagen-induced DDR1 signaling and epithelial-mesenchymal transition, dose-dependently suppressed colony formation of pancreatic cancer cells, and exhibited promising in vivo therapeutic efficacy in orthotopic mouse models of pancreatic cancer.

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2-Amino-2,3-dihydro-1 H-indene-5-carboxamide-Based Discoidin Domain Receptor 1 (DDR1) Inhibitors: Design, Synthesis, and in Vivo Antipancreatic Cancer Efficacy

Abstract

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