Discovery of BPR1R024, an Orally Active and Selective CSF1R Inhibitor that Exhibits Antitumor and Immunomodulatory Activity in a Murine Colon Tumor Model

Colony-stimulating factor-1 receptor (CSF1R) is implicated in tumor-associated macrophage (TAM) repolarization and has emerged as a promising target for cancer immunotherapy. Herein, we describe the discovery of orally active and selective CSF1R inhibitors by property-driven optimization of BPR1K871...

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Veröffentlicht in:Journal of medicinal chemistry 2021-10, Vol.64 (19), p.14477-14497
Hauptverfasser: Lee, Kun-Hung, Yen, Wan-Ching, Lin, Wen-Hsing, Wang, Pei-Chen, Lai, You-Liang, Su, Yu-Chieh, Chang, Chun-Yu, Wu, Cai-Syuan, Huang, Yu-Chen, Yang, Chen-Ming, Chou, Ling-Hui, Yeh, Teng-Kuang, Chen, Chiung-Tong, Shih, Chuan, Hsieh, Hsing-Pang
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Sprache:eng
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Zusammenfassung:Colony-stimulating factor-1 receptor (CSF1R) is implicated in tumor-associated macrophage (TAM) repolarization and has emerged as a promising target for cancer immunotherapy. Herein, we describe the discovery of orally active and selective CSF1R inhibitors by property-driven optimization of BPR1K871 (9), our clinical multitargeting kinase inhibitor. Molecular docking revealed an additional nonclassical hydrogen-bonding (NCHB) interaction between the unique 7-aminoquinazoline scaffold and the CSF1R hinge region, contributing to CSF1R potency enhancement. Structural studies of CSF1R and Aurora kinase B (AURB) demonstrated the differences in their back pockets, which inspired the use of a chain extension strategy to diminish the AURA/B activities. A lead compound BPR1R024 (12) exhibited potent CSF1R activity (IC50 = 0.53 nM) and specifically inhibited protumor M2-like macrophage survival with a minimal effect on antitumor M1-like macrophage growth. In vivo, oral administration of 12 mesylate delayed the MC38 murine colon tumor growth and reversed the immunosuppressive tumor microenvironment with the increased M1/M2 ratio.
ISSN:0022-2623
1520-4804
DOI:10.1021/acs.jmedchem.1c01006