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 published the artcile< Discovery of BPR1R024, an Orally Active and Selective CSF1R Inhibitor that Exhibits Antitumor and Immunomodulatory Activity in a Murine Colon Tumor Model>, Safety of 2-Amino-4-bromobenzoic acid, the main research area is quinazoline derivative preparation oral CSF1R inhibitor antitumor immunomodulator.
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 clin. multitargeting kinase inhibitor. Mol. docking revealed an addnl. 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.
Journal of Medicinal Chemistry published new progress about Anti-inflammatory agents. 20776-50-5 belongs to class bromides-buliding-blocks, and the molecular formula is C7H6BrNO2, Safety of 2-Amino-4-bromobenzoic acid.
Referemce:
Bromide – Wikipedia,
bromide – Wiktionary