國家衛生研究院 NHRI:Item 3990099045/13738

NHRI > Institute of Biotechnology and Pharmaceutical Research > Hsing-Pang Hsieh > Periodical Articles > Item 3990099045/13738

Please use this identifier to cite or link to this item: http://ir.nhri.org.tw/handle/3990099045/13738

Title:	Discovery of BPR1R024, an orally active and selective CSF1R inhibitor that exhibits antitumor and immunomodulatory activity in a murine colon tumor model
Authors:	Lee, KH;Yen, WC;Lin, WH;Wang, PC;Lai, YL;Su, YC;Chang, CY;Wu, CS;Huang, YC;Yang, CM;Chou, LH;Yeh, TK;Chen, CT;Shih, C;Hsieh, HP
Contributors:	Institute of Biotechnology and Pharmaceutical Research
Abstract:	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.
Date:	2021-10-14
Relation:	Journal of Medicinal Chemistry. 2021 Oct 14;64(19):14477-14497.
Link to:	http://dx.doi.org/10.1021/acs.jmedchem.1c01006
JIF/Ranking 2023:	http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcAuth=NHRI&SrcApp=NHRI_IR&KeyISSN=0022-2623&DestApp=IC2JCR
Cited Times(WOS):	https://www.webofscience.com/wos/woscc/full-record/WOS:000709633100028
Cited Times(Scopus):	https://www.scopus.com/inward/record.url?partnerID=HzOxMe3b&scp=85117095471
Appears in Collections:	[Hsing-Pang Hsieh] Periodical Articles [Wan-Ching Yen] Periodical Articles [Teng-Kuang Yeh] Periodical Articles [Chiung-Tong Chen] Periodical Articles [Chuan Shih(2014-2017)] Periodical Articles

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