文献类型：期刊文献

英文题名：Discovery of novel CSF1R inhibitor for triple-negative breast cancer (TNBC) treatment through TAMs reprogramming

作者：Sha, Wenjie[1];Yan, Zitong[1];Wu, Yunpeng[1];Wang, Caolin[1];Cen, Yiting[1];Du, Husheng[1];Yu, Panpan[1];Chang, Longfeng[2];Pang, Xuelian[1];Chen, Ziqi[1];Li, Shiliang[1,2];Zhao, Zhenjiang[1];Jiang, Hualiang[1,3];Li, Honglin[1,2,4];Chen, Zhuo[1,4]

机构：[1]East China Univ Sci & Technol, Sch Pharm, Shanghai 200237, Peoples R China;[2]East China Normal Univ, Innovat Ctr AI & Drug Discovery ICAIDD, Sch Pharm, Shanghai 200062, Peoples R China;[3]Chinese Acad Sci, State Key Lab Drug Res, Shanghai Inst Mat Med, 555 Zuchongzhi Rd, Shanghai 201203, Peoples R China;[4]Meilong Rd 130, Shanghai 200237, Peoples R China

年份：2026

卷号：250

外文期刊名：BIOCHEMICAL PHARMACOLOGY

收录：;WOS:【SCI-EXPANDED(收录号:WOS:001754732800001)】；

基金：This work was supported in part by the National Natural Science Foundation of China (82425104 and 82150208 to H.L.) ; the National Key R & D Program of China (2022YFC3400501, 2022YFC3400504) .

语种：英文

外文关键词：CSF1R; Kinase inhibitor; TAMs; Antitumor; Tumor microenvironment; TNBC

摘要：Triple-negative breast cancer (TNBC), characterized by a lack of therapeutic targets and an immunosuppressive ("cold") tumor microenvironment (TME), is the most aggressive breast cancer subtype with poor prognosis and high recurrence. Tumor-associated macrophages (TAMs), which extensively infiltrate these "cold" TME, have emerged as a promising therapeutic target. Colony-stimulating factor 1 receptor (CSF1R) is currently the most important clinically validated target that directly regulates the survival and differentiation of TAMs. However, CSF1R modulation remains underexplored for treating TNBC, while existing CSF1R inhibitors induced high hepatotoxicity due to defects in kinase selectivity. In this article, we identified a novel CSF1R inhibitor, LL-08, which possessed greater CSF1R inhibitory activity (IC50 = 1.023 v.s. 5.716 nM) than pexidartinib. Moreover, LL-08 was able to inhibit the differentiation of TAMs as well as the production of the inflammation-suppressive factor IL-10. It also restored the ability of CD8+ T cells to secrete IFN-gamma in a co-culture system between TAMs and splenic T cells, while possessing higher selectivity between TAMs and normal liver cells. In a TNBC xenotransplantation model, LL-08 exerted greater anti-tumor activity by reducing TAMs infiltration in tumors and increasing the proportion of CD8+ T cells. More importantly, LL-08 caused less damage to the liver than pexidartinib, which was in accordance with its enzymatic and cellular selectivity. In summary, LL-08 is a highly active and selective CSF1R inhibitor, showing potential for TNBC treatment by TAMs reprogramming.