Tumor-associated macrophages (TAMs) are major components of leukocytic infiltrate of tumors. It has been reported that high TAMs density is associated with poor clinical prognosis. Within the tumor microenvironment, TAMs rely on signaling through CSF-1/CSF-1 Receptor kinase axis to promote tumor growth, angiogenesis, and metastasis. Therefore, decrease of TAMs density in tumors through inhibition of CSF-1R kinase is considered a potential target for drug development. In this study, we report that a novel small molecule DCR-0064 inhibits CSF-1R kinase with IC50 value below 10 nM and possesses specificity for CSF-1R over other tyrosine or serine/threonine kinases. DCR-0064 selectively inhibits CSF-1 induced growth of M-NFS-60 myeloid cells and effectively suppresses intracellular CSF-1R activation with IC50 value less than 100 nM. The potency and selectivity of DCR-0064 is superior to the current lead CSF-1R inhibitor, PLX3397, which is in phase III clinical development for treating tenosynovial giant cell tumor. The selectively growth inhibitory activity of DCR-0064 is consistent with inhibition of CSF-1R signaling. Oral administration of DCR-0064 reduces TAMs density in vivo in mice. DCR-0064 is being developed as a candidate for preclinical development.

Citation Format: Chu-Bin Liao, Shao-Zheng Peng, Chen-Hsuan Ho, Chao-Pin Lee, Jia-Ming Chang, Hung-Jyun Huang, Sian-Yi Ciou, Yu-Chih Pan, Yu-Kai Chen. A potent and selective CSF-1R inhibitor, DCR-0064, inhibits colony stimulating factor 1 signaling in vitro and in vivo [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3206. doi:10.1158/1538-7445.AM2017-3206