jm0c00936_si_004.csv (4.3 kB)

Discovery of IACS-9439, a Potent, Exquisitely Selective, and Orally Bioavailable Inhibitor of CSF1R

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posted on 2020-08-18, 18:09 authored by Barbara Czako, Joseph. R. Marszalek, Jason P. Burke, Pijus Mandal, Paul G. Leonard, Jason B. Cross, Faika Mseeh, Yongying Jiang, Edward Q. Chang, Erika Suzuki, Jeffrey J. Kovacs, Ningping Feng, Sonal Gera, Angela L. Harris, Zhen Liu, Robert A. Mullinax, Jihai Pang, Connor A. Parker, Nakia D. Spencer, Simon S. Yu, Qi Wu, Martin R. Tremblay, Keith Mikule, Keith Wilcoxen, Timothy P. Heffernan, Giulio F. Draetta, Philip Jones

Tumor-associated macrophages (TAMs) have a significant presence in the tumor stroma across multiple human malignancies and are believed to be beneficial to tumor growth. Targeting CSF1R has been proposed as a potential therapy to reduce TAMs, especially the protumor, immune-suppressive M2 TAMs. Additionally, the high expression of CSF1R on tumor cells has been associated with poor survival in certain cancers, suggesting tumor dependency and therefore a potential therapeutic target. The CSF1–CSF1R signaling pathway modulates the production, differentiation, and function of TAMs; however, the discovery of selective CSF1R inhibitors devoid of type III kinase activity has proven to be challenging. We discovered a potent, highly selective, and orally bioavailable CSF1R inhibitor, IACS-9439 (1). Treatment with 1 led to a dose-dependent reduction in macrophages, promoted macrophage polarization toward the M1 phenotype, and led to tumor growth inhibition in MC38 and PANC02 syngeneic tumor models.