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.

中文翻译：

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IACS-9439的发现，它是CSF1R的强效，选择性和口服生物利用性抑制剂。

肿瘤相关的巨噬细胞（TAM）在多种人类恶性肿瘤的肿瘤基质中均具有显着存在，并被认为对肿瘤的生长有益。已经提出了靶向CSF1R作为减少TAM，尤其是降低肿瘤，免疫抑制性M2 TAM的潜在疗法。另外，CSF1R在肿瘤细胞上的高表达与某些癌症的不良存活有关，提示肿瘤依赖性，因此是潜在的治疗靶标。CSF1-CSF1R信号通路调节TAM的产生，分化和功能。然而，事实证明，发现缺乏III型激酶活性的选择性CSF1R抑制剂具有挑战性。我们发现了一种有效的，高选择性的，口服生物利用的CSF1R抑制剂IACS-9439（1）。治疗用1导致巨噬细胞剂量依赖性降低，促进巨噬细胞向M1表型极化，并导致MC38和PANC02同基因肿瘤模型中的肿瘤生长抑制。