当前位置:
X-MOL 学术
›
J. Med. Chem.
›
论文详情
Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)
Discovery of IACS-9439, a Potent, Exquisitely Selective, and Orally Bioavailable Inhibitor of CSF1R.
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2020-07-29 , DOI: 10.1021/acs.jmedchem.0c00936 Barbara Czako 1 , Joseph R Marszalek 2 , Jason P Burke 1 , Pijus Mandal 1 , Paul G Leonard 1 , Jason B Cross 1 , Faika Mseeh 1 , Yongying Jiang 1 , Edward Q Chang 2 , Erika Suzuki 2 , Jeffrey J Kovacs 2 , Ningping Feng 2 , Sonal Gera 2 , Angela L Harris 2 , Zhen Liu 1 , Robert A Mullinax 2 , Jihai Pang 1 , Connor A Parker 1 , Nakia D Spencer 2 , Simon S Yu 1 , Qi Wu 1 , Martin R Tremblay 3 , Keith Mikule 3 , Keith Wilcoxen 3 , Timothy P Heffernan 2 , Giulio F Draetta 4 , Philip Jones 1
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2020-07-29 , DOI: 10.1021/acs.jmedchem.0c00936 Barbara Czako 1 , Joseph R Marszalek 2 , Jason P Burke 1 , Pijus Mandal 1 , Paul G Leonard 1 , Jason B Cross 1 , Faika Mseeh 1 , Yongying Jiang 1 , Edward Q Chang 2 , Erika Suzuki 2 , Jeffrey J Kovacs 2 , Ningping Feng 2 , Sonal Gera 2 , Angela L Harris 2 , Zhen Liu 1 , Robert A Mullinax 2 , Jihai Pang 1 , Connor A Parker 1 , Nakia D Spencer 2 , Simon S Yu 1 , Qi Wu 1 , Martin R Tremblay 3 , Keith Mikule 3 , Keith Wilcoxen 3 , Timothy P Heffernan 2 , Giulio F Draetta 4 , Philip Jones 1
Affiliation
![]() |
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:
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。
更新日期:2020-09-10
中文翻译:
![](https://scdn.x-mol.com/jcss/images/paperTranslation.png)
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。