Miles Dillon H, Yan Xuelei, Thomas-Tran Rhiannon, Fournier Jeremy, Sharif Ehesan U, Drew Samuel L, Mata Guillaume, Lawson Kenneth V, Ginn Elaine, Wong Kent, Soni Divyank, Dhanota Puja, Shaqfeh Stefan G, Meleza Cesar, Chen Ada, Pham Amber T, Park Timothy, Swinarski Debbie, Banuelos Jesus, Schindler Ulrike, Walters Matthew J, Walker Nigel P, Zhao Xiaoning, Young Stephen W, Chen Jie, Jin Lixia, Leleti Manmohan Reddy, Powers Jay P, Jeffrey Jenna L
Arcus Biosciences, Inc., Hayward, California 94545, United States.
ACS Med Chem Lett. 2020 Sep 24;11(11):2244-2252. doi: 10.1021/acsmedchemlett.0c00387. eCollection 2020 Nov 12.
The successful application of immunotherapy in the treatment of cancer relies on effective engagement of immune cells in the tumor microenvironment. Phosphoinositide 3-kinase γ (PI3Kγ) is highly expressed in tumor-associated macrophages, and its expression levels are associated with tumor immunosuppression and growth. Selective inhibition of PI3Kγ offers a promising strategy in immuno-oncology, which has led to the development of numerous potent PI3Kγ inhibitors with variable selectivity profiles. To facilitate further investigation of the therapeutic potential of PI3Kγ inhibition, we required a potent and PI3Kγ-selective tool compound with sufficient metabolic stability for use in future studies. Herein, we describe some of our efforts to realize this goal through the systematic study of SARs within a series of 7-azaindole-based PI3Kγ inhibitors. The large volume of data generated from this study helped guide our subsequent lead optimization efforts and will inform further development of PI3Kγ-selective inhibitors for use in immunomodulation.
免疫疗法在癌症治疗中的成功应用依赖于肿瘤微环境中免疫细胞的有效参与。磷酸肌醇3激酶γ（PI3Kγ）在肿瘤相关巨噬细胞中高表达，其表达水平与肿瘤免疫抑制和生长相关。选择性抑制PI3Kγ在免疫肿瘤学中提供了一种有前景的策略，这已导致开发出许多具有不同选择性特征的强效PI3Kγ抑制剂。为了促进对PI3Kγ抑制治疗潜力的进一步研究，我们需要一种强效且对PI3Kγ具有选择性的工具化合物，其具有足够的代谢稳定性以用于未来的研究。在此，我们描述了我们通过对一系列基于7-氮杂吲哚的PI3Kγ抑制剂的构效关系进行系统研究来实现这一目标的一些努力。这项研究产生的大量数据有助于指导我们后续的先导化合物优化工作，并将为用于免疫调节的PI3Kγ选择性抑制剂的进一步开发提供信息。
