Liang Rui, Tomita Daisuke, Sasaki Yusuke, Ginn John, Michino Mayako, Huggins David J, Baxt Leigh, Kargman Stacia, Shahid Maaz, Aso Kazuyoshi, Duggan Mark, Stamford Andrew W, DeStanchina Elisa, Liverton Nigel, Meinke Peter T, Foley Michael A, Phillips Richard E
Tri-Institutional Therapeutics Discovery Institute, 413 East 69th Street, New York, New York 10021, United States.
Department of Physiology and Biophysics, Weill Cornell Medical College, New York, New York 10021, United States.
ACS Med Chem Lett. 2022 Feb 10;13(3):377-387. doi: 10.1021/acsmedchemlett.1c00448. eCollection 2022 Mar 10.
Aberrant gene-silencing through dysregulation of polycomb protein activity has emerged as an important oncogenic mechanism in cancer, implicating polycomb proteins as important therapeutic targets. Recently, an inhibitor targeting EZH2, the methyltransferase component of PRC2, received U.S. Food and Drug Administration approval following promising clinical responses in cancer patients. However, the current array of EZH2 inhibitors have poor brain penetrance, limiting their use in patients with central nervous system malignancies, a number of which have been shown to be sensitive to EZH2 inhibition. To address this need, we have identified a chemical strategy, based on computational modeling of pyridone-containing EZH2 inhibitor scaffolds, to minimize P-glycoprotein activity, and here we report the first brain-penetrant EZH2 inhibitor, TDI-6118 (compound ). Additionally, in the course of our attempts to optimize this compound, we discovered TDI-11904 (compound ), a novel, highly potent, and peripherally active EZH2 inhibitor based on a 7 member ring structure.
通过多梳蛋白活性失调导致的异常基因沉默已成为癌症中一种重要的致癌机制，这意味着多梳蛋白是重要的治疗靶点。最近，一种靶向EZH2（PRC2的甲基转移酶成分）的抑制剂在癌症患者中取得了有前景的临床反应后，获得了美国食品药品监督管理局的批准。然而，目前一系列的EZH2抑制剂脑渗透性较差，限制了它们在中枢神经系统恶性肿瘤患者中的应用，其中一些已被证明对EZH2抑制敏感。为满足这一需求，我们基于含吡啶酮的EZH2抑制剂支架的计算模型，确定了一种化学策略以最小化P-糖蛋白活性，在此我们报告首个具有脑渗透性的EZH2抑制剂TDI-6118（化合物）。此外，在我们优化该化合物的过程中，我们发现了TDI-11904（化合物），一种基于7元环结构的新型、高效且具有外周活性的EZH2抑制剂。
