Diluvio Giulia, Kelley Tanya T, Lahiry Mohini, Alvarez-Trotta Annamil, Kolb Ellen M, Shersher Elena, Astudillo Luisana, Kovall Rhett A, Schürer Stephan C, Capobianco Anthony J
Molecular Oncology Program, The DeWitt Daughtry Family Department of Surgery, Miller School of Medicine, University of Miami, Miami, FL 33136, USA.
Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, FL 33136, USA.
Mol Ther Oncolytics. 2023 Feb 22;28:307-320. doi: 10.1016/j.omto.2023.02.008. eCollection 2023 Mar 16.
Notch activation complex kinase (NACK) is a component of the Notch transcriptional machinery critical for the Notch-mediated tumorigenesis. However, the mechanism through which NACK regulates Notch-mediated transcription is not well understood. Here, we demonstrate that NACK binds and hydrolyzes ATP and that only ATP-bound NACK can bind to the Notch ternary complex (NTC). Considering this, we sought to identify inhibitors of this ATP-dependent function and, using computational pipelines, discovered the first small-molecule inhibitor of NACK, Z271-0326, that directly blocks the activity of Notch-mediated transcription and shows potent antineoplastic activity in PDX mouse models. In conclusion, we have discovered the first inhibitor that holds promise for the efficacious treatment of Notch-driven cancers by blocking the Notch activity downstream of the NTC.
Notch激活复合激酶（NACK）是Notch转录机制的一个组成部分，对Notch介导的肿瘤发生至关重要。然而，NACK调节Notch介导的转录的机制尚不清楚。在此，我们证明NACK能结合并水解ATP，并且只有结合ATP的NACK才能与Notch三元复合物（NTC）结合。基于此，我们试图鉴定这种ATP依赖性功能的抑制剂，并通过计算流程发现了第一种NACK小分子抑制剂Z271-0326，它直接阻断Notch介导的转录活性，并在PDX小鼠模型中显示出强大的抗肿瘤活性。总之，我们发现了第一种有望通过阻断NTC下游的Notch活性有效治疗Notch驱动癌症的抑制剂。
