基于片段法开发新型ACK1/TNK2抑制剂

Development of novel ACK1/TNK2 inhibitors using a fragment-based approach.

作者信息

Lawrence Harshani R, Mahajan Kiran, Luo Yunting, Zhang Daniel, Tindall Nathan, Huseyin Miles, Gevariya Harsukh, Kazi Sakib, Ozcan Sevil, Mahajan Nupam P, Lawrence Nicholas J

机构信息

§Department of Oncologic Sciences, University of South Florida, Tampa, Florida 33620, United States.

出版信息

J Med Chem. 2015 Mar 26;58(6):2746-63. doi: 10.1021/jm501929n. Epub 2015 Mar 17.

The tyrosine kinase ACK1, a critical signal transducer regulating survival of hormone-refractory cancers, is an important therapeutic target, for which there are no selective inhibitors in clinical trials to date. This work reports the discovery of novel and potent inhibitors for ACK1 tyrosine kinase (also known as TNK2) using an innovative fragment-based approach. Focused libraries were designed and synthesized by selecting fragments from reported ACK inhibitors to create hybrid structures in a mix and match process. The hybrid library was screened by enzyme-linked immunosorbent assay-based kinase inhibition and (33)P HotSpot assays. Systematic structure-activity relationship studies led to the identification of compound (R)-9b, which shows potent in vitro (IC50 = 56 nM, n = 3, (33)P HotSpot assay) and in vivo (IC50 < 2 μM, human cancer cell lines) ACK1 inhibition. Both (R)-9b and (S)-9b were stable in human plasma and displayed a long half-life (t(1/2) > 6 h).

酪氨酸激酶ACK1是调节激素难治性癌症存活的关键信号转导分子，是一个重要的治疗靶点，目前尚无选择性抑制剂进入临床试验阶段。本研究报道了采用创新的基于片段的方法发现了新型强效ACK1酪氨酸激酶（也称为TNK2）抑制剂。通过从已报道的ACK抑制剂中选择片段，在混合匹配过程中创建杂合结构，设计并合成了聚焦文库。通过基于酶联免疫吸附测定的激酶抑制和³³P热点分析筛选杂合文库。系统的构效关系研究导致鉴定出化合物（R）-9b，其在体外（IC50 = 56 nM，n = 3，³³P热点分析）和体内（IC50 < 2 μM，人癌细胞系）均显示出强效的ACK1抑制作用。（R）-9b和（S）-9b在人血浆中均稳定，且半衰期长（t1/2 > 6 h）。