Design of Selective PAK1 Inhibitor G-5555: Improving Properties by Employing an Unorthodox Low-pKa Polar Moiety
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- 作者：Chudi O. Ndubaku ; James J. Crawford ; Joy Drobnick ; Ignacio Aliagas ; David Campbell ; Ping Dong ; Laura M. Dornan ; Sergio Duron ; Jennifer Epler ; Lewis Gazzard ; Christopher E. Heise ; Klaus P. Hoeflich ; Diana Jakubiak ; Hank La ; Wendy Lee ; Baiwei Lin ; Joseph P. Lyssikatos ; Jasna Maksimoska ; Ronen Marmorstein ; Lesley J. Murray ; Thomas O鈥橞rien ; Angela Oh ; Sreemathy Ramaswamy ; Weiru Wang ; Xianrui Zhao ; Yu Zhong ; Elizabeth Blackwood ; Joachim Rudolph
- 刊名：ACS Medicinal Chemistry Letters
- 出版年：2015
- 出版时间：December 10, 2015
- 年：2015
- 卷：6
- 期：12
- 页码：1241-1246
- 全文大小：422K
- ISSN：1948-5875
文摘
Signaling pathways intersecting with the p21-activated kinases (PAKs) play important roles in tumorigenesis and cancer progression. By recognizing that the limitations of FRAX1036 (1) were chiefly associated with the highly basic amine it contained, we devised a mitigation strategy to address several issues such as hERG activity. The 5-amino-1,3-dioxanyl moiety was identified as an effective means of reducing pKa and logP simultaneously. When positioned properly within the scaffold, this group conferred several benefits including potency, pharmacokinetics, and selectivity. Mouse xenograft PK/PD studies were carried out using an advanced compound, G-5555 (12), derived from this approach. These studies concluded that dose-dependent pathway modulation was achievable and paves the way for further in vivo investigations of PAK1 function in cancer and other diseases.