Journal of Bioequivalence & Bioavailability

Discovery of novel scaffolds for p21-activated kinase 4 inhibitors targeting C- terminal

6^th World Congress on Bioavailability & Bioequivalence: BA/BE Studies Summit

August 17-19, 2015 Chicago, USA

Dongmei Zhao, Chenzhou Hao, Shuai Song, Jing Guo, Qiaoling Zhang and Maosheng Cheng

Scientific Tracks Abstracts: J Bioequiv Availab

Abstract:

P21-activated kinases (PAKs) are a family of serine/threonine kinases that act downstream of Rho GTPases, Rac and Cdc42. PAKs
play a critical role in cytoskeletal organization, cell cycle progression, migration and invasion, and cell survival. PAK4, as the
principal member of group II PAKs, mainly regulate its functions via a kinase domain in the C terminal, where all of the existing PAK4
inhibitors target. In this study, a series of novel 1-phenanthryl- tetrahydroisoquinoline analogues have been designed and synthesized
as a novel class of small-molecule PAK4 inhibitors to fit into the cavity of PAK4. All of the target compounds were evaluated for their
in vitro PAK4 inhibitory activities and antiproliferative activities. Its affinity to C-termini of PAK4 was confirmed by BSA (Biotin-
Streptavidin assay). Furthermore, this compound inhibits the invasion and migration of A549 tumor cells by regulating PAK4-Lim
domain kinase 1 (LIMK1)-Cofilin signaling pathways in vitro, and exhibits anti-tumor activity in vivo in the A549 tumor xenografts
model.