Study On The Design, Synthesis And Activity Of PAK1 Inhibitors

P21-activated kinase (PAKs) is a class of evolutionarily conserved serine/threonine protein kinase, has been considered to be one of the key regulatory factors in signaling network of tumor cells. In this thesis, PAK1 is the main subject, we briefly described the structure and function of the PAK1 subtypes, and reviewed the development of PAK1 inhibitor.Based on the PAK1 allosteric inhibitor IPA-3, we used Molecular Field Analysis Method, designed a series of disulfide to inhibit PAK1 activation, then block its signal transduction to enhance selectivity. In total, three kinds of disulfide were synthesized, including 7 aniline disulfide compounds (Ph01, Ph03-Ph08),6 indole disulfide compouds (In01-In06), and 1 naphthalene disulfide compound (Na01). All the compounds were confirmed by’H-NMR and LC-MS. Nine of the compounds are not reported by literature. Later, we used the Computer-aided drug design technology to construct the conformation of non-active allosteric domain of PAK1, then used Molecular Field Similarity Method and dock to explore the mode of action between all the disulfide compouds and IPA-3.We tested the inhibitory activity of Disulfide compounds, aimed at the Thr423 phosphorylation site of PAK1 antibody, by detecting PAK1 activity in gastric cancer cells. The results showed that under different concentration (0,10,30μM), compounds Ph-04 and Ph-07 showed strong inhibitory activity on PAK1, the inhibitory activity was equal to the positive control IPA-3, and with the increase of the drug concentration, inhibitory activity increased.