Advances in the 1-phenanthryl-tetrahydroisoquinoline series of PAK4 inhibitors: potent agents restrain tumor cell growth and invasion

Abstract

A new series of novel 1-phenanthryl-tetrahydroisoquinoline derivatives were designed, synthesized and biologically evaluated for their PAK4 inhibitory activities and anti-proliferative effects against three cancer cell lines A549, MCF-7 and HT-1080. Among them, compound 12a exhibited the most potent inhibitory activity against PAK4 with an IC50 value of 0.42 μM. Moreover, this compound inhibited the invasion of A549 tumor cells by regulating the PAK4-LIMK1-cofilin signaling pathway in vitro, and exhibited anti-tumor activity in vivo in the A549 tumor xenograft model. To further evaluate the binding mode of 12a with PAK4, the biotinylated 12a derivative has been synthesized and it was used for immunoprecipitation assay. Intriguingly, our observations suggest that 12a interacts with both the N- and C-termini of PAK4.

Total Synthesis of Phenanthropiperidine Alkaloids by Sequential Alkylation of N,N‐Dibenzylaminoacetonitrile

“…HRMS (ESI + , CH 3 OH/CH 2 Cl 2 , 90 : 10, C 19 H 20 O 5 Na [M+Na] + ) calcd 351.12029, found 351.1205. The analytical data were in agreement with those reported in the literature [28a] …”

“…Methyl ( E )‐2,3‐bis(3,4‐dimethoxyphenyl)acrylate, 7 a . From an adapted procedure reported in the literature [28a] . A one‐necked one bottom 500 mL flask, equipped with a reflux condenser was charged with 16.0 g (46.46 mmol, 1.0 equiv.)…”

Structure-Based Design of 6-Chloro-4-aminoquinazoline-2-carboxamide Derivatives as Potent and Selective p21-Activated Kinase 4 (PAK4) Inhibitors

“…Migration and invasion assays were performed using modified Boyden chambers with a polycarbonate nucleopore membrane, as previously described …”

“…The viability of cells was determined using the MTT assay method as previously described. 24 Wound Healing Assay. For the wound healing assay, A549 cells were cultured to confluence in six-well plates and wounded using a sterilized pipet tip to make a straight scratch.…”

“…Our research group has focused on the discovery and optimization of PAK4 inhibitors as new therapeutic agents for over a decade, − and we identified quinazoline-based compound 9 (LCH-7749944) as a moderate PAK4 inhibitor via structure-based virtual screening in 2012 . Compound 9 was notable in that it possessed higher potency against PAK4 than PAK1 and significantly inhibited the migration and invasion of human gastric cancer cells in conjunction with the concomitant blockage of the PAK4/LIMK1/cofilin and PAK4/MEK-1/ERK1/2/MMP2 pathways.…”