Effects of p21-activated kinase 1 inhibition on 11q13-amplified ovarian cancer cells

Abstract

p21-activated kinases (PAKs) are Cdc42/Rac–activated serine-threonine protein kinases that regulate of several key cancer-relevant signaling pathways, such as the Mek/Erk, PI3K/Akt, and Wnt/b-catenin signaling pathways. Pak1 is frequently overexpressed and/or hyperactivated in different human cancers, including human breast, ovary, prostate, and brain cancer, due to amplification of the PAK1 gene in an 11q13 amplicon. Genetic or pharmacological inactivation of Pak1 has been shown to reduce proliferation of different cancer cells in vitro and reduce tumor progression in vivo. In this work, we examined the roles of Pak1 in cellular and animal models of PAK1-amplified ovarian cancer. We found that inhibition of Pak1 leads to decreased proliferation and migration in PAK1 amplified/overexpressed ovarian cancer cells, and has no effect in cell that lack such amplification/overexpression. Further, we observed that loss of Pak1 function causes 11q13 amplified ovarian cancer cells to arrest in the G2/M phase of the cell cycle. This arrest correlates with activation of p53 and p21Cip and decreased expression of cyclin B1. These findings suggest that small molecule inhibitors of Pak1 may play a therapeutic role in the ~25% of ovarian cancers characterized by PAK1 gene amplification.

Targeting PAK1

“…An advanced member of this series, FRAX1036 (PDB ID:5DFP), exhibits high PAK1 potency (PAK1 Ki = 23 nM), refined kinome selectivity [42, 46, 47], and represents a useful tool compound for single and combinatorial experimental therapeutics [42, 46–48]. However, all of these early FRAX compounds were found to have strong adverse inhibition of hERG potassium channels.…”

“…Such “signalopathies” include several tumorigenic disorders, primarily cancers associated with PAK1 amplification [8, 47]. Positioned downstream of difficult-to-target oncogenes such as RAS, PAK1 might open a new window for disruption of RAS-driven tumorigenesis [11, 38, 64].…”

“…To address this issue, better selection of tumor types may be required. Recent work from our group and others [46, 47, 68] suggests that using PAK1 gene amplification as a biomarker might select for tumor cells that are sensitive to PAK1 inhibition, and it will be instructive to test NVS-PAK1-1 and similar isoform-selective Pak inhibitors in this setting. Similarly, tumors bearing activating mutations in the small GTPase RAC1 ( e.g ., ~5% of melanoma) [69, 70], which encodes a direct activator of group I Paks, might be good candidates for consideration for future anti-Pak agents.…”

Synthesis and evaluation of a series of 4-azaindole-containing p21-activated kinase-1 inhibitors

“…Table 2 summarizes the SAR of aminopyrazole analogs with various substituted 4-azaindole tails (7)(8)(9)(10). Modeling indicated that extending the (S)-a-methyl vector might be tolerated due to the large degree of flexibility in the glycine-rich loop in the PAK1 kinase domain.…”

“…In recent years there have been several studies suggesting therapeutic potential of small molecule PAK1 inhibitors in breast cancer cell lines 8 and in ovarian cancers that are characterized by PAK1 gene amplification. 9 To date, no PAK inhibitor has advanced to proof-of-concept studies in human. A PAK1 selective inhibitor would be a valuable tool compound to test the efficacy and safety associated with inhibiting group 1 PAK isoforms.…”