Discovery of Pyrroloaminopyrazoles as Novel PAK Inhibitors

Guo, Cunlan; McAlpine, Indrawan; Zhang, Junhu; Knighton, Daniel R.; Kephart, Susan E.; Johnson, Matthew; Li, Haitao; Bouzida, Djamal; Yang, Anle; Dong, Liming; Marakovits, Joseph; Tikhe, Jayashree; Richardson, Paul; Guo, Lisa; Kania, Robert S.; Edwards, Martin P.; Kraynov, Eugenia; Christensen, James G.; Piraino, Joseph; Lee, Joseph; Dagostino, Eleanor; Del-Carmen, C.; Deng, Yao; Smeal, Tod; Murray, Brion W.

doi:10.1021/jm300204j

Cited by 49 publications

(30 citation statements)

References 17 publications

(59 reference statements)

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“…21 Recent studies with PAK4 inhibitors, PF-3758309, LCH-7749944, and several pyrroloaminopyrazole compounds suggested the inhibition of anchorage-independent survival in cell lines and abrogated growth in multiple human xenograft tumors. 22, 23, 24 On the other hand, studies with RNAi-mediated PAK4 knockdown also confirmed decreased proliferation, migration and invasion in vitro and significantly reduced in vivo tumor growth in nude mice, suggesting that the PAK4 knockdown is sufficient to abrogate tumor progression. 25, 26, 27 PAK4 overexpression protected cells from different apoptotic stimuli including radiation, serum deficiency and TNF α -induced cleavage of PARP and caspase-3.…”

Section: Discussionmentioning

confidence: 94%

Functional cooperativity by direct interaction between PAK4 and MMP-2 in the regulation of anoikis resistance, migration and invasion in glioma

et al. 2012

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Gliomas display anoikis resistance, enhanced invasion in to the adjacent brain parenchyma and eventually recur despite using the standard therapies. Our studies on increased anoikis sensitization in matrix metalloproteinase-2 (MMP-2)-knockdown 4910 and 5310 human glioma xenograft cells were interestingly correlated with p21-activated kinase 4 (PAK4) inhibition, prompting us to further investigate the role of PAK4 in glioma. Here, we report the PAK4 upregulation in positive correlation with increasing glioma pathological grades. The siRNA-mediated PAK4 knockdown elevated anoikis, and inhibited invasion and migration by downregulating MMP-2, αvβ3-integrin and phospho-epidermal growth factor receptor (phospho-EGFR). The cDNA-PCR arrays revealed a transcriptional suppression of essential proteins involved in cell proliferation and adhesion in PAK4-knockdown cells. Most importantly, glutathione S-transferase pull-down assays demonstrated the MMP-2 as a new PAK4-interacting protein which binds to PAK4 kinase domain. Individual EGFR/ErbB2 inhibitor and αvβ3 antibody treatments in PAK4si-treated cells indicated the regulation of αvβ3/EGFR survival signaling by PAK4. Overexpression of PAK4 significantly reversed the MMP2si-induced cell death in both cell lines. Codepletion of PAK4 and MMP-2 resulted in robust anoikis-mediated cell death, and severely inhibited invasive and migratory properties in these cells. PAK4si inhibited in vivo tumor growth in nude mice by inhibiting MMP-2, β3-integrin and phospho-EGFR levels in tumors. Our findings indicate a physical association between PAK4 and MMP-2, and suggest the future therapeutic potential of PAK4/MMP-2 dual targeting in glioma treatment.

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Section: Discussionmentioning

confidence: 94%

Functional cooperativity by direct interaction between PAK4 and MMP-2 in the regulation of anoikis resistance, migration and invasion in glioma

et al. 2012

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“…Pak1 and Pak2 share high structural homology within their catalytic domains. Pak2, however, is the predominant isoform in BMMCs, sug- gesting that small molecule Pak inhibitors would most likely demonstrate a Pak2 phenotype in mast cells, possibly resulting in severe anaphylaxis (31)(32)(33). These findings also point to our limited understanding of the differences between Pak1 and Pak2 in terms of regulation and substrate specificity.…”

Section: Discussionmentioning

confidence: 99%

Pak2 Kinase Restrains Mast Cell FcϵRI Receptor Signaling through Modulation of Rho Protein Guanine Nucleotide Exchange Factor (GEF) Activity

Kosoff

Chow

Radu

et al. 2013

Journal of Biological Chemistry

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Background:The protein kinase Pak1 stimulates mast cell degranulation, but the role of the more abundant isoform Pak2 in these cells is unknown. Results: Pak2, unlike Pak1, inhibits mast cell degranulation via a GEF-H1-RhoA pathway. Conclusion: Pak2 mediates signals between Fc⑀RI and secretion through regulation of the GEF responsible for RhoA activation. Significance: Pak2 has an opposing role to Pak1 in mast cell degranulation.

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“…Unfortunately, this trial was stopped in phase I due to pharmacokinetic issues. More recently, derivatives of PF-3758309 have been described with much improved pharmacologic properties, raising hope that this class of compound may yet have clinical utility (74). …”

Section: Clinical-translational Advancesmentioning

confidence: 99%

Molecular Pathways: Targeting RAC–p21-Activated Serine–Threonine Kinase Signaling in RAS-Driven Cancers

Baker

Chow

Chernoff

et al. 2014

Clinical Cancer Research

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Cancers driven by oncogenic Ras proteins encompass some of the most deadly human cancer types, and there is a pressing need to develop therapies for these diseases. While recent studies suggest that mutant Ras proteins may yet be druggable, the most promising and advanced efforts involve inhibitors of Ras effector signaling. Most efforts to target Ras signaling have been aimed at the ERK mitogen-activated protein kinase and the phosphatidylinositol 3-kinase signaling networks. However, to date, no inhibitors of these Ras effector pathways have been effective against RAS mutant cancers. This ineffectiveness is due, in part, to the involvement of additional effectors in Ras-dependent cancer growth, such as the Rac small GTPase and the p21-activated serine-threonine kinases (PAK). PAK proteins are involved in many survival, cell motility, and proliferative pathways in the cell and may present a viable new target in Ras-driven cancers. In this review, we address the role and therapeutic potential of Rac and Group I PAK proteins in driving mutant Ras cancers.

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Discovery of Pyrroloaminopyrazoles as Novel PAK Inhibitors

Cited by 49 publications

References 17 publications

Functional cooperativity by direct interaction between PAK4 and MMP-2 in the regulation of anoikis resistance, migration and invasion in glioma

Functional cooperativity by direct interaction between PAK4 and MMP-2 in the regulation of anoikis resistance, migration and invasion in glioma

Pak2 Kinase Restrains Mast Cell FcϵRI Receptor Signaling through Modulation of Rho Protein Guanine Nucleotide Exchange Factor (GEF) Activity

Molecular Pathways: Targeting RAC–p21-Activated Serine–Threonine Kinase Signaling in RAS-Driven Cancers

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