The DOI matches its Crossref record; 1 of the 1 references it cites were found in a registry or an index.
An allosteric kinase inhibitor binds the p21-activated kinase autoregulatory domain covalently
Abstract
Kinases are important therapeutic targets in oncology due to their frequent deregulation in cancer. Typical ATP-competitive kinase inhibitors, however, also inhibit off-target kinases that could lead to drug toxicity. Allosteric inhibitors represent an alternative approach to achieve greater kinase selectivity, although examples of such compounds are few. Here, we elucidate the mechanism of action of IPA-3, an allosteric inhibitor of Pak kinase activation. We show that IPA-3 binds covalently to the Pak1 regulatory domain and prevents binding to the upstream activator Cdc42. Preactivated Pak1, however, is neither inhibited nor bound significantly by IPA-3, demonstrating exquisite conformational specificity of the interaction. Using radiolabeled IPA-3, we show that inhibitor binding is specific and reversible in reducing environments. Finally, cell experiments using IPA-3 implicate Pak1 in phorbol-ester–stimulated membrane ruffling. This study reveals a novel allosteric mechanism for kinase inhibition through covalent targeting of a regulatory domain. [Mol Cancer Ther 2009;8(9):2559–65]
Overview
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
In the citing paper
“Administration of IPA-3, a specific inhibitor of PAK124, exerted similar effects on PI3K-AKT (Fig. 7j), colony formation and apoptosis in these cells (Fig. 8c, d).”
From Gadd45g insufficiency drives the pathogenesis of myeloproliferative neoplasms (2024) · cites this paper as [24]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Citations
Cites
Drug-target residence time and its implications for lead optimization
Copeland, R. A., Pompliano, D. L., & Meek, T. D. (2006) · Nature Reviews Drug Discovery · doi:10.1038/nrd2082 · Cited by 1,464
Research works printed but not linked: 28
- Deacon, 2008, An isoform-selective, small-molecule inhibitor targets the autoregulatory mechanism of p21-activated kinase, Chem Biol, 15, 322, 10.1016/j.chembiol.2008.03.005 · DOI · Paper page
- Eswaran, 2009, Targeting group II PAKs in cancer and metastasis, Cancer Metastasis Rev, 28, 209, 10.1007/s10555-008-9181-4 · DOI
- Kumar, 2006, p21-activated kinases in cancer, Nat Rev Cancer, 6, 459, 10.1038/nrc1892 · DOI
- Vadlamudi, 2003, P21-activated kinases in human cancer, Cancer Metastasis Rev, 22, 385, 10.1023/A:1023729130497 · DOI
- Vadlamudi, 2004, p21-activated kinase 1: an emerging therapeutic target, Cancer Treat Res, 119, 77, 10.1007/1-4020-7847-1_5 · DOI
- Lei, 2000, Structure of PAK1 in an autoinhibited conformation reveals a multistage activation switch, Cell, 102, 387, 10.1016/S0092-8674(00)00043-X · DOI
- Parrini, 2002, Pak1 kinase homodimers are autoinhibited in trans and dissociated upon activation by Cdc42 and Rac1, Mol Cell, 9, 73, 10.1016/S1097-2765(01)00428-2 · DOI
- Allen, 2009, p21-activated kinase regulates mast cell degranulation via effects on calcium mobilization and cytoskeletal dynamics, Blood, 113, 2695, 10.1182/blood-2008-06-160861 · DOI
- Ammoun, 2008, Dissecting and targeting the growth factor-dependent and growth factor-independent extracellular signal-regulated kinase pathway in human schwannoma, Cancer Res, 68, 5236, 10.1158/0008-5472.CAN-07-5849 · DOI
- Takahashi, 2009, Membrane transport of WAVE2 and lamellipodia formation require Pak1 that mediates phosphorylation and recruitment of stathmin/Op18 to Pak1-2-kinesin complex, Cell Signal, 21, 695, 10.1016/j.cellsig.2009.01.007 · DOI
- Modha, 2008, The Rac1 polybasic region is required for interaction with its effector PRK1, J Biol Chem, 283, 1492, 10.1074/jbc.M706760200 · DOI
- Peterson, 2001, A chemical inhibitor of N-WASP reveals a new mechanism for targeting protein interactions, Proc Natl Acad Sci U S A, 98, 10624, 10.1073/pnas.201393198 · DOI
- Prehoda, 2000, Integration of multiple signals through cooperative regulation of the N-WASP-Arp2/3 complex, Science, 290, 801, 10.1126/science.290.5492.801 · DOI
- Rennefahrt, 2007, Specificity profiling of Pak kinases allows identification of novel phosphorylation sites, J Biol Chem, 282, 15667, 10.1074/jbc.M700253200 · DOI
- Buchwald, 2001, Conformational switch and role of phosphorylation in PAK activation, Mol Cell Biol, 21, 5179, 10.1128/MCB.21.15.5179-5189.2001 · DOI
- Peterson, 2006, Biochemical suppression of small-molecule inhibitors: a strategy to identify inhibitor targets and signaling pathway components, Chem Biol, 13, 443, 10.1016/j.chembiol.2006.02.009 · DOI
- Dharmawardhane, 1997, Localization of p21-activated kinase 1 (PAK1) to pinocytic vesicles and cortical actin structures in stimulated cells, J Cell Biol, 138, 1265, 10.1083/jcb.138.6.1265 · DOI
- Dharmawardhane, 2000, Regulation of macropinocytosis by p21-activated kinase-1, Mol Biol Cell, 11, 3341, 10.1091/mbc.11.10.3341 · DOI
- Koh, 2008, Cdc42- and Rac1-mediated endothelial lumen formation requires Pak2, Pak4 and Par3, and PKC-dependent signaling, J Cell Sci, 121, 989, 10.1242/jcs.020693 · DOI
- Schirmer, 2006, Targeted covalent inactivation of protein kinases by resorcylic acid lactone polyketides, Proc Natl Acad Sci U S A, 103, 4234, 10.1073/pnas.0600445103 · DOI
- Yuan, 2007, Covalent reactions of wortmannin under physiological conditions, Chem Biol, 14, 321, 10.1016/j.chembiol.2007.02.007 · DOI
- Wymann, 1996, Wortmannin inactivates phosphoinositide 3-kinase by covalent modification of Lys-802, a residue involved in the phosphate transfer reaction, Mol Cell Biol, 16, 1722, 10.1128/MCB.16.4.1722 · DOI
- Gonzales, 2008, Antitumor activity and pharmacokinetic properties of PF-00299804, a second-generation irreversible pan-erbB receptor tyrosine kinase inhibitor, Mol Cancer Ther, 7, 1880, 10.1158/1535-7163.MCT-07-2232 · DOI · Paper page
- Reindl, 2008, Inhibition of polo-like kinase 1 by blocking polo-box domain-dependent protein-protein interactions, Chem Biol, 15, 459, 10.1016/j.chembiol.2008.03.013 · DOI
- Kudo, 1999, Leptomycin B inactivates CRM1/exportin 1 by covalent modification at a cysteine residue in the central conserved region, Proc Natl Acad Sci U S A, 96, 9112, 10.1073/pnas.96.16.9112 · DOI
- Shan, 1999, Selective, covalent modification of β-tubulin residue Cys-239 by T138067, an antitumor agent with in vivo efficacy against multidrug-resistant tumors, Proc Natl Acad Sci U S A, 96, 5686, 10.1073/pnas.96.10.5686 · DOI
- Buccione, 2004, Foot and mouth: podosomes, invadopodia and circular dorsal ruffles, Nat Rev Mol Cell Biol, 5, 647, 10.1038/nrm1436 · DOI · Paper page
- Orth, 2006, Get off my back! Rapid receptor internalization through circular dorsal ruffles, Cancer Res, 66, 11094, 10.1158/0008-5472.CAN-06-3397 · DOI
Cited by
Gadd45g insufficiency drives the pathogenesis of myeloproliferative neoplasms
Zhang, P., You, N., Ding, Y., Zhu, W., Wang, N., Xie, Y., Huang, W., Ren, Q., Qin, T., Fu, R., et al. (2024) · Nature Communications · doi:10.1038/s41467-024-47297-2 · Cited by 11
Metadata
- Authors
- Viaud, J., & Peterson, J. R.
- Venue
- Molecular Cancer Therapeutics
- Published
- 2009-09-01
- Volume
- 8
- Issue
- 9
- Pages
- 2559-2565
- ISSN
- 1535-7163
- 1538-8514
- PMC
- PMC2782767
- Cited by
- 104
- References
- 1
- Language
- en
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
