Inhibition of p38 MAP kinase by utilizing a novel allosteric binding site

Pargellis, Christopher A.; Tong, Liang; Churchill, Laurie; Cirillo, Pier F.; Gilmore, Thomas D.; Graham, Anne G.; Grob, Peter M.; Hickey, Eugene R.; Moss, Neil; Pav, Susan; Regan, John

doi:10.1038/nsb770

Cited by 832 publications

(904 citation statements)

References 25 publications

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“…Other kinases undergo substantial rearrangements of the loop with the DFG phenylalanine flipping out of the active site. An example of that is the so called ''DFG out'' conformation in Abl (18) and p38 kinases (19). Our model suggests that, after inactivation, the DFG motif retains the ''DFG in'' configuration.…”

Section: Resultsmentioning

confidence: 99%

Surface comparison of active and inactive protein kinases identifies a conserved activation mechanism

Kornev

Haste²,

Taylor³

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

673

746

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The surface comparison of different serine-threonine and tyrosine kinases reveals a set of 30 residues whose spatial positions are highly conserved. The comparison between active and inactive conformations identified the residues whose positions are the most sensitive to activation. Based on these results, we propose a model of protein kinase activation. This model explains how the presence of a phosphate group in the activation loop determines the position of the catalytically important aspartate in the AspPhe-Gly motif. According to the model, the most important feature of the activation is a ''spine'' formation that is dynamically assembled in all active kinases. The spine is comprised of four hydrophobic residues that we detected in a set of 23 eukaryotic and prokaryotic kinases. It spans the molecule and plays a coordinating role in activated kinases. The spine is disordered in the inactive kinases and can explain how stabilization of the whole molecule is achieved upon phosphorylation.protein surface ͉ graph theory

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Section: Resultsmentioning

confidence: 99%

Surface comparison of active and inactive protein kinases identifies a conserved activation mechanism

Kornev

Haste²,

Taylor³

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

673

746

View full text Add to dashboard Cite

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“…BMS-354825 is in clinical development for imatinib-resistant chronic myeloid leukemia (19,32). BIRB-796 is a p38 inhibitor that has been in clinical trials for inflammatory disease (23). MLN-518 and SU-11248 are inhibitors of wild-type and activated KIT and FLT3 (33)(34)(35)(36), and both have been in clinical trials for treatment of acute myeloid leukemia (25, 37) (Pharmaprojects database).…”

Section: Methodsmentioning

confidence: 99%

Inhibition of drug-resistant mutants of ABL, KIT, and EGF receptor kinases

Carter

Wodicka

Shah

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

521

390

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To realize the full potential of targeted protein kinase inhibitors for the treatment of cancer, it is important to address the emergence of drug resistance in treated patients. Mutant forms of BCR-ABL, KIT, and the EGF receptor (EGFR) have been found that confer resistance to the drugs imatinib, gefitinib, and erlotinib. The mutations weaken or prevent drug binding, and interestingly, one of the most common sites of mutation in all three kinases is a highly conserved ''gatekeeper'' threonine residue near the kinase active site. We have identified existing clinical compounds that bind and inhibit drug-resistant mutant variants of ABL, KIT, and EGFR. We found that the Aurora kinase inhibitor VX-680 and the p38 inhibitor BIRB-796 inhibit the imatinib-and BMS-354825-resistant ABL(T315I) kinase. The KIT͞FLT3 inhibitor SU-11248 potently inhibits the imatinib-resistant KIT(V559D͞T670I) kinase, consistent with the clinical efficacy of SU-11248 against imatinib-resistant gastrointestinal tumors, and the EGFR inhibitors EKB-569 and CI-1033, but not GW-572016 and ZD-6474, potently inhibit the gefitiniband erlotinib-resistant EGFR(L858R͞T790M) kinase. EKB-569 and CI-1033 are already in clinical trials, and our results suggest that they should be considered for testing in the treatment of gefitinib͞ erlotinib-resistant non-small cell lung cancer. The results highlight the strategy of screening existing clinical compounds against newly identified drug-resistant mutant variants to find compounds that may serve as starting points for the development of nextgeneration drugs, or that could be used directly to treat patients that have acquired resistance to first-generation targeted therapy. drug resistance ͉ gatekeeper mutation ͉ kinase inhibitor

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“…In certain examples such as C-Met (PDB code: 1RLW), AKT (PDB code: 2GU8), and p38 (PDB code: 1KV1) kinases, against which NSC 109555 was found to be poorly active (IC50 > 10 lM), the inhibitor had a very poor fit to the ATP-binding pocket due to multiple steric constraints. [32][33][34] This analysis is, of course, qualitative in nature as there are more influences on inhibitor binding than just steric interactions. For instance, overall protein dynamics may influence the selectivity of kinases for inhibitor binding, as has been observed in some instances.…”

Section: Structural Insights Into Chk2 Selectivitymentioning

confidence: 99%

Crystal structure of checkpoint kinase 2 in complex with NSC 109555, a potent and selective inhibitor

et al. 2008

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Checkpoint kinase 2 (Chk2), a ser/thr kinase involved in the ATM-Chk2 checkpoint pathway, is activated by genomic instability and DNA damage and results in either arrest of the cell cycle to allow DNA repair to occur or apoptosis if the DNA damage is severe. Drugs that specifically target Chk2 could be beneficial when administered in combination with current DNAdamaging agents used in cancer therapy. Recently, a novel inhibitor of Chk2, NSC 109555, was identified that exhibited high potency (IC 50 = 240 nM) and selectivity. This compound represents a new chemotype and lead for the development of novel Chk2 inhibitors that could be used as therapeutic agents for the treatment of cancer. To facilitate the discovery of new analogs of NSC 109555 with even greater potency and selectivity, we have solved the crystal structure of this inhibitor in complex with the catalytic domain of Chk2. The structure confirms that the compound is an ATP-competitive inhibitor, as the electron density clearly reveals that it occupies the ATPbinding pocket. However, the mode of inhibition differs from that of the previously studied structure of Chk2 in complex with debromohymenialdisine, a compound that inhibits both Chk1 and Chk2. A unique hydrophobic pocket in Chk2, located very close to the bound inhibitor, presents an opportunity for the rational design of compounds with higher binding affinity and greater selectivity.

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Inhibition of p38 MAP kinase by utilizing a novel allosteric binding site

Cited by 832 publications

References 25 publications

Surface comparison of active and inactive protein kinases identifies a conserved activation mechanism

Surface comparison of active and inactive protein kinases identifies a conserved activation mechanism

Inhibition of drug-resistant mutants of ABL, KIT, and EGF receptor kinases

Crystal structure of checkpoint kinase 2 in complex with NSC 109555, a potent and selective inhibitor

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