The kinetics of binding to p38 MAP kinase by analogues of BIRB 796

doi:10.1016/S0960-894X(03)00656-5

Bioorganic & Medicinal Chemistry Letters

Volume 13, Issue 18, 15 September 2003, Pages 3101-3104

https://doi.org/10.1016/S0960-894X(03)00656-5 Get rights and content

Abstract

BIRB 796, a member of the N-pyrazole-N′-naphthly urea class of p38 MAPK inhibitors, binds to the kinase with both slow association and dissociation rates. Prior to binding, the kinase undergoes a reorganization of the activation loop exposing a critical binding domain. We demonstrate that, independent of the loop movement, association rates are governed by low energy conformations of the inhibitor and polar functionality on the tolyl ring. As anticipated, the dissociation rates of the inhibitors from the kinase are slowed by lipophilic and hydrogen bond interactions. The value of structure-kinetic relationships (SKR) in drug design is discussed.

Abstract

We demonstrate the rates of association and dissociation of binding for analogues of the potent p38 MAP kinase inhibitor, BIRB 796, are influenced by lipophilic and hydrogen bond interactions and low energy conformations of the compounds.

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Citation Excerpt :
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The p38 MAPK cascade is a key signaling pathway linked to a multitude of physiological functions and of central importance in inflammatory and autoimmune diseases. Although studied extensively, little is known about how conformation-specific inhibitors alter signaling outcomes. Here, we have explored the highly dynamic back pocket of p38 MAPK with allosteric urea fragments. However, screening against known off-targets showed that these fragments maintained the selectivity issues of their parent compound BIRB-796, while combination with the hinge-binding motif of VPC-00628 greatly enhanced inhibitor selectivity. Further efforts focused therefore on the exploration of the αC-out pocket of p38 MAPK, yielding compound 137 as a highly selective type-II inhibitor. Even though 137 is structurally related to a recent p38 type-II chemical probe, SR-318, the data presented here provide valuable insights into back-pocket interactions that are not addressed in SR-318 and it provides an alternative chemical tool with good cellular activity targeting also the p38 back pocket.
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Kinases are a family of enzymes that catalyze the transfer of the ɤ-phosphate group from ATP to a protein's residue. Malfunctioning kinases are involved in many health problems such as cardiovascular diseases, diabetes, and cancer. Kinases transitions between multiple conformations of inactive to active forms attracted considerable interest.
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The kinetics of binding to p38 MAP kinase by analogues of BIRB 796

Abstract

Abstract

Curr. Opin. Immunol.

Mol. Med. Today

Cell. Signal

Immunopharmacology

Annu. Rev. Immunol.

N. Engl. J. Med.

Drugs

BioDrugs

Arthritis Rheum.

Cell. Mol. Life Sci.

Curr. Med. Chem.