Comparison of the ATP Binding Sites of Protein Kinases Using Conformationally Diverse Bisindolylmaleimides

Abstract

The conformation of a bisindolylmaleimide may be controlled by the size of a macrocyclic ring in which it is constrained. A range of techniques were used to demonstrate that the tether controls both the ratio of the two limiting conformers (syn and anti) in solution and the extent of conjugation between the maleimide and indole rings. Screening the conformationally diverse bisindolylmaleimides against a panel of protein kinases allowed their ATP binding sites to be compared using a chemical approach which, like sequence alignment, does not require detailed structural information. This approach lead to the conclusion that several AGC group protein kinases (including PKCalpha, PKCbeta, MSK1, p70 S6K, PDK-1, and MAPKAP-K1alpha) may be best inhibited by bisindolylmaleimides which adopt a compressed approximately C2-symmetric anti conformation; in constrast, GSK3beta may be best inhibited by bisindolylmaleimides whose ground state is a distorted syn conformation. It is concluded that PDK-1, whose structure has been determined by X-ray crystallography, and its mutants, may serve as particularly useful surrogates for the study of PKC inhibitors.

Small‐Molecule Inhibitors of PDK1

“…In line with this notion, a further study comparing ATP binding sites of different PK using a series of conformationally diverse BIM showed that AGC kinases such as PDK1, PKC, MSK1, p70S6K, and MAPKAPK1a were most potently inhibited by BIM that have a compressed conformation. [32] Substituted thienoA C H T U N G T R E N N U N G [3,2-c]pyridine-7-carboxamides…”

A Preliminary Assessment of the Structure-Activity Relationship of Benzimidazole-Based Anti-Proliferative Agents

“…Three potential binding modes were evaluated for celecoxib (1) and the N-tolyl substituted benzimidazole (9). The binding modes were calculated for the interaction of the sulfonamide group with polar residues in the protein (Ser160/Ala162, Mode 1, Fig.…”

“…The phosphorylation process can be inhibited by small ligands that are able to bind to the PDK1 active site and displace ATP [8,9]. In the absence of ATP, PDK1 is unable to gain an active conformation and therefore cannot phosphorylate its substrates or enhance the biological mechanisms that lead to the formation and survival of tumors.…”

“…Molecular modeling studies conducted for the pyrazole derivatives shows that the molecule forms hydrogen bonds with Ser160 and Ala162. The interaction promotes binding and ATP inhibition in PDK1 and has been exploited in the design of other PDK1 ligands [7,[9][10][11]. This binding mode was reevaluated for celecoxib and its derivatives to reveal that a more stable protein-ligand complex could be afforded through electronic interaction with Glu209 and Asp223 [12].…”

New para–para Stilbenophanes: Synthesis by McMurry Coupling, Conformational Analysis and Inhibition of Tubulin Polymerisation

“…[6] Conformational restriction is a method for exploring the influence of molecular geometry on physicochemical and biological properties [7] that can be achieved by several approaches, including the macrocyclisation of open-chain active models. [8] This has been applied to diverse types of compounds, [9] such as bisindole derivatives, [10] and it has recently been used as a tool for a systematic search for new active derivatives in different cell assays. [11] Although it is a very interesting approach for modulating the activity-selectivity of analogues based on highly potent lead compounds, it has not yet been applied to active stilbenes and we have only recently published preliminary work addressing this issue.…”