Exploration of type II binding mode: A privileged approach for kinase inhibitor focused drug discovery?

Abstract

The ATP site of kinases displays remarkable conformational flexibility when accommodating chemically diverse small molecule inhibitors. The so-called activation segment, whose conformation controls catalytic activity and access to the substrate binding pocket, can undergo a large conformational change with the active state assuming a 'DFG-in' and an inactive state assuming a 'DFG-out' conformation. Compounds that preferentially bind to the DFG-out conformation are typically called 'type II' inhibitors in contrast to 'type I' inhibitors that bind to the DFG-in conformation. This review surveys the large number of type II inhibitors that have been developed and provides an analysis of their crystallographically determined binding modes. Using a small library of type II inhibitors, we demonstrate that more than 200 kinases can be targeted, suggesting that type II inhibitors may not be intrinsically more selective than type I inhibitors.

Figure 1

Representative X-ray structures and demonstration of binding modes. (A) ATP complexes with IRK (PDB ID: 1IR3) in type I binding. (B) Gefitinib complexes with EGFR (PDB ID: 2ITY) in type I binding. (C) Imatinib complexes with Abl (PDB ID: 1IEP) in type II binding. (D) GNF-2 complexes with Abl (PDB ID: 3K5V) type IV binding. (E) Akt allosteric inhibitor complexes with Akt (PDB: 3O96); (F) PD318088 complexes with MEK1 (PDB: 1S9J) in type III binding. (G) Dasatinib complexes with BTK (PDB ID: 3OCT). (H) PF-00215955 complexes with p38 (PDB ID: 3K3I).

Figure 2

FDA-approved kinase inhibitors with binding modes.

Figure 3

Examples of known type II kinase inhibitors.

Figure 4

Analysis of X-ray crystal structure confirmed type II conformation (DFG-out) kinases. (A) Treespot demonstration of type II conformation (DFG-out) kinase distribution. (B) Analysis of gate keeper residues. (C) Demonstration of DFG-out A-loop-R (direct to C-Helix) conformation (PDB ID: 1M52). (D) Demonstration of DFG-out A-loop-L (direct to Hinge) conformation (PDB ID: 1IEP).

Figure 5

Schematic representation of type II kinase inhibitors constitution.

Figure 6

Chemical structures and S(1) score of 12 in-house generated/published inhibitors.

Figure 7

Analysis of selectivity profiling revealed type II binding kinases. (A) Treespot demonstration of kinase distribution among kinome. (B) Analysis of gatekeeper residues among the type II inhibitor targeted kinases. (C) Analysis of gatekeeper residues among the kinome. (D) Statistics of most targeted kinases by type II inhibitors. (E) Treespot demonstration of most targeted kinase distribution among kinome. (F) Analysis of gatekeeper residues of most targeted kinases by type II inhibitors.