Crystal structures of ASK1‐inhibtor complexes provide a platform for structure‐based drug design

Abstract

ASK1, a member of the MAPK Kinase Kinase family of proteins has been shown to play a key role in cancer, neurodegeneration and cardiovascular diseases and is emerging as a possible drug target. Here we describe a 'replacement-soaking' method that has enabled the highthroughput X-ray structure determination of ASK1/ligand complexes. Comparison of the X-ray structures of five ASK1/ligand complexes from 3 different chemotypes illustrates that the ASK1 ATP binding site is able to accommodate a range of chemical diversity and different binding modes. The replacement-soaking system is also able to tolerate some protein flexibility. This crystal system provides a robust platform for ASK1/ligand structure determination and future structure based drug design.

Structure-Based Design of ASK1 Inhibitors as Potential Agents for Heart Failure

“…7 Key structural features with respect to ligand interactions within the ATP binding site were identified using our internal database as well as public domain crystal structures of small molecules in ASK1 and published pharmacophore models. 8,9 Figure 1 illustrates the cocrystal structure of 1 in hASK1 (PDB: 3VW6) and highlights the key interactions between 1 and the ASK1 ATP binding pocket. Binding to the kinase hinge is characterized by a hydrogen bonding interaction with the backbone NH and carbonyl of Val757.…”

Alkylation of Staurosporine to Derive a Kinase Probe for Fluorescence Applications

“…Although the 4′‐methylamine is oriented towards solvent‐accessible space, it is involved in binding to the protein. In many crystal structures the 4′‐methylamine can be seen to be binding to acidic side chain residues in the kinase; for example, Glu127 and Glu170 in the case of PKA, and Asp807 in the case of ASK1 . For kinases that hydrogen bond via aspartate or glutamate to the 4′‐methylamine nitrogen of staurosporine, a 7‐ to 80‐fold decrease in affinity was observed upon acylation of this moiety to introduce a PEG linker .…”

“…In many crystal structures the 4'-methylamine can be seen to be binding to acidic side chain residues in the kinase;f or example, Glu127 and Glu170 in the case of PKA, [21] and Asp807 in the case of ASK1. [22] For kinases that hydrogen bond via aspartate or glutamate to the 4'-methylamine nitrogen of staurosporine, a7 -t o8 0-foldd ecrease in affinity was observed upon acylation of this moiety to introduce aP EG linker. [9] However,a cylation did not affect the inhibition of c-Src by ar ecently developed covalently bindinga ffinity probe.…”

7-Azaindole: A Versatile Scaffold for Developing Kinase Inhibitors

“…The observation that both "normal" and "flipped" binding modes are possible in Janus kinase 2 (JAK2; TK), c-Met (Met; TK), and apoptosis signalregulating kinase 1 (ASK1; STK) kinases suggests that the binding mode is not dependent on kinase structural features. Rather, it would depend on the ligand structure, because 2-substituted derivatives of the azaindole give only "flipped" binding mode (compounds 7-11 [19][20][21][22][23] in Fig. 4).…”