A fragment-based approach applied to a highly flexible target: Insights and challenges towards the inhibition of HSP70 isoforms.

ABSTRACT: The heat shock protein 70s (HSP70s) are molecular chaperones implicated in many cancers and of significant interest as targets for novel cancer therapies. Several HSP70 inhibitors have been reported, but because the majority have poor physicochemical properties and for many the exact mode of action is poorly understood, more detailed mechanistic and structural insight into ligand-binding to HSP70s is urgently needed. Here we describe the first comprehensive fragment-based inhibitor exploration of an HSP70 enzyme, which yielded an amino-quinazoline fragment that was elaborated to a novel ATP binding site ligand with different physicochemical properties to known adenosine-based HSP70 inhibitors. Crystal structures of amino-quinazoline ligands bound to the different conformational states of t

SUBMITTER: Jones AM 

PROVIDER: S-EPMC5052559 | biostudies-literature | 2016 Oct

REPOSITORIES: biostudies-literature