Adenosine-derived inhibitors of 78 kDa glucose regulated protein (Grp78) ATPase: insights into isoform selectivity

  • J Med Chem. 2011 Jun 23;54(12):4034-41. doi: 10.1021/jm101625x.
Alba T Macias  1 ,  Douglas S Williamson ,  Nicola Allen ,  Jenifer Borgognoni ,  Alexandra Clay ,  Zoe Daniels ,  Pawel Dokurno ,  Martin J Drysdale ,  Geraint L Francis ,  Christopher J Graham ,  Rob Howes ,  Natalia Matassova ,  James B Murray ,  Rachel Parsons ,  Terry Shaw ,  Allan E Surgenor ,  Lindsey Terry ,  Yikang Wang ,  Mike Wood ,  Andrew J Massey
Affiliations
  • 1. Vernalis (R&D) Ltd., Granta Park, Great Abington, Cambridge, CB21 6GB, UK. [email protected]
PMID: 21526763 DOI: 10.1021/jm101625x
Abstract

78 kDa glucose-regulated protein (Grp78) is a heat shock protein (HSP) involved in protein folding that plays a role in Cancer cell proliferation. Binding of adenosine-derived inhibitors to Grp78 was characterized by surface plasmon resonance and isothermal titration calorimetry. The most potent compounds were 13 (VER-155008) with K(D) = 80 nM and 14 with K(D) = 60 nM. X-ray crystal structures of Grp78 bound to ATP, ADPnP, and adenosine derivative 10 revealed differences in the binding site between Grp78 and homologous proteins.