Hsp90 inhibition with resorcyclic acid lactones (RALs).
Heat shock protein 90 (Hsp90) is an ATP-dependent chaperone which is involved in the post-translational maturation and stabilization of over one hundred proteins ("its clients"). In the absence of Hsp90's chaperoning, its clients are misfolded and degraded via ubiquitin-proteasome pathway. It has become the focus of intense drug discovery efforts as its activity has been implicated in diverse pathologies ranging from oncology to neurodegenerative and infectious diseases. The most promising inhibitors reported to date inhibit the ATPase activity by binding to the N-terminal ATP pocket. Radicicol, a member of the resorcylic acid lactones (RALs), represents an important pharmacophore to this end. Efforts towards the development of this pharmacophore and its SAR are reviewed herein.
Institut de Science et d'Ingénierie Supramoleculaires, Université de Strasbourg, CNRS (UMR7006), Strasbourg, France. winssinger@isis.u-strasbg.fr
Nicolas
N
Winssinger
Jean-Gonzague
JG
Fontaine
Sofia
S
Barluenga
D000251:Adenosine Triphosphatases / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000737:chemistry / Q000378:metabolism; D000818:Animals; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry; D006801:Humans; D018942:Macrolides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
D018841:HSP90 Heat-Shock Proteins; D018942:Macrolides; D000255:Adenosine Triphosphate; D000251:Adenosine Triphosphatases; C035359:monorden