title: Design strategies to target crystallographic waters applied to the Hsp90 molecular chaperone.
abstract: A series of novel and potent small molecule Hsp90 inhibitors was optimized using X-ray crystal structures. These compounds bind in a deep pocket of the Hsp90 enzyme that is partially comprised by residues Asn51 and Ser52. Displacement of several water molecules observed crystallographically in this pocket using rule-based strategies led to significant improvements in inhibitor potency. An optimized inhibitor (compound 17) exhibited potent Hsp90 inhibition in ITC, biochemical, and cell-based assays (K(d)=1.3 nM, K(i)=15 nM, and cellular IC(50)=0.5 μM).
authors: Pfizer Worldwide Research and Development, La Jolla Laboratories, San Diego, CA 92121, USA. peipei.kung@pfizer.com
authors: Pei-Pei
authors: PP
authors: Kung
authors: Piet-Jan
authors: PJ
authors: Sinnema
authors: Paul
authors: P
authors: Richardson
authors: Michael J
authors: MJ
authors: Hickey
authors: Ketan S
authors: KS
authors: Gajiwala
authors: Fen
authors: F
authors: Wang
authors: Buwen
authors: B
authors: Huang
authors: Guy
authors: G
authors: McClellan
authors: Jeff
authors: J
authors: Wang
authors: Karen
authors: K
authors: Maegley
authors: Simon
authors: S
authors: Bergqvist
authors: Pramod P
authors: PP
authors: Mehta
authors: Robert
authors: R
authors: Kania