Design strategies to target crystallographic waters applied to the Hsp90 molecular chaperone |
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| Authors: | Kung Pei-Pei Sinnema Piet-Jan Richardson Paul Hickey Michael J Gajiwala Ketan S Wang Fen Huang Buwen McClellan Guy Wang Jeff Maegley Karen Bergqvist Simon Mehta Pramod P Kania Robert |
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| Affiliation: | a Pfizer Worldwide Research and Development, La Jolla Laboratories, 10770, Science Center Dr., San Diego, CA 92121, USA
b Syncom B. V., Kadijk 3, 9747AT Groningen, The Netherlands |
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| 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 (Kd = 1.3 nM, Ki = 15 nM, and cellular IC50 = 0.5 μM). |
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| Keywords: | Hsp90 inhibitor Structure-based design technique Pyrrolopyrimidine |
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