Title | 4-Amino derivatives of the Hsp90 inhibitor CCT018159 |
Publication Type | Journal Article |
Year of Publication | 2006 |
Authors | Barril, X, Beswick MC, Collier A, Drysdale MJ, Dymock BW, Fink A, Grant K, Howes R, Jordan AM, Massey A, Surgenor A, Wayne J, Workman P, Wright L |
Journal | Bioorganic & medicinal chemistry letters |
Volume | 16 |
Issue | 9 |
Pagination | 2543 - 2548 |
Date Published | 2006/05/01/ |
Keywords | 2-Ring/chemical synthesis/chemistry/pharmacology; Humans; Models, Binding Sites; Crystallography, Molecular; Molecular Structure; Pyrazoles/chemical synthesis/chemistry/pharmacology; Structure-Activity Relationship, X-Ray; HSP90 Heat-Shock Proteins/antagonists & inhibitors; Heterocyclic Compounds |
Abstract | Novel piperazinyl, morpholino and piperidyl derivatives of the pyrazole-based Hsp90 inhibitor CCT018159 are described. Structure-activity relationships have been elucidated by X-ray co-crystal analysis of the new compounds bound to the N-terminal domain of human Hsp90. Key features of the binding mode are essentially identical to the recently reported potent analogue VER-49009. The most potent of the new compounds has a methylsulfonylbenzyl substituent appended to the piperazine nitrogen, possesses an IC50 of less than 600 nM binding against the enzyme and demonstrates low micromolar inhibition of tumour cell proliferation. |