1. Discovery and design of novel HSP90 inhibitors using multiple fragment-based design strategies
- Author
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Stephen W. Fesik, Sarah A. Dorwin, Diane Bartley, Karl A. Walter, Steven W. Elmore, Uri S. Ladror, Jun Chen, Jamey Mack, Sha Jin, Kunzer Aaron R, Russell A. Judge, Paul L. Richardson, Christopher L. Lynch, Philip J. Hajduk, Jean M. Severin, Chang Park, Stephen K. Tahir, Michael D. Wendt, Edward D. Matayoshi, Andrew M. Petros, Jeffrey R. Huth, Wang Xilu, and Kerry M. Swift
- Subjects
Models, Molecular ,Protein Conformation ,Molecular Sequence Data ,Aminopyridines ,Crystallography, X-Ray ,Ligands ,Biochemistry ,Protein structure ,Heat shock protein ,Drug Discovery ,Humans ,HSP90 Heat-Shock Proteins ,Enzyme Inhibitors ,Nuclear Magnetic Resonance, Biomolecular ,Malignant phenotype ,Pharmacology ,chemistry.chemical_classification ,biology ,Molecular Structure ,Organic Chemistry ,Active site ,Hsp90 ,Peptide Fragments ,Enzyme ,chemistry ,Chaperone (protein) ,Drug Design ,biology.protein ,Molecular Medicine - Abstract
The molecular chaperone HSP90 has been shown to facilitate cancer cell survival by stabilizing key proteins responsible for a malignant phenotype. We report here the results of parallel fragment-based drug design approaches in the design of novel HSP90 inhibitors. Initial aminopyrimidine leads were elaborated using high-throughput organic synthesis to yield nanomolar inhibitors of the enzyme. Second site leads were also identified which bound to HSP90 in two distinct conformations, an 'open' and 'closed' form. Intriguingly, linked fragment approaches targeting both of these conformations were successful in producing novel, micromolar inhibitors. Overall, this study shows that, with only a few fragment hits, multiple lead series can be generated for HSP90 due to the inherent flexibility of the active site. Thus, ample opportunities exist to use these lead series in the development of clinically useful HSP90 inhibitors for the treatment of cancers.
- Published
- 2007