Discovery and design of novel HSP90 inhibitors using multiple fragment-based design strategies.

Huth JR, Park C, Petros AM, Kunzer AR, Wendt MD, Wang X, Lynch CL, Mack JC, Swift KM, Judge RA, Chen J, Richardson PL, Jin S, Tahir SK, Matayoshi ED, Dorwin SA, Ladror US, Severin JM, Walter KA, Bartley DM, Fesik SW, Elmore SW, Hajduk PJ
Chem Biol Drug Des. 2007 70 (1): 1-12

PMID: 17630989 · DOI:10.1111/j.1747-0285.2007.00535.x

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.

MeSH Terms (13)

Aminopyridines Crystallography, X-Ray Drug Design Enzyme Inhibitors HSP90 Heat-Shock Proteins Humans Ligands Models, Molecular Molecular Sequence Data Molecular Structure Nuclear Magnetic Resonance, Biomolecular Peptide Fragments Protein Conformation

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