2WI3: Orally Active 2-Amino Thienopyrimidine Inhibitors Of The Hsp90 Chaperone

Citation:
Abstract
Inhibitors of the Hsp90 molecular chaperone are showing considerable promise as potential molecular therapeutic agents for the treatment of cancer. Here we describe novel 2-aminothieno[2,3-d]pyrimidine ATP competitive Hsp90 inhibitors, which were designed by combining structural elements of distinct low affinity hits generated from fragment-based and in silico screening exercises in concert with structural information from X-ray protein crystallography. Examples from this series have high affinity (IC50 = 50-100 nM) for Hsp90 as measured in a fluorescence polarization (FP) competitive binding assay and are active in human cancer cell lines where they inhibit cell proliferation and exhibit a characteristic profile of depletion of oncogenic proteins and concomitant elevation of Hsp72. Several examples (34a, 34d and 34i) caused tumor growth regression at well tolerated doses when administered orally in a human BT474 human breast cancer xenograft model.
PDB ID: 2WI3Download
MMDB ID: 75545
PDB Deposition Date: 2009/5/8
Updated in MMDB: 2010/10
Experimental Method:
x-ray diffraction
Resolution: 1.9  Å
Source Organism:
Similar Structures:
Biological Unit for 2WI3: monomeric; determined by author and by software (PQS)
Molecular Components in 2WI3
Label Count Molecule
Protein (1 molecule)
1
Heat Shock Protein, HSP 90-alpha(Gene symbol: HSP90AA1)
Molecule annotation
Chemicals (2 molecules)
1
1
2
1
* Click molecule labels to explore molecular sequence information.

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