SMALL MOLECULE COMPOSITIONS FOR BINDING TO HSP90

摘要

Structural differences in binding pockets of members of the HSP90 family are exploited to achieve differential degradation of k nases and other signaling proteins by using small molecules which interact with the N-terminal binding pocket with an affinity greater than ADP and different from ansamycin antibiotics for at least one HSP90 family species (Figure 5). These small molecules are soluble in aqueous media, providing a further advantage over ansamycins. Pharmaceutical compositions contain a carrier and a molecule that includes a moiety which binds to the N-terminal pocket of at least one member of the HSP90 family. Such binding moieties have anti proliferative activity against tumor cells which depend on proteins requiring chaperones of the HSP90 family. Different chemical species have different activity, allowing the selection of Her2 degradation without degradation of Raf kinase. Thus, the binding moieties possess inherent targeting capacity. The small molecules can be linked to targeting moieties to target the activity to specific classes of cells. The invention includes treatment of diseases, including cancers. Dimeric forms of the binding moieties may be employed.