National Center for
4NH9: Correlation Between Chemotype-dependent Binding Conformations Of Hsp90 Alpha/beta And Isoform Selectivity
Correlation between chemotype-dependent binding conformations of HSP90alpha/beta and isoform selectivity-Implications for the structure-based design of HSP90alpha/beta selective inhibitors for treating neurodegenerative diseases
Bioorg. Med. Chem. Lett. (2014) 24 p.204-208
HSP90 continues to be a target of interest for neurodegeneration indications. Selective knockdown of the HSP90 cytosolic isoforms alpha and beta is sufficient to reduce mutant huntingtin protein levels in vitro. Chemotype-dependent binding conformations of HSP90alpha/beta appear to strongly influence isoform selectivity. The rational design of HSP90alpha/beta inhibitors selective versus the mitochondrial (TRAP1) and endoplasmic reticulum (GRP94) isoforms offers a potential mitigating strategy for mechanism-based toxicities. Better tolerated HSP90 inhibitors would be attractive for targeting chronic neurodegenerative diseases such as Huntington's disease.