STA-2842 

STA-2842 is a small molecule agent that inhibits heat shock protein 90 (HSP90) to treat autosomal dominant polycystic kidney disease (ADPKD). The disease is caused by inherited mutations in the PKD1 or PKD2 genes that aberrantly activate multiple signaling proteins and pathways that regulate cell proliferation. Through network construction, we found that many HSP90 client proteins associated with ADPKD are regulated by HSP90. STA-2842 induced degradation of these clients in Pkd1?/? primary kidney cells and in vivo. In experiments using conditional Cre-mediated in vivo knockout of Pkd1 in mice, we found that weekly administration of STA-2842 for 10 weeks significantly reduced initial renal cyst formation and kidney growth in mice and slowed disease progression in mice with pre-existing cysts. These improved disease phenotypes were accompanied by improvements in renal function markers and reductions in the expression and activity of HSP90 clients and their effectors, with the extent of this inhibition correlating with the extent of cyst expansion in individual animals. Pharmacokinetic analysis showed that HSP90 was overexpressed in cystic kidney tissue and HSP90 inhibitors were selectively retained in cystic tissue, which is similar to the situation in solid tumors. These results provide a preliminary basis for evaluating HSP90 inhibitors as therapeutic agents for ADPKD.

550.65

C₂₉H₃₈N₆O₅

1046490-67-8

O=C(C1=NN=C(N1C2=CC=C(CN3CCOCC3)C=C2)C4=C(O)C=C(O)C(C(C)C)=C4)NCCN5CCOCC5

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• [1]. Inhibiting the HSP90 chaperone slows cyst growth in a mouse model of autosomal dominant polycystic kidney disease