Structure–Activity Relationship of SPOP Inhibitors against Kidney Cancer

Speckle-type POZ protein (SPOP) is
overexpressed in the nucleus
and misallocated in the cytoplasm in almost all the clear-cell renal
cell carcinomas (ccRCCs), which leads to kidney tumorigenesis. Previously,
we elucidated that the oncogenic SPOP-signaling pathway in ccRCC could
be suppressed by 6b that inhibits SPOP-mediated protein
interactions. Herein, we have established a structure–activity
relationship for 6b analogues as SPOP inhibitors. Compound 6lc suppresses the viability and inhibits the colony formation
of ccRCC cell lines driven by cytoplasmic SPOP, superior to 6b. Compound 6lc binds to the SPOP protein in
vitro and disrupts SPOP binding to phosphatase-and-tensin homologue
(PTEN) in HEK293T cells, which causes the observable phenomena: a
decline in the ubiquitination of PTEN, elevated levels of both PTEN
and dual-specificity phosphatase 7, and decreased levels of phosphorylated
AKT and ERK when ccRCC cell lines are exposed to 6lc in
a dose–response manner. Taken together, compound 6lc is a potent candidate against kidney tumorigenesis.