Discovery and Optimization of Pyrrolopyrimidine Derivatives as Selective Disruptors of the Perinucleolar Compartment, a Marker of Tumor Progression toward Metastasis

The
perinucleolar compartment (PNC) is a dynamic subnuclear body
found at the periphery of the nucleolus. The PNC is enriched with
RNA transcripts and RNA-binding proteins, reflecting different states
of genome organization. PNC prevalence positively correlates with
cancer progression and metastatic capacity, making it a useful marker
for metastatic cancer progression. A high-throughput, high-content
assay was developed to identify novel small molecules that selectively
reduce PNC prevalence in cancer cells. We identified and further optimized
a pyrrolopyrimidine series able to reduce PNC prevalence in PC3M cancer
cells at submicromolar concentrations without affecting cell viability.
Structure–activity relationship exploration of the structural
elements necessary for activity resulted in the discovery of several
potent compounds. Analysis of in vitro drug-like
properties led to the discovery of the bioavailable analogue, metarrestin,
which has shown potent antimetastatic activity with improved survival
in rodent models and is currently being evaluated in a first-in-human
phase 1 clinical trial.