Pharmacokinetic evaluation of the PNC disassembler metarrestin in wild-type and Pdx1-Cre;LSL-Kras^G12D/+;Tp53^R172H/+ (KPC) mice, a genetically engineered model of pancreatic cancer.

ABSTRACT:

Purpose

Metarrestin is a first-in-class small molecule clinical candidate capable of disrupting the perinucleolar compartment, a subnuclear structure unique to metastatic cancer cells. This study aims to define the pharmacokinetic (PK) profile of metarrestin and the pharmacokinetic/pharmacodynamic relationship of metarrestin-regulated markers.

Methods

PK studies included the administration of single or multiple dose of metarrestin at 3, 10, or 25 mg/kg via intravenous (IV) injection, gavage (PO) or with chow to wild-type C57BL/6 mice and KPC mice bearing autochthonous pancreatic tumors. Metarrestin concentrations were analyzed by UPLC-MS/MS. Pharmacodynamic assays included mRNA expression profiling by RNA-seq and qRT-PCR for KPC mice.

Results

Metarrestin had a moderat

SUBMITTER: Vilimas T 

PROVIDER: S-EPMC6267684 | biostudies-literature | 2018 Dec

REPOSITORIES: biostudies-literature