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- W2246389842 abstract "14586 Background: PRLX 93936 is a novel small molecule exhibiting therapeutic potential in an array of in vitro and in vivo tumor models many with limited treatment options such as melanoma. Developed and characterized in cell-based phenotypic assays, PRLX 93936 is a product of extensive SAR work originating from a small molecule identified in a synthetic lethal screen against isogenic cell lines engineered to differentially express several genes including activated RasV12. Methods: Assays measuring cell survival, cytostasis, cell cycle activity and mechanisms of death were employed to characterize the biological activity of the compound. Structural analogs were designed and tested for antiproliferative activity against normal cells and lines derived from tumors with dissimilar causative mutations. Western blotting and mRNA analyses were used to characterize the Ras pathway activation status of the cell panel. In vivo testing of the compound was performed in mice harboring xenografts of human tumor origin. Results: Potent and selective in vitro activity was observed against tumor cell lines derived from breast, colon, lung, melanoma, ovary, kidney and pancreas. Ras pathway activation as evidenced by high mRNA levels and/or the presence of phosphorylated Mek and Erk proteins was observed in many sensitive lines. PRLX 93936 can rapidly affect ion flux, cell cycle, and mitochondrial membrane polarization ultimately inducing caspase dependent apoptosis. Mass spectrometry-based proteomics experiments indicated that both PRLX 93936 and its parent compound can bind to mitochondrial VDAC proteins. Results in multiple tumor xenograft models produced responses from complete regression to tumor-growth inhibition following PO, IV, or IP administration. Responsive in vivo tumor models include: OVCAR-5 (ovarian), SK-Mel28 (melanoma) as well as some derived from sarcoma, pancreas, colon, non small cell lung cancer and multiple myeloma. Toxicology studies indicated drug tolerance at potentially therapeutic levels based on body surface area scaling. Conclusions: Preclinical pharmacodynamic and toxicological studies, suggest that PRLX 93936 has great therapeutic potential and therefore, Prolexys initiated a Phase I clinical trial in August, 2007. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Prolexys Pharmaceuticals, Inc. Prolexys Pharmaceuticals, Inc." @default.
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- W2246389842 date "2008-05-20" @default.
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- W2246389842 title "Selective in vitro and in vivo anti-tumor activity of PRLX 93936 in biological models of melanoma and ovarian cancer" @default.
- W2246389842 doi "https://doi.org/10.1200/jco.2008.26.15_suppl.14586" @default.
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