Abstract #4693: A novel small molecule, PRLX 93936, displays antitumor activity in vitro and in vivo against multiple models of melanoma
Authors: Paul Robbins, Michael Pierce, Christopher Clemens, Raj Gopal Venkat, Shuping Lai, Matthew Rebentisch, Anna Senina, Robert Becklin, Brad VanWagenen, Vlad O'Mel, John Peltier, Tracy Erkkila, Sudhir Sahasrabudhe
Journal: Cancer Research (2009)

PRLX 93936 has demonstrated therapeutic potential in models of human tumors including examples with limited treatment options such as melanoma. Developed and characterized at Prolexys Pharmaceuticals, PRLX 93936 is a product of extensive SAR work originating from a molecule identified in a screen against isogenic cell lines differentially expressing genes such as activated RasV12 (Dolma et.al, Cancer Cell 3: 285-296, 2003). A family of biologically active molecules with enhanced pharmacokinetic and pharmacologic characteristics was created and evaluated against normal and tumor cell lines. PRLX 93936 displayed potent and selective activity against tumor cell lines derived from breast, colon, lung, melanoma, ovary, kidney and pancreas. In vitro testing identifed 5 melanoma lines as sensitive to PRLX 93936 including: LOX IMVI (B-Raf, CDKN2A), M14 (B-Raf, CDKN2A, p53), SK-MEL2 (N-Ras, p53), SK-MEL28 (B-Raf, EGFR, p53), SK-MEL5 (B-Raf, CDKN2A, STK11), UACC-62 (B-Raf, CDKN2A, PTEN). Melanoma lines which did not appear to be responsive included: UACC-257 (B-Raf), MALME-3M (B-Raf, CDKN2A), A375 (B-Raf, CDKN2A), A2058 (B-Raf, PTEN, RB1, p53). The pharmacogenomic profile has not been determined, however, COMPARE analysis of PRLX 93936 in the NCI 60 panel of cell lines indicated that it is functionally unique among the agents tested. Characterization of treated cells shows that selective activation of MAPK and JNK pathway members is correlated with compound sensitivity. Hit profiling studies which examined PRLX 93936 binding or inhibition of enzyme activity against CYP450 enzymes, cell surface receptors and action potential mediating cardiac ion channels showed little response. Kinase profiling of PRLX 93936 against evolutionarily diverse enzymes revealed no significant inhibitory activity. Proteomics experiments identified the mitochondrial protein VDAC (Voltage Dependent Anion Channel) as a specific binding protein and potential molecular target of PRLX 93936 Yagoda et al., Nature. Jun 14;447(7146):864-8. In sensitive cells, PRLX 93936, treatment induces caspase dependent apoptosis, cell cycle arrest, ion flux and cell shrinkage leading to death and tumor growth inhibition. In vivo testing in tumor xenograft models mirrored the in vitro findings producing a range of responses from complete regression to tumor-growth inhibition in a dose-dependent manner following oral (PO), intravenous (IV), or intraperitoneal (IP) administration. Xenografts derived from the melanoma cell line SK-MEL28 underwent complete and durable regression following oral administration (QDx5) of PRLX 93936, while xenografts derived from the A375 cell line showed only modest growth inhibition in response to intraperitoneal treatment with PRLX 93936 (QDx5). Phase I studies with PRLX 93936 in patients with advanced solid tumors are ongoing (initiated August, 2007).   Citation Information:  In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 4693.