RGNCY-0057 (PRLX93936 Erastin analogue)
PRLX93936 is a novel small molecule structural analogue of erastin with potential antineoplastic activity in an array of in vitro and in vivo tumor models, many with limited treatment options such as melanoma. PRLX93936 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. PRLX93936 appears to inhibit mitochondrial outer membrane protein voltage-dependent anion channels (VDAC) 2 and 3, resulting in an oxidative, non-apoptotic cell death. PRLS93936 exhibits greater lethality in cell lines harboring mutations in the GTPase protein oncogenes HRAS and KRAS or the serine-threonine protein kinase oncogene BRAF than in non-tumorigenic cell lines. VDACs 2 and 3 are up-regulated in a wide variety of tumor cell lines. In vivo tumor models responsive to PRLX93936 include: OVCAR-5 (ovarian), SK-Mel28 (melanoma) as well as some derived from sarcoma, pancreas, colon, non-small cell lung cancer and multiple myeloma. Preclinical pharmacodynamic and toxicological studies suggested that PRLX93936 had therapeutic potential and entered a Phase 1 clinical trial in 2007.
Systematic Name: 3-(2-ethoxyphenyl)-2-(piperazin-1-ylmethyl)quinazolin-4(3H)-one
Mol Wt: 364.45
Tags: Small molecules, Kinase, Melanoma, serine/threonine kinase, myeloma, Tumor, BRAF, Oncogene, RGNCY-0057, PRLX93936, Erastin, VDAC, RasV12, HRAS, KRAS