ABSTRACT
The RAS-RAF-MEK-MAPK cascade is an essential signaling pathway, with activation typically mediated through cell surface receptors. The kinase inhibitors vemurafenib and dabrafenib, which target oncogenic BRAF V600E, have shown significant clinical efficacy in melanoma patients harboring this mutation. Because of paradoxical pathway activation, both agents were demonstrated to promote growth and metastasis of tumor cells with RAS mutations in preclinical models and are contraindicated for treatment of cancer patients with BRAF WT background, including patients with KRAS or NRAS mutations. In order to eliminate the issues associated with paradoxical MAPK pathway activation and to provide therapeutic benefit to patients with RAS mutant cancers, we sought to identify a compound not only active against BRAF V600E but also wild type BRAF and CRAF. On the basis of its superior in vitro and in vivo profile, compound 13 was selected for further development and is currently being evaluated in phase I clinical studies.
Subject(s)
Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Phenylurea Compounds/chemistry , Phenylurea Compounds/pharmacology , Proto-Oncogene Proteins B-raf/genetics , Pyrimidines/chemistry , Pyrimidines/pharmacology , ras Proteins/metabolism , Animals , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacokinetics , Biological Availability , Cell Line, Tumor/drug effects , Chemistry Techniques, Synthetic , Dogs , Female , Half-Life , Humans , Male , Mice, Nude , Molecular Targeted Therapy , Mutation , Phenylurea Compounds/chemical synthesis , Phenylurea Compounds/pharmacokinetics , Proto-Oncogene Proteins B-raf/antagonists & inhibitors , Proto-Oncogene Proteins B-raf/metabolism , Proto-Oncogene Proteins c-raf/metabolism , Pyrimidines/chemical synthesis , Pyrimidines/pharmacokinetics , Rats, Sprague-Dawley , Structure-Activity Relationship , Xenograft Model Antitumor Assays , ras Proteins/geneticsABSTRACT
The anti-proliferative activity of acylated heterocyclic sulfonamides is described in Vascular Endothelial Growth Factor-dependent Human Umbilical Vascular Endothelial Cells (VEGF-HUVEC) and in HCT116 tumor cells in a soft agar diffusion assay.
Subject(s)
Cell Proliferation/drug effects , Sulfonamides/chemical synthesis , Sulfonamides/pharmacology , Cell Line, Tumor , Cells, Cultured , Heterocyclic Compounds, 2-Ring/chemical synthesis , Heterocyclic Compounds, 2-Ring/pharmacology , Humans , Inhibitory Concentration 50 , Structure-Activity Relationship , Umbilical Veins/cytology , Vascular Endothelial Growth Factor AABSTRACT
Two closely related diaryl acylsulfonamides were recently reported as potent antitumor agents against a broad spectrum of human tumor xenografts (colon, lung, breast, ovary, and prostate) in nude mice. Especially intriguing was their activity against colorectal cancer xenografts. In this paper, rapid parallel synthesis along with traditional medicinal chemistry techniques were used to quickly delineate the structure-activity relationships of the substitution patterns in both phenyl rings of the acylsufonamide anti-proliferative scaffold. Although the molecular target of the compounds remains unclear, we determined that the vascular endothelial growth factor-dependent human umbilical vein endothelial cells assay in combination with a soft agar disk diffusion assay allowed for optimization of potency in the series. The pharmacokinetic properties and in vivo activity in an HCT116 xenograft model are reported for representative compounds.
