BioCentury
ARTICLE | Distillery Therapeutics

Cancer

October 27, 2016 7:00 AM UTC

In vitro and cell culture studies identified agonists of RXR heterodimerization that could help treat colorectal cancer, CTCL and other cancers without causing the metabolic and cutaneous side effects of Targretin bexarotene. Chemical synthesis and testing of Targretin analogs in a human colorectal cancer cell line identified 10 compounds that agonized RXR homodimerization - a requirement for RXR-dependent transcription - with EC50 values of 7.9-364.3 nM. In a human CTCL cell line, the compounds decreased proliferation compared with vehicle. In human colorectal cancer cell line-based transcription assays, seven of the compounds increased RXR-dependent transcription and nine increased the RXR-dependent/SREBP-dependent transcription ratio - a marker of Targretin-induced hypertriglyceridemia - compared with Targretin. In an HEK cell-based transcription assay, at least six of the compounds decreased RAR-dependent transcription - a marker of Targretin-induced cutaneous toxicity. Next steps include testing the compounds in animal models of breast and lung cancer.

Eisai Co. Ltd., Minophagen Pharmaceutical Co. Ltd., and Valeant Pharmaceuticals International Inc. market Targretin bexarotene, an RXR agonist, to treat cutaneous T cell lymphoma (CTCL)...