New retinoid derivatives as backups of adarotene

Adarotene (ST1926) (WO03/011808) belongs to a so-called class of atypical retinoids. It represents a new first-in-class potent proapoptotic and cytodifferentiating agent, and was selected by Sigma-Tau for clinical development as a “chemotherapy enhancer” in solid tumors (ovarian ca.). In pre-clinical models of haematological as well as solid tumors, Adarotene induced a DNA damage response and affected the modulation of cancer cell survival pathways. When used in combination with other anticancer agents, Adarotene showed a significant synergistic effect in most of the combinations and models tested.(1-4) A possible mechanism has also been described.(5-6) The presence of the phenolic hydroxyl group on Adarotene structure, allowed a rapid O-glucuronidation as a major mechanism of elimination of the drug, favoring a fast excretion of its glucuronide metabolite in the urines. In order to protect the phenolic hydroxyl and improve the “drug-like” properties of the drug, a series of new derivatives have been synthesized. According to chemical structure, these can be grouped into three classes: ether-, carbamate- and ester-derivatives. All of them have been studied and evaluated for their stability at different pH (1.2 - 6.8 - 7.4). The cytotoxic activity in vitro on NCI-H460 non-small cell lung carcinoma and A2780 ovarian tumor cells was also tested.(7) A potential back-up of Adarotene has been selected to be evaluated in vivo tumor models.