Conformationally Defined Rexinoids and Their Efficacy in the Prevention of Mammary Cancers

摘要

(2E,4E,6Z,8Z)-8-(3′,4′-Dihydro-1′(2H)-naphthalen-1′-ylidene)-3,7-dimethyl-2,3,6-octatrienoinic acid (UAB30) is currently undergoing clinical evaluation as a novel cancer prevention agent. In efforts to develop even more highly potent rexinoids that prevent breast cancer without toxicity, we further explore here the structure-activity relationship of two separate classes of rexinoids. UAB30 belongs to the class II rexinoids and possesses a 9Z-tetraenoic acid chain bonded to a tetralone ring, whereas the class I rexinoids contain the same 9Z-tetraenoic acid chain bonded to a di-substituted cyclohexenyl ring. Among the twelve Class I and Class II rexinoids evaluated, the Class I rexinoid >11 is most effective in preventing breast cancers in an in vivo rat model alone or in combination with tamoxifen. Rexinoid >11 also reduces the size of established tumors and exhibits a therapeutic effect. However, >11 induces hypertriglyceridemia at its effective dose. On the other hand rexinoid >10 does not increase triglyceride levels while being effective in the in vivo chemoprevention assay. X-ray studies of four rexinoids bound to the ligand binding domain of the retinoid X receptor reveal key structural aspects that enhance potency as well as those that enhance the synthesis of lipids.