10.1021/acs.jmedchem.5b00829.s001 Venkatram R. Atigadda Venkatram R. Atigadda Gang Xia Gang Xia Anil Deshpande Anil Deshpande Lizhi Wu Lizhi Wu Natalia Kedishvili Natalia Kedishvili Craig D. Smith Craig D. Smith Helen Krontiras Helen Krontiras Kirby I. Bland Kirby I. Bland Clinton J. Grubbs Clinton J. Grubbs Wayne J. Brouillette Wayne J. Brouillette Donald D. Muccio Donald D. Muccio Conformationally Defined Rexinoids and Their Efficacy in the Prevention of Mammary Cancers American Chemical Society 2015 increase triglyceride levels retinoid X receptor Conformationally Defined Rexinoids rexinoid 11 acid class II rexinoids hand rexinoid 10 vivo rat model disubstituted cyclohexenyl ring breast cancer tetralone ring vivo chemoprevention assay novel cancer prevention agent 12 class breast cancers Rexinoid 11 UAB 30 ligand binding domain 2015-10-08 00:00:00 Journal contribution https://acs.figshare.com/articles/journal_contribution/Conformationally_Defined_Rexinoids_and_Their_Efficacy_in_the_Prevention_of_Mammary_Cancers/2123893 (2<i>E</i>,4<i>E</i>,6<i>Z</i>,8<i>Z</i>)-8-(3′,4′-Dihydro-1′(2<i>H</i>)-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 9<i>Z</i>-tetraenoic acid chain bonded to a tetralone ring, whereas the class I rexinoids contain the same 9<i>Z</i>-tetraenoic acid chain bonded to a disubstituted cyclohexenyl ring. Among the 12 class I and class II rexinoids evaluated, the class I rexinoid <b>11</b> is most effective in preventing breast cancers in an in vivo rat model alone or in combination with tamoxifen. Rexinoid <b>11</b> also reduces the size of established tumors and exhibits a therapeutic effect. However, <b>11</b> induces hypertriglyceridemia at its effective dose. On the other hand rexinoid <b>10</b> 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.