jm5b00829_si_002.xlsx (11.65 kB)
Conformationally Defined Rexinoids and Their Efficacy in the Prevention of Mammary Cancers
dataset
posted on 2015-10-08, 00:00 authored by Venkatram
R. Atigadda, Gang Xia, Anil Deshpande, Lizhi Wu, Natalia Kedishvili, Craig D. Smith, Helen Krontiras, Kirby I. Bland, Clinton
J. Grubbs, Wayne J. Brouillette, Donald D. Muccio(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 disubstituted cyclohexenyl
ring. Among the 12 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.
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increase triglyceride levelsretinoid X receptorConformationally Defined Rexinoidsrexinoid 11acidclass II rexinoidshand rexinoid 10vivo rat modeldisubstituted cyclohexenyl ringbreast cancertetralone ringvivo chemoprevention assaynovel cancer prevention agent12 classbreast cancersRexinoid 11UAB 30ligand binding domain
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