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.