Adamantyl-substituted retinoid-derived molecules that interact with the orphan nuclear receptor small heterodimer partner: effects of replacing the 1-adamantyl or hydroxyl group on inhibition of cancer cell growth, induction of cancer cell apoptosis, and inhibition of SRC homology 2 domain-containing protein tyrosine phosphatase-2 activity.
(E)-4-[3-(1-Adamantyl)-4'-hydroxyphenyl]-3-chlorocinnamic acid (3-Cl-AHPC) induces the cell-cycle arrest and apoptosis of leukemia and cancer cells. Studies demonstrated that 3-Cl-AHPC bound to the atypical orphan nuclear receptor small heterodimer partner (SHP). Although missing a DNA-binding domain, SHP heterodimerizes with the ligand-binding domains of other nuclear receptors to repress their abilities to induce or inhibit gene expression. 3-Cl-AHPC analogues having the 1-adamantyl and phenolic hydroxyl pharmacophoric elements replaced with isosteric groups were designed, synthesized, and evaluated for their inhibition of proliferation and induction of human cancer cell apoptosis. Structure-anticancer activity relationship studies indicated the importance of both groups to apoptotic activity. Docking of 3-Cl-AHPC and its analogues to an SHP computational model that was based on the crystal structure of ultraspiracle complexed with 1-stearoyl-2-palmitoylglycero-3-phosphoethanolamine suggested why these 3-Cl-AHPC groups could influence SHP activity. Inhibitory activity against Src homology 2 domain-containing protein tyrosine phosphatase 2 (Shp-2) was also assessed. The most active Shp-2 inhibitor was found to be the 3'-(3,3-dimethylbutynyl) analogue of 3-Cl-AHPC.
Dawson
Marcia I
MI
Cancer Center and Inflammatory and Infectious Disease Center, Burnham Institute for Medical Research, La Jolla, California 92037, USA. mdawson@burnham.org
Xia
Zebin
Z
Jiang
Tao
T
Ye
Mao
M
Fontana
Joseph A
JA
Farhana
Lulu
L
Patel
Bhaumik
B
Xue
Li Ping
LP
Bhuiyan
Mohammad
M
Pellicciari
Roberto
R
Macchiarulo
Antonio
A
Nuti
Roberto
R
Zhang
Xiao-Kun
XK
Han
Young-Hoon
YH
Tautz
Lutz
L
Hobbs
Peter D
PD
Jong
Ling
L
Waleh
Nahid
N
Chao
Wan-Ru
WR
Feng
Gen-Sheng
GS
Pang
Yuhong
Y
Su
Ying
Y