TY - JOUR
T1 - Pin1 and Par14 peptidyl prolyl isomerase inhibitors block cell proliferation
AU - Uchida, Takafumi
AU - Takamiya, Mari
AU - Takahashi, Morito
AU - Miyashita, Hitoshi
AU - Ikeda, Hisafumi
AU - Terada, Toru
AU - Matsuo, Yo
AU - Shirouzu, Mikako
AU - Yokoyama, Shigeyuki
AU - Fujimori, Fumihiro
AU - Hunter, Tony
N1 - Funding Information:
We thank Y. Mori for providing the chemical library, S. Amari for the molecular modeling, and M. Fujimura and C. Uchida for support throughout this research. This study was supported by a grant of the Japanese Ministry of Education, Culture, Sports, Science and Technology to T.U. T.H. is a Frank and Else Schilling American Cancer Society Research Professor.
PY - 2003/1/1
Y1 - 2003/1/1
N2 - Disruption of the parvulin family peptidyl prolyl isomerase (PPIase) Pin1 gene delays reentry into the cell cycle when quiescent primary mouse embryo fibroblasts are stimulated with serum. Since Pin1 regulates cell cycle progression, a Pin1 inhibitor would be expected to block cell proliferation. To identify such inhibitors, we screened a chemical compound library for molecules that inhibited human Pin1 PPIase activity in vitro. We found a set of compounds that inhibited Pin1 PPIase activity in vitro with low μM IC50s and inhibited the growth of several cancer lines. Among the inhibitors, PiB, diethyl-1,3,6,8-tetrahydro-1,3,6,8-tetraoxobenzo[lmn][3,8] phenanthroline-2,7-diacetate ethyl 1,3,6,8-tetrahydro-1,3,6,8-tetraoxo-benzo[lmn][3,8] phenanthroline-(2H,7H)-diacetate, had the least nonspecific toxicity. These results suggest that Pin1 inhibitors could be used as a novel type of anticancer drug that acts by blocking cell cycle progression.
AB - Disruption of the parvulin family peptidyl prolyl isomerase (PPIase) Pin1 gene delays reentry into the cell cycle when quiescent primary mouse embryo fibroblasts are stimulated with serum. Since Pin1 regulates cell cycle progression, a Pin1 inhibitor would be expected to block cell proliferation. To identify such inhibitors, we screened a chemical compound library for molecules that inhibited human Pin1 PPIase activity in vitro. We found a set of compounds that inhibited Pin1 PPIase activity in vitro with low μM IC50s and inhibited the growth of several cancer lines. Among the inhibitors, PiB, diethyl-1,3,6,8-tetrahydro-1,3,6,8-tetraoxobenzo[lmn][3,8] phenanthroline-2,7-diacetate ethyl 1,3,6,8-tetrahydro-1,3,6,8-tetraoxo-benzo[lmn][3,8] phenanthroline-(2H,7H)-diacetate, had the least nonspecific toxicity. These results suggest that Pin1 inhibitors could be used as a novel type of anticancer drug that acts by blocking cell cycle progression.
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U2 - 10.1016/S1074-5521(02)00310-1
DO - 10.1016/S1074-5521(02)00310-1
M3 - Article
C2 - 12573694
AN - SCOPUS:0037256548
VL - 10
SP - 15
EP - 24
JO - Cell Chemical Biology
JF - Cell Chemical Biology
SN - 2451-9448
IS - 1
ER -
