Molecular properties and preclinical pharmacology of JNJ-1250132, a steroidal progesterone receptor modulator that inhibits binding of the receptor to DNA in vitro |
| |
Authors: | Allan George F Palmer Elizabeth Musto Amy Lai Muh-Tsann Clancy Joanna Palmer Stephen |
| |
Institution: | Department of Reproductive Therapeutics, Johnson & Johnson Pharmaceutical Research and Development, 1000 US Route, 202 South, P.O. Box 300, Raritan, NJ 08869, USA. gallan@prdus.jnj.com |
| |
Abstract: | Progesterone receptor modulators have diverse potential therapeutic uses, including the treatment of endometriosis, uterine fibroids and breast cancer. Here we describe the molecular properties and preclinical pharmacology of a new steroidal progestin antagonist, JNJ-1250132. The compound is a high affinity ligand for the progesterone receptor, possessing cross-reactivity with other steroid receptors comparable to that of steroidal antagonists such as mifepristone. It inhibits progestin-inducible alkaline phosphatase gene expression in T47D human breast cancer cells, and also inhibits their in vitro proliferation. It inhibits gestation in rats and progesterone-dependent endometrial transformation in rabbits with efficacies comparable to mifepristone. Like mifepristone, it is a glucocorticoid antagonist in vivo. In cell-free DNA binding assays, the compound inhibits binding of the human progesterone receptor to a progesterone response element, and thus is similar to onapristone in this regard. In contrast, as judged by proteolytic analysis, JNJ-1250132 induces a receptor conformation more similar to that induced by mifepristone, which promotes receptor binding to DNA. Therefore, JNJ-1250132 has unique effects on the progesterone receptor that may translate into a novel clinical profile. |
| |
Keywords: | Steroid Progesterone receptor Antagonist DNA binding Preclinical pharmacology Receptor conformation |
本文献已被 ScienceDirect PubMed 等数据库收录! |
|