1. Academic Validation
  2. Bentamapimod (JNK Inhibitor AS602801) Induces Regression of Endometriotic Lesions in Animal Models

Bentamapimod (JNK Inhibitor AS602801) Induces Regression of Endometriotic Lesions in Animal Models

  • Reprod Sci. 2016 Jan;23(1):11-23. doi: 10.1177/1933719115600553.
Stephen S Palmer 1 Melis Altan 2 Deborah Denis 2 Enrico Gillio Tos 3 Jean-Pierre Gotteland 4 Kevin G Osteen 5 Kaylon L Bruner-Tran 5 Selvaraj G Nataraja 6
Affiliations

Affiliations

  • 1 EMD Serono Research Institute, Billerica, MA, USA TocopheRx, Inc, Burlington, MA, USA stephen@tocopherx.com.
  • 2 EMD Serono Research Institute, Billerica, MA, USA.
  • 3 RBM, Ivrea, Italy.
  • 4 PregLem SA, Geneva, Switzerland.
  • 5 Dept. of Obstetrics and Gynecology, Vanderbilt University, Nashville, TN, USA.
  • 6 EMD Serono Research Institute, Billerica, MA, USA TocopheRx, Inc, Burlington, MA, USA.
Abstract

Endometriosis is an estrogen (ER)-dependent gynecological disease caused by the growth of endometrial tissue at extrauterine sites. Current endocrine therapies address the estrogenic aspect of disease and offer some relief from pain but are associated with significant side effects. Immune dysfunction is also widely believed to be an underlying contributor to the pathogenesis of this disease. This study evaluated an inhibitor of c-Jun N-terminal kinase, bentamapimod (AS602801), which interrupts immune pathways, in 2 rodent endometriosis models. Treatment of nude mice bearing xenografts biopsied from women with endometriosis (BWE) with 30 mg/kg AS602801 caused 29% regression of lesion. Medroxyprogesterone acetate (MPA) or progesterone (PR) alone did not cause regression of BWE lesions, but combining 10 mg/kg AS602801 with MPA caused 38% lesion regression. In human endometrial organ cultures (from healthy women), treatment with AS602801 or MPA reduced matrix metalloproteinase-3 (MMP-3) release into culture medium. In organ cultures established with BWE, PR or MPA failed to inhibit MMP-3 secretion, whereas AS602801 alone or MPA + AS602801 suppressed MMP-3 production. In an autologous rat endometriosis model, AS602801 caused 48% regression of lesions compared to GnRH antagonist Antide (84%). AS602801 reduced inflammatory cytokines in endometriotic lesions, while levels of cytokines in ipsilateral horns were unaffected. Furthermore, AS602801 enhanced natural killer cell activity, without apparent negative effects on uterus. These results indicate that bentamapimod induced regression of endometriotic lesions in endometriosis rodent animal models without suppressing ER action. c-Jun N-terminal kinase inhibition mediated a comprehensive reduction in cytokine secretion and moreover was able to overcome PR resistance.

Keywords

JNK inhibitor; MMP; MPA.; bentamapimod; cytokine; endometriosis; progesterone.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-14761
    99.32%, JNK抑制剂
    JNK