Targeting Mast Cells in Endometriosis with Janus Kinase 3 Inhibitor, JANEX‐1

Abstract

Endometriosis (EMS) is a chronic inflammatory disease of multifactorial etiology characterized by implantation and growth of endometrial glands and stroma outside the uterine cavity. EMS is a significant public health issue as it affects 15-20% of women in their reproductive age. Clinical symptoms may include pelvic pain, dysmenorrhea, dyspareunia, pelvic/abdominal masses, and infertility. Symptomatic treatments such as surgical resection and/or hormonal suppression of ovarian function and analgesics are not as effective as desired. Consequently, there is an enormous unmet need to develop effective medical therapy capable of preventing the occurrence and recurrence of EMS without undesirable side-effects. EMS-associated intra-abdominal bleeding episodes, local inflammation, adhesions, and i.p. immunologic dysfunction leads to pelvic nociception and pelvic pain. Increasing evidence supports the involvement of allergic-type inflammation in EMS. Invasion of mast cells, degranulation, and proliferation of interstitial component are observed in endometriotic lesions. Presence of activated and degranulating mast cells within the nerve structures can contribute to the development of pain and hyperalgesia by direct effects on primary nociceptive neurons. Therefore, treatments targeting endometrial mast cells may prove effective in preventing or alleviating EMS-associated symptoms. The Janus kinase 3 (JAK3) is abundantly expressed in mast cells and is required for the full expression of high-affinity IgE receptor-mediated mast cell inflammatory sequelae. JANEX-1/WHI-P131 is a rationally designed novel JAK3 inhibitor with potent anti-inflammatory activity in several cellular and in vivo animal models of inflammation, including mouse models of peritonitis, colitis, cellulitis, sunburn, and airway inflammation with favorable toxicity and pharmacokinetic profile. We hypothesize that JAK3 inhibitors, especially JANEX-1, may prove useful to prevent or alleviate the symptoms of EMS.