title: KAG-308, a newly-identified EP4-selective agonist shows efficacy for treating ulcerative colitis and can bring about lower risk of colorectal carcinogenesis by oral administration.
abstract: Agonists for EP4 receptor, a prostaglandin E2 receptor subtype, appear to be a promising therapeutic strategy for ulcerative colitis (UC) due to their anti-inflammatory and epithelial regeneration activities. However, the clinical development of orally-available EP4 agonists for mild to moderate UC has not yet been reported. Furthermore, the possibility of an increased risk of colitis-associated cancer (CAC) through direct proliferative effects on epithelial cells via EP4 signaling has not been ruled out. Recently, we identified KAG-308 as an orally-available EP4-selective agonist. Here, we investigated the pharmacological and pharmacokinetic profiles of KAG-308. Then, we compared KAG-308 and sulfasalazine (SASP) for their abilities to prevent colitis and promote mucosal healing in a mouse model of dextran sulfate sodium (DSS)-induced colitis. Finally, the effect of KAG-308 treatment on CAC was evaluated in an azoxymethane (AOM)/DSS-induced CAC mouse model. KAG-308 selectively activated EP4 and potently inhibited tumor necrosis factor-α production in peripheral whole blood and T cells. Oral administration of KAG-308, which showed relatively high bioavailability, suppressed the onset of DSS-induced colitis and promoted histological mucosal healing, while SASP did not. KAG-308 also prevented colorectal carcinogenesis by inhibiting colitis development and consequently decreasing mortality in a CAC model, whereas SASP had marginal effects. In contrast, MF-482, an EP4 antagonist, increased mortality. These results indicated that orally-administered KAG-308 suppressed colitis development and promoted mucosal healing. Moreover, it exhibited preventive effects on colorectal carcinogenesis, and thus may be a new therapeutic strategy for the management of UC that confers a reduced risk of colorectal carcinogenesis.
authors.affiliation: Pharmacology Department, Drug Research Center, Kaken Pharmaceutical Co., Ltd, 14 Shinomiya, Minamigawara-cho, Yamashina-ku, Kyoto 607-8042, Japan. Electronic address: watanabe_yusuke@kaken.co.jp.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Watanabe
authors.affiliation: Drug Research Center, Kaken Pharmaceutical Co., Ltd, 14 Shinomiya, Minamigawara-cho, Yamashina-ku, Kyoto 607-8042, Japan.
authors.forename: Takahiko
authors.initials: T
authors.lastname: Murata
authors.affiliation: Pharmacology Department, Drug Research Center, Kaken Pharmaceutical Co., Ltd, 14 Shinomiya, Minamigawara-cho, Yamashina-ku, Kyoto 607-8042, Japan.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Amakawa
authors.affiliation: Pharmacology Department, Drug Research Center, Kaken Pharmaceutical Co., Ltd, 14 Shinomiya, Minamigawara-cho, Yamashina-ku, Kyoto 607-8042, Japan.
authors.forename: Yoshihide
authors.initials: Y
authors.lastname: Miyake
authors.affiliation: Pharmacology Department, Drug Research Center, Kaken Pharmaceutical Co., Ltd, 14 Shinomiya, Minamigawara-cho, Yamashina-ku, Kyoto 607-8042, Japan.
authors.forename: Tango
authors.initials: T
authors.lastname: Handa
authors.affiliation: Life Science Division, AGC Chemicals, Asahi Glass Co., Ltd., 1-5-1 Marunouchi, Chiyoda-ku, Tokyo 100-8405, Japan.
authors.forename: Katsuhiko
authors.initials: K
authors.lastname: Konishi
authors.affiliation: Research and Development Division, AGC Chemicals, Asahi Glass Co., Ltd, 1150 Hazawa-cho, Kanagawa-ku, Yokohama 221-8755, Japan.
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Matsumura
authors.affiliation: Department of Diagnostic Pathology (DDP) & Research Center of Diagnostic Pathology (RC-DiP), Gifu Municipal Hospital, 7-1 Kashima-Cho, Gifu 500-8513, Japan.
authors.forename: Takuji
authors.initials: T
authors.lastname: Tanaka
authors.affiliation: Kyoto Pharmaceutical University, 5 Misasagi-Nakauchicho, Yamashina-ku, Kyoto 607-8414, Japan.
authors.forename: Koji
authors.initials: K
authors.lastname: Takeuchi
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001397:Azoxymethane / Q000378:metabolism; D001565:Benzoates / Q000633:toxicity; D001682:Biological Availability; D002478:Cells, Cultured; D003093:Colitis, Ulcerative / Q000139:chemically induced / Q000188:drug therapy*; D003110:Colonic Neoplasms / Q000139:chemically induced / Q000188:drug therapy / Q000517:prevention & control*; D003521:Cyclopropanes / Q000633:toxicity; D016264:Dextran Sulfate / Q000378:metabolism; D011464:Epoprostenol / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D005260:Female; D064368:Healthy Volunteers; D006801:Humans; D007413:Intestinal Mucosa / Q000187:drug effects; D051379:Mice; D058309:Receptors, Prostaglandin E, EP4 Subtype / Q000819:agonists* / Q000037:antagonists & inhibitors; D012460:Sulfasalazine / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000097:blood
chemical_list: D001565:Benzoates; D003521:Cyclopropanes; C000607040:KAG-308; C000607041:MF-482; D058309:Receptors, Prostaglandin E, EP4 Subtype; D014409:Tumor Necrosis Factor-alpha; D012460:Sulfasalazine; D016264:Dextran Sulfate; D011464:Epoprostenol; D001397:Azoxymethane
keywords: Colitis; Colorectal carcinogenesis; Mucosal healing; Orally-available EP(4) agonist