Biological effects of prostaglandin E2-EP4 antagonist (AAT-008) in murine colon cancer in vivo: enhancement of immune response to radiotherapy and potential as a radiosensitizer

Article

Author: Wang, Zhen ; Kondo, Takuhito ; Katsuki, Shohei ; Shibamoto, Yuta ; Takahashi, Yutaka ; Sugie, Chikao ; Ogawa, Kazuhiko ; Murai, Taro ; Nakashima, Masahiro ; Manabe, Yoshihiko ; Takaoka, Taiki

Prostaglandin E2 (PGE2) promotes tumor growth and metastasis by acting on a family of four receptors (EP1-4).We investigated the radiosensitizing effects of a newly developed antagonist of PGE2-EP4 (AAT-008) in mouse colon cancer cells in vivo and explored the mechanism using flow cytometry (FCM).CT26WT cells grown in Balb/c mice were used.AAT-008 at doses of 0, 3, 10, and 30 mg/kg/day was orally administered once or twice daily for up to 19 days.On day 3, the tumors were irradiated at 9 Gy in the radiotherapy (RT) group.Tumor sizes were measured every other day.For the first FCM series, AAT-008 (10 mg/kg/day) was administered from day 0 to 18 and RT (9 Gy) was given on day 3.The population of effector T cells (Teff), defined as CD45+CD8+CD69+, in the tumors was investigated on day 19.For the second FCM series, AAT-008 (30 mg/kg/day) was administered from day 0 to 12.The populations of Teff and regulatory T cells (Treg), and the ratio of Teff/Treg were investigated on day 13.The growth delay effect of AAT-008 administered alone (3-30 mg/kg/day) appeared minimal.In the first growth delay experiment where AAT-008 was administered once daily, the combined effect of AAT-008 (30 mg/kg/day) and RT appeared additive.In the second growth delay experiment where AAT-008 was administered twice daily, the combined effect appeared additive at 3 and 10 mg/kg/day and supra-additive at 30 mg/kg/day.In the first FCM series, the mean Teff proportions in the tumors were 43% and 31% in the 10 mg + RT and 0 mg + RT groups, resp.Notably, 67% Teff was observed in responsive mice in the 10 mg + RT group.In the second FCM series, the mean Treg proportion and Teff/Treg ratio in the 0 mg + RT and 30 mg + RT groups were 4.0% and 1.5%, resp. (P = 0.04) and 10 and 22, resp. (P = 0.04).AAT-008 potentially enhances the radiosensitivity of colon cancer cells, apparently by stimulating the immune system against the cancer cells.

01 Mar 2017·Bioorganic & Medicinal Chemistry LettersQ4 · MEDICINE

Discovery of AAT-008, a novel, potent, and selective prostaglandin EP4 receptor antagonist

Q4 · MEDICINE

Article

Author: Nakao, Kazunari ; Yamagishi, Tatsuya ; Okumura, Yoshiyuki ; Nukui, Seiji

Starting from acylsufonamide HTS hit 2, a novel series of para-N-acylaminomethylbenzoic acids was identified and developed as selective prostaglandin EP4 receptor antagonists. Structural modifications on lead compound 4a were explored with the aim of improving potency, physicochemical properties, and animal PK predictive of QD (once a day) dosing regimen in human. These efforts led to the discovery of the clinical candidate AAT-008 (4j), which exhibited significantly improved pharmacological profiles over grapiprant (1).

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Indication	Highest Phase	Country/Location	Organization	Date
Neoplasms	IND Approval	CN	AskAt, Inc.	-
Osteoarthritis	Preclinical	JP	AskAt, Inc.	-
Psoriasis	Preclinical	JP	AskAt, Inc.	-

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