Discovery of Hydroxyamidine Derivatives as Highly
Potent,Selective Indoleamine-2,3-dioxygenase 1 Inhibitors |
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| Authors: | Fangfang Jin Qiyue Hu Hongbo Fei Hejun Lv Shenglan Wang Bin Gui Junzhen Zhang Wangyang Tu Yun Zhang Lei Zhang Hong Wan Limin Zhang Bin Hu Fanglong Yang Chang Bai Feng He Lianshan Zhang Weikang Tao |
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| Institution: | †Shanghai Hengrui Pharmaceutical Co., Ltd., 279 Wenjing Road, Shanghai 200245, China;‡Jiangsu Hengrui Medicine Co., Ltd., Lianyungang, Jiangsu 222047, China;§Chengdu Suncadia Medicine Co., Ltd., 88 South Keyuan Road, Chengdu, Sichuan 610000, China |
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| Abstract: | In this study, a series of novel hydroxyamidine derivatives were identified as potent and selective IDO1 inhibitors by structure-based drug design. Among them, compounds 13–15 and 18 exhibited favorable enzymatic and cellular activities. Compound 18 showed improved bioavailability in mouse, rat, and dog (F% = 44%, 58.8%, 102.1%, respectively). With reasonable in vivo pharmacokinetic properties, compound 18 was further evaluated in a transgenic MC38 xenograft mouse model. The combination of compound 18 with PD-1 monoclonal antibody showed a synergistic antitumor effect. These data indicated that compound 18 as a potential cancer immunotherapy agent should warrant further investigation. |
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| Keywords: | IDO1 cancer immunotherapy hydroxyamidine
derivatives lead optimization structure-based
drug design bioisostere |
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