Phenyl Benzenesulfonylhydrazides Exhibit Selective Indoleamine 2,3-Dioxygenase Inhibition with Potent <i>in Vivo</i> Pharmacodynamic Activity and Antitumor Efficacy

Lin, Shu Yu; Yeh, Teng Kuang; Kuo, Ching Chuan; Song, Jen Shin; Cheng, Ming; Liao, Fang Yu; Chao, Min Wu; Huang, Hsu‐Shan; Chen, Yi Lin; Yang, Chun; Wu, Mine Hsine; Hsieh, Chia Ling; Hsiao, Wen-Chi; Peng, Yi; Wu, Jian; Lin, Li; Sun, Manwu; Chao, Yu Sheng; Shih, Chuan; Wu, Su Ying; Pan, Shiow Lin; Hung, Ming‐Shiu; Ueng, Shau‐Hua

doi:10.1021/acs.jmedchem.5b01640

Cited by 67 publications

(25 citation statements)

References 37 publications

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“…Preclinically, a number of new IDO1 inhibitor scaffolds have been reported, many of which are covered in a recent review (61). Of particular recent note, identification of a benzenesulfonylhydrazide series of inhibitors (112) yielded compound 40 as a potent IDO1 inhibitor in cells with EC50=68 nM, 59% oral bioavailability, the administration of which produced significant tumor growth delay without body weight loss in mouse tumor models (113). …”

Section: Discovery and Preclinical Development Of Ido1 Inhibitorsmentioning

confidence: 99%

Discovery of IDO1 Inhibitors: From Bench to Bedside

et al. 2017

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Small molecule inhibitors of indoleamine 2,3-dioxygenase-1 (IDO1) are emerging at the vanguard of experimental agents in oncology. Here pioneers of this new drug class provide a bench-to-bedside review on preclinical validation of IDO1 as a cancer therapeutic target and on the discovery and development of a set of mechanistically distinct compounds – indoximod, epacadostat and navoximod – that were first to be evaluated as IDO inhibitors in clinical trials. As ‘immunometabolic adjuvants’ to widen therapeutic windows, IDO inhibitors may leverage not only immuno-oncology modalities but also chemotherapy and radiotherapy as standards of care in the oncology clinic.

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Section: Discovery and Preclinical Development Of Ido1 Inhibitorsmentioning

confidence: 99%

Discovery of IDO1 Inhibitors: From Bench to Bedside

et al. 2017

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“…Identification of a benzenesulfonylhydrazide series of inhibitors [136] seeded work yielding a potent IDO1 inhibitor of EC50=68 nM in cells and 59% oral bioavailability which produced significant tumor growth delay without body weight loss [137]. Several pharmaceutical companies report compounds in late-stage preclinical development or early clinical testing.…”

Section: Therapeutic Approaches To Block Ido Functionmentioning

confidence: 99%

Inflammatory Reprogramming with IDO1 Inhibitors: Turning Immunologically Unresponsive ‘Cold’ Tumors ‘Hot’

Prendergast¹,

Mondal²,

Dey³

et al. 2018

Trends in Cancer

134

116

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We discuss how small molecule inhibitors of the tryptophan catabolic enzyme indoleamine 2,3-dioxygenase (IDOi) represent a vanguard of new immunometabolic adjuvants to safely enhance the efficacy of cancer immunotherapy, radiotherapy or 'immunogenic' chemotherapy by leveraging responses to tumor neoantigens. IDO activation in cancer supports inflammatory processes that IDOi can re-program to help clear tumors by blunting tumor neovascularization and restoring immunosurveillance. Studies of regulatory and effector pathways illuminate IDO as an inflammatory modifier. Recent work suggests that coordinate targeting of the Trp catabolic enzymes TDO and IDO2 may also safely broaden efficacy. Understanding IDOi as adjuvants to turn immunologically 'cold' tumors 'hot' can seed new concepts in how to improve the efficacy of cancer therapy while limiting its collateral damage.

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“…The crystal structures of the hAChE (PDB ID: 4EY7) 28 and hBChE (PDB ID: 4TPK) 29 were derived from the RCSB Protein Data Bank. Docking studies were carried out using the Discovery Studio 2016 for compound 15b and compound 15j.…”

Section: Molecular Docking Studymentioning

confidence: 99%