Discovery and structure–activity relationships of phenyl benzenesulfonylhydrazides as novel indoleamine 2,3-dioxygenase inhibitors

Cheng, Ming‐Chuan; Hung, Ming‐Shiu; Song, Jen‐Shin; Lin, Shu‐Yu; Liao, Fang-Yu; Wu, Mine-Hsine; Hsiao, Wen-Chi; Hsieh, Chia‐Ling; Wu, Jane-Yii; Chao, Yu‐Sheng; Shih, Chuan; Wu, Su-Ying; Ueng, Shau‐Hua

doi:10.1016/j.bmcl.2014.05.084

Cited by 48 publications

(39 citation statements)

References 25 publications

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“…To the best of our knowledge, there are only two other structural classes reported to date with similar nanomolar-level cell-based potency 19,32,33,46 and both of these have been developed for clinical evaluation.…”

Section: Resultsmentioning

confidence: 99%

O-alkylhydroxylamines as rationally-designed mechanism-based inhibitors of indoleamine 2,3-dioxygenase-1

Malachowski

Winters

DuHadaway

et al. 2016

European Journal of Medicinal Chemistry

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Indoleamine 2,3-dioxygenase-1 (IDO1) is a promising therapeutic target for the treatment of cancer, chronic viral infections, and other diseases characterized by pathological immune suppression. Recently important advances have been made in understanding IDO1’s catalytic mechanism. Although much remains to be discovered, there is strong evidence that the mechanism proceeds through a heme-iron bound alkylperoxy transition or intermediate state. Accordingly, we explored stable structural mimics of the alkylperoxy species and provide evidence that such structures do mimic the alkylperoxy transition or intermediate state. We discovered that O-benzylhydroxylamine, a commercially available compound, is a potent sub-micromolar inhibitor of IDO1. Structure-activity studies of over forty derivatives of O-benzylhydroxylamine led to further improvement in inhibitor potency, particularly with the addition of halogen atoms to the meta position of the aromatic ring. The most potent derivatives and the lead, O-benzylhydroxylamine, have high ligand efficiency values, which are considered an important criterion for successful drug development. Notably, two of the most potent compounds demonstrated nanomolar-level cell-based potency and limited toxicity. The combination of the simplicity of the structures of these compounds and their excellent cellular activity makes them quite attractive for biological exploration of IDO1 function and antitumor therapeutic applications.

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Section: Resultsmentioning

confidence: 99%

O-alkylhydroxylamines as rationally-designed mechanism-based inhibitors of indoleamine 2,3-dioxygenase-1

Malachowski

Winters

DuHadaway

et al. 2016

European Journal of Medicinal Chemistry

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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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“…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

146

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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Discovery and structure–activity relationships of phenyl benzenesulfonylhydrazides as novel indoleamine 2,3-dioxygenase inhibitors

Cited by 48 publications

References 25 publications

O-alkylhydroxylamines as rationally-designed mechanism-based inhibitors of indoleamine 2,3-dioxygenase-1

O-alkylhydroxylamines as rationally-designed mechanism-based inhibitors of indoleamine 2,3-dioxygenase-1

Discovery of IDO1 Inhibitors: From Bench to Bedside

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

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