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

Shu Yu Lin, Teng Kuang Yeh, Ching Chuan Kuo, Jen Shin Song, Ming Fu Cheng, Fang Yu Liao, Min Wu Chao, Han Li Huang, Yi Lin Chen, Chun Yu Yang, Mine Hsine Wu, Chia Ling Hsieh, Wenchi Hsiao, Yi Hui Peng, Jian Sung Wu, Li Mei Lin, Manwu Sun, Yu Sheng Chao, Chuan Shih, Su Ying WuShiow Lin Pan, Ming Shiu Hung, Shau Hua Ueng

Research output: Contribution to journalArticle

32 Citations (Scopus)

Abstract

Tryptophan metabolism has been recognized as an important mechanism in immune tolerance. Indoleamine 2,3-dioxygenase plays a key role in local tryptophan metabolism via the kynurenine pathway and has emerged as a therapeutic target for cancer immunotherapy. Our prior study identified phenyl benzenesulfonyl hydrazide 2 as a potent in vitro (though not in vivo) inhibitor of indoleamine 2,3-dioxygenase. Further lead optimization to improve in vitro potencies and pharmacokinetic profiles resulted in N′-(4-bromophenyl)-2-oxo-2,3-dihydro-1H-indole-5-sulfonyl hydrazide 40, which demonstrated 59% oral bioavailability and 73% of tumor growth delay without apparent body weight loss in the murine CT26 syngeneic model, after oral administration of 400 mg/kg. Accordingly, 40, is proposed as a potential drug lead worthy of advanced preclinical evaluation.

Original languageEnglish
Pages (from-to)419-430
Number of pages12
JournalJournal of Medicinal Chemistry
Volume59
Issue number1
DOIs
Publication statusPublished - Jan 14 2016

Fingerprint

Indoleamine-Pyrrole 2,3,-Dioxygenase
Tryptophan
Kynurenine
Immune Tolerance
Immunotherapy
Biological Availability
Oral Administration
Weight Loss
Neoplasms
Pharmacokinetics
Body Weight
Growth
Pharmaceutical Preparations
In Vitro Techniques
Therapeutics
benzenesulfohydrazide
indoline

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

Cite this

Phenyl Benzenesulfonylhydrazides Exhibit Selective Indoleamine 2,3-Dioxygenase Inhibition with Potent in Vivo Pharmacodynamic Activity and Antitumor Efficacy. / Lin, Shu Yu; Yeh, Teng Kuang; Kuo, Ching Chuan; Song, Jen Shin; Cheng, Ming Fu; Liao, Fang Yu; Chao, Min Wu; Huang, Han Li; Chen, Yi Lin; Yang, Chun Yu; Wu, Mine Hsine; Hsieh, Chia Ling; Hsiao, Wenchi; Peng, Yi Hui; Wu, Jian Sung; Lin, Li Mei; Sun, Manwu; Chao, Yu Sheng; Shih, Chuan; Wu, Su Ying; Pan, Shiow Lin; Hung, Ming Shiu; Ueng, Shau Hua.

In: Journal of Medicinal Chemistry, Vol. 59, No. 1, 14.01.2016, p. 419-430.

Research output: Contribution to journalArticle

Lin, SY, Yeh, TK, Kuo, CC, Song, JS, Cheng, MF, Liao, FY, Chao, MW, Huang, HL, Chen, YL, Yang, CY, Wu, MH, Hsieh, CL, Hsiao, W, Peng, YH, Wu, JS, Lin, LM, Sun, M, Chao, YS, Shih, C, Wu, SY, Pan, SL, Hung, MS & Ueng, SH 2016, 'Phenyl Benzenesulfonylhydrazides Exhibit Selective Indoleamine 2,3-Dioxygenase Inhibition with Potent in Vivo Pharmacodynamic Activity and Antitumor Efficacy', Journal of Medicinal Chemistry, vol. 59, no. 1, pp. 419-430. https://doi.org/10.1021/acs.jmedchem.5b01640
Lin, Shu Yu ; Yeh, Teng Kuang ; Kuo, Ching Chuan ; Song, Jen Shin ; Cheng, Ming Fu ; Liao, Fang Yu ; Chao, Min Wu ; Huang, Han Li ; Chen, Yi Lin ; Yang, Chun Yu ; Wu, Mine Hsine ; Hsieh, Chia Ling ; Hsiao, Wenchi ; Peng, Yi Hui ; Wu, Jian Sung ; Lin, Li Mei ; Sun, Manwu ; Chao, Yu Sheng ; Shih, Chuan ; Wu, Su Ying ; Pan, Shiow Lin ; Hung, Ming Shiu ; Ueng, Shau Hua. / Phenyl Benzenesulfonylhydrazides Exhibit Selective Indoleamine 2,3-Dioxygenase Inhibition with Potent in Vivo Pharmacodynamic Activity and Antitumor Efficacy. In: Journal of Medicinal Chemistry. 2016 ; Vol. 59, No. 1. pp. 419-430.
@article{484e14120ebf4921b4fe6a33c0b0926f,
title = "Phenyl Benzenesulfonylhydrazides Exhibit Selective Indoleamine 2,3-Dioxygenase Inhibition with Potent in Vivo Pharmacodynamic Activity and Antitumor Efficacy",
abstract = "Tryptophan metabolism has been recognized as an important mechanism in immune tolerance. Indoleamine 2,3-dioxygenase plays a key role in local tryptophan metabolism via the kynurenine pathway and has emerged as a therapeutic target for cancer immunotherapy. Our prior study identified phenyl benzenesulfonyl hydrazide 2 as a potent in vitro (though not in vivo) inhibitor of indoleamine 2,3-dioxygenase. Further lead optimization to improve in vitro potencies and pharmacokinetic profiles resulted in N′-(4-bromophenyl)-2-oxo-2,3-dihydro-1H-indole-5-sulfonyl hydrazide 40, which demonstrated 59{\%} oral bioavailability and 73{\%} of tumor growth delay without apparent body weight loss in the murine CT26 syngeneic model, after oral administration of 400 mg/kg. Accordingly, 40, is proposed as a potential drug lead worthy of advanced preclinical evaluation.",
author = "Lin, {Shu Yu} and Yeh, {Teng Kuang} and Kuo, {Ching Chuan} and Song, {Jen Shin} and Cheng, {Ming Fu} and Liao, {Fang Yu} and Chao, {Min Wu} and Huang, {Han Li} and Chen, {Yi Lin} and Yang, {Chun Yu} and Wu, {Mine Hsine} and Hsieh, {Chia Ling} and Wenchi Hsiao and Peng, {Yi Hui} and Wu, {Jian Sung} and Lin, {Li Mei} and Manwu Sun and Chao, {Yu Sheng} and Chuan Shih and Wu, {Su Ying} and Pan, {Shiow Lin} and Hung, {Ming Shiu} and Ueng, {Shau Hua}",
year = "2016",
month = "1",
day = "14",
doi = "10.1021/acs.jmedchem.5b01640",
language = "English",
volume = "59",
pages = "419--430",
journal = "Journal of Medicinal Chemistry",
issn = "0022-2623",
publisher = "American Chemical Society",
number = "1",

}

TY - JOUR

T1 - Phenyl Benzenesulfonylhydrazides Exhibit Selective Indoleamine 2,3-Dioxygenase Inhibition with Potent in Vivo Pharmacodynamic Activity and Antitumor Efficacy

AU - Lin, Shu Yu

AU - Yeh, Teng Kuang

AU - Kuo, Ching Chuan

AU - Song, Jen Shin

AU - Cheng, Ming Fu

AU - Liao, Fang Yu

AU - Chao, Min Wu

AU - Huang, Han Li

AU - Chen, Yi Lin

AU - Yang, Chun Yu

AU - Wu, Mine Hsine

AU - Hsieh, Chia Ling

AU - Hsiao, Wenchi

AU - Peng, Yi Hui

AU - Wu, Jian Sung

AU - Lin, Li Mei

AU - Sun, Manwu

AU - Chao, Yu Sheng

AU - Shih, Chuan

AU - Wu, Su Ying

AU - Pan, Shiow Lin

AU - Hung, Ming Shiu

AU - Ueng, Shau Hua

PY - 2016/1/14

Y1 - 2016/1/14

N2 - Tryptophan metabolism has been recognized as an important mechanism in immune tolerance. Indoleamine 2,3-dioxygenase plays a key role in local tryptophan metabolism via the kynurenine pathway and has emerged as a therapeutic target for cancer immunotherapy. Our prior study identified phenyl benzenesulfonyl hydrazide 2 as a potent in vitro (though not in vivo) inhibitor of indoleamine 2,3-dioxygenase. Further lead optimization to improve in vitro potencies and pharmacokinetic profiles resulted in N′-(4-bromophenyl)-2-oxo-2,3-dihydro-1H-indole-5-sulfonyl hydrazide 40, which demonstrated 59% oral bioavailability and 73% of tumor growth delay without apparent body weight loss in the murine CT26 syngeneic model, after oral administration of 400 mg/kg. Accordingly, 40, is proposed as a potential drug lead worthy of advanced preclinical evaluation.

AB - Tryptophan metabolism has been recognized as an important mechanism in immune tolerance. Indoleamine 2,3-dioxygenase plays a key role in local tryptophan metabolism via the kynurenine pathway and has emerged as a therapeutic target for cancer immunotherapy. Our prior study identified phenyl benzenesulfonyl hydrazide 2 as a potent in vitro (though not in vivo) inhibitor of indoleamine 2,3-dioxygenase. Further lead optimization to improve in vitro potencies and pharmacokinetic profiles resulted in N′-(4-bromophenyl)-2-oxo-2,3-dihydro-1H-indole-5-sulfonyl hydrazide 40, which demonstrated 59% oral bioavailability and 73% of tumor growth delay without apparent body weight loss in the murine CT26 syngeneic model, after oral administration of 400 mg/kg. Accordingly, 40, is proposed as a potential drug lead worthy of advanced preclinical evaluation.

UR - http://www.scopus.com/inward/record.url?scp=84955140232&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84955140232&partnerID=8YFLogxK

U2 - 10.1021/acs.jmedchem.5b01640

DO - 10.1021/acs.jmedchem.5b01640

M3 - Article

C2 - 26653033

AN - SCOPUS:84955140232

VL - 59

SP - 419

EP - 430

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

SN - 0022-2623

IS - 1

ER -