Strategic Incorporation of Polarity in Heme-Displacing Inhibitors of Indoleamine-2,3-dioxygenase-1 (IDO1)
Catherine White
1
,
Meredeth A Mcgowan
1
,
Hua Zhou
1
,
Nunzio Sciammetta
1
,
Xavier Fradera
1
,
Jongwon Lim
1
,
Elizabeth Joshi
1
,
Christine Andrews
1
,
Elliott Nickbarg
1
,
Phillip Cowley
1
,
Sarah Trewick
1
,
Martin Augustin
2
,
Konstanze Von Koenig
2
,
Charles A. Lesburg
1
,
Karin Otte
1
,
Ian Knemeyer
1
,
Hyun Woo
1
,
Wensheng Yu
1
,
Mangeng Cheng
1
,
Peter Spacciapoli
1
,
Prasanthi Geda
1
,
Xuelei Song
1
,
Nadya Smotrov
1
,
Patrick Curran
1
,
Mee Ra Heo
1
,
Pravien Abeywickrema
1
,
J Richard Miller
1
,
Yongxin Han
1
1
Department of Chemistry, Computational and Structural Chemistry, Pharmacokinetics, Pharmacodynamics & Drug Metabolism, Quantitative Biosciences, Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, Massachusetts 02115, United States.
|
2
Proteros biostructures GmbH, 82152 Martinsried, Germany
|
Publication type: Journal Article
Publication date: 2020-03-10
scimago Q1
wos Q2
SJR: 0.805
CiteScore: 5.8
Impact factor: 4.0
ISSN: 19485875
PubMed ID:
32292563
Organic Chemistry
Drug Discovery
Biochemistry
Abstract
Indoleamine-2,3-dioxygenase-1 (IDO1) has emerged as a target of significant interest to the field of cancer immunotherapy, as the upregulation of IDO1 in certain cancers has been linked to host immune evasion and poor prognosis for patients. In particular, IDO1 inhibition is of interest as a combination therapy with immune checkpoint inhibition. Through an Automated Ligand Identification System (ALIS) screen, a diamide class of compounds was identified as a promising lead for the inhibition of IDO1. While hit 1 possessed attractive cell-based potency, it suffered from a significant right-shift in a whole blood assay, poor solubility, and poor pharmacokinetic properties. Through a physicochemical property-based approach, including a focus on lowering AlogP98 via the strategic introduction of polar substitution, compound 13 was identified bearing a pyridyl oxetane core. Compound 13 demonstrated improved whole blood potency and solubility, and an improved pharmacokinetic profile resulting in a low predicted human dose.
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32
Total citations:
32
Citations from 2024:
5
(15.63%)
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MLA
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GOST
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White C. et al. Strategic Incorporation of Polarity in Heme-Displacing Inhibitors of Indoleamine-2,3-dioxygenase-1 (IDO1) // ACS Medicinal Chemistry Letters. 2020. Vol. 11. No. 4. pp. 550-557.
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White C., Mcgowan M. A., Zhou H., Sciammetta N., Fradera X., Lim J., Joshi E., Andrews C., Nickbarg E., Cowley P., Trewick S., Augustin M., Von Koenig K., Lesburg C. A., Otte K., Knemeyer I., Woo H., Yu W., Cheng M., Spacciapoli P., Geda P., Song X., Smotrov N., Curran P., Heo M. R., Abeywickrema P., Miller J. R., Bennett D. J., Han Y. Strategic Incorporation of Polarity in Heme-Displacing Inhibitors of Indoleamine-2,3-dioxygenase-1 (IDO1) // ACS Medicinal Chemistry Letters. 2020. Vol. 11. No. 4. pp. 550-557.
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RIS
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TY - JOUR
DO - 10.1021/acsmedchemlett.0c00010
UR - https://doi.org/10.1021/acsmedchemlett.0c00010
TI - Strategic Incorporation of Polarity in Heme-Displacing Inhibitors of Indoleamine-2,3-dioxygenase-1 (IDO1)
T2 - ACS Medicinal Chemistry Letters
AU - White, Catherine
AU - Mcgowan, Meredeth A
AU - Zhou, Hua
AU - Sciammetta, Nunzio
AU - Fradera, Xavier
AU - Lim, Jongwon
AU - Joshi, Elizabeth
AU - Andrews, Christine
AU - Nickbarg, Elliott
AU - Cowley, Phillip
AU - Trewick, Sarah
AU - Augustin, Martin
AU - Von Koenig, Konstanze
AU - Lesburg, Charles A.
AU - Otte, Karin
AU - Knemeyer, Ian
AU - Woo, Hyun
AU - Yu, Wensheng
AU - Cheng, Mangeng
AU - Spacciapoli, Peter
AU - Geda, Prasanthi
AU - Song, Xuelei
AU - Smotrov, Nadya
AU - Curran, Patrick
AU - Heo, Mee Ra
AU - Abeywickrema, Pravien
AU - Miller, J Richard
AU - Bennett, David Jonathan
AU - Han, Yongxin
PY - 2020
DA - 2020/03/10
PB - American Chemical Society (ACS)
SP - 550-557
IS - 4
VL - 11
PMID - 32292563
SN - 1948-5875
ER -
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@article{2020_White,
author = {Catherine White and Meredeth A Mcgowan and Hua Zhou and Nunzio Sciammetta and Xavier Fradera and Jongwon Lim and Elizabeth Joshi and Christine Andrews and Elliott Nickbarg and Phillip Cowley and Sarah Trewick and Martin Augustin and Konstanze Von Koenig and Charles A. Lesburg and Karin Otte and Ian Knemeyer and Hyun Woo and Wensheng Yu and Mangeng Cheng and Peter Spacciapoli and Prasanthi Geda and Xuelei Song and Nadya Smotrov and Patrick Curran and Mee Ra Heo and Pravien Abeywickrema and J Richard Miller and David Jonathan Bennett and Yongxin Han},
title = {Strategic Incorporation of Polarity in Heme-Displacing Inhibitors of Indoleamine-2,3-dioxygenase-1 (IDO1)},
journal = {ACS Medicinal Chemistry Letters},
year = {2020},
volume = {11},
publisher = {American Chemical Society (ACS)},
month = {mar},
url = {https://doi.org/10.1021/acsmedchemlett.0c00010},
number = {4},
pages = {550--557},
doi = {10.1021/acsmedchemlett.0c00010}
}
Cite this
MLA
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White, Catherine, et al. “Strategic Incorporation of Polarity in Heme-Displacing Inhibitors of Indoleamine-2,3-dioxygenase-1 (IDO1).” ACS Medicinal Chemistry Letters, vol. 11, no. 4, Mar. 2020, pp. 550-557. https://doi.org/10.1021/acsmedchemlett.0c00010.