Discovery of Potent and Orally Available Bicyclo[1.1.1]pentane-Derived Indoleamine-2,3-dioxygenase 1 (IDO1) Inhibitors

Overview

Journal ACS Med Chem Lett

Publisher American Chemical Society

Specialty Chemistry

Date 2020 Aug 25

PMID 32832022

Citations 21

Authors

Qinglin Pu

Hongjun Zhang

Liangqin Guo

Mangeng Cheng

Amy C Doty

Heidi Ferguson

Xavier Fradera

Charles A Lesburg

Meredeth A McGowan

J Richard Miller

Prasanthi Geda

Xuelei Song

Karin Otte

Nunzio Sciammetta

Nicolas Solban

Wensheng Yu

David L Sloman

Hua Zhou

Alfred Lammens

Lars Neumann

David Jonathan Bennett

Alexander Pasternak

Yongxin Han

Affiliations

Soon will be listed here.

Abstract

Indoleamine-2,3-dioxygenase 1 (IDO1) inhibition and its combination with immune checkpoint inhibitors like have drawn considerable attention from both academia and the pharmaceutical industry. Here, we describe the discovery of a novel class of highly potent IDO1 heme-displacing inhibitors featuring a unique bicyclo[1.1.1]pentane motif. Compound , evolving from an ALIS (automated ligand identification system) hit, exhibited excellent potency but lacked the desired pharmacokinetic profile due to extensive amide hydrolysis of the benzamide moiety. Replacing the central phenyl ring in with a bicyclo[1.1.1]pentane bioisostere effectively circumvented the amide hydrolysis issue, resulting in the discovery of compound with a favorable overall profile such as excellent potency, selectivity, pharmacokinetics, and a low predicted human dose.

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References

Lewis-Ballester A, Pham K, Batabyal D, Karkashon S, Bonanno J, Poulos T . Structural insights into substrate and inhibitor binding sites in human indoleamine 2,3-dioxygenase 1. Nat Commun. 2017; 8(1):1693. PMC: 5700043. DOI: 10.1038/s41467-017-01725-8. View

Ricciuti B, Leonardi G, Puccetti P, Fallarino F, Bianconi V, Sahebkar A . Targeting indoleamine-2,3-dioxygenase in cancer: Scientific rationale and clinical evidence. Pharmacol Ther. 2018; 196:105-116. DOI: 10.1016/j.pharmthera.2018.12.004. View

Adams J, Smothers J, Srinivasan R, Hoos A . Big opportunities for small molecules in immuno-oncology. Nat Rev Drug Discov. 2015; 14(9):603-22. DOI: 10.1038/nrd4596. View

Wang X, Sun S, Dong Q, Wu X, Tang W, Xing Y . Recent advances in the discovery of indoleamine 2,3-dioxygenase 1 (IDO1) inhibitors. Medchemcomm. 2020; 10(10):1740-1754. PMC: 7003884. DOI: 10.1039/c9md00208a. View

Locke G, Bernhard S, Senge M . Nonconjugated Hydrocarbons as Rigid-Linear Motifs: Isosteres for Material Sciences and Bioorganic and Medicinal Chemistry. Chemistry. 2018; 25(18):4590-4647. DOI: 10.1002/chem.201804225. View

Annis D, Nickbarg E, Yang X, Ziebell M, Whitehurst C . Affinity selection-mass spectrometry screening techniques for small molecule drug discovery. Curr Opin Chem Biol. 2007; 11(5):518-26. DOI: 10.1016/j.cbpa.2007.07.011. View

Mykhailiuk P . Saturated bioisosteres of benzene: where to go next?. Org Biomol Chem. 2019; 17(11):2839-2849. DOI: 10.1039/c8ob02812e. View

Nelp M, Kates P, Hunt J, Newitt J, Balog A, Maley D . Immune-modulating enzyme indoleamine 2,3-dioxygenase is effectively inhibited by targeting its apo-form. Proc Natl Acad Sci U S A. 2018; 115(13):3249-3254. PMC: 5879690. DOI: 10.1073/pnas.1719190115. View

Tang J, Yu J, Hubbard-Lucey V, Neftelinov S, Hodge J, Lin Y . Trial watch: The clinical trial landscape for PD1/PDL1 immune checkpoint inhibitors. Nat Rev Drug Discov. 2018; 17(12):854-855. DOI: 10.1038/nrd.2018.210. View

10.

Brochez L, Chevolet I, Kruse V . The rationale of indoleamine 2,3-dioxygenase inhibition for cancer therapy. Eur J Cancer. 2017; 76:167-182. DOI: 10.1016/j.ejca.2017.01.011. View

11.

Stepan A, Subramanyam C, Efremov I, Dutra J, OSullivan T, DiRico K . Application of the bicyclo[1.1.1]pentane motif as a nonclassical phenyl ring bioisostere in the design of a potent and orally active γ-secretase inhibitor. J Med Chem. 2012; 55(7):3414-24. DOI: 10.1021/jm300094u. View

12.

Komiya T, Huang C . Updates in the Clinical Development of Epacadostat and Other Indoleamine 2,3-Dioxygenase 1 Inhibitors (IDO1) for Human Cancers. Front Oncol. 2018; 8:423. PMC: 6180183. DOI: 10.3389/fonc.2018.00423. View

13.

Zhang H, Liu K, Pu Q, Achab A, Ardolino M, Cheng M . Discovery of Amino-cyclobutarene-derived Indoleamine-2,3-dioxygenase 1 (IDO1) Inhibitors for Cancer Immunotherapy. ACS Med Chem Lett. 2019; 10(11):1530-1536. PMC: 6862341. DOI: 10.1021/acsmedchemlett.9b00344. View

14.

Whitehurst C, Yao Z, Murphy D, Zhang M, Taremi S, Wojcik L . Application of affinity selection-mass spectrometry assays to purification and affinity-based screening of the chemokine receptor CXCR4. Comb Chem High Throughput Screen. 2012; 15(6):473-85. DOI: 10.2174/138620712800563945. View

15.

Muller A, Manfredi M, Zakharia Y, Prendergast G . Inhibiting IDO pathways to treat cancer: lessons from the ECHO-301 trial and beyond. Semin Immunopathol. 2018; 41(1):41-48. DOI: 10.1007/s00281-018-0702-0. View

16.

Long G, Dummer R, Hamid O, Gajewski T, Caglevic C, Dalle S . Epacadostat plus pembrolizumab versus placebo plus pembrolizumab in patients with unresectable or metastatic melanoma (ECHO-301/KEYNOTE-252): a phase 3, randomised, double-blind study. Lancet Oncol. 2019; 20(8):1083-1097. DOI: 10.1016/S1470-2045(19)30274-8. View

17.

Alsaab H, Sau S, Alzhrani R, Tatiparti K, Bhise K, Kashaw S . PD-1 and PD-L1 Checkpoint Signaling Inhibition for Cancer Immunotherapy: Mechanism, Combinations, and Clinical Outcome. Front Pharmacol. 2017; 8:561. PMC: 5572324. DOI: 10.3389/fphar.2017.00561. View

18.

Platten M, Wick W, Van den Eynde B . Tryptophan catabolism in cancer: beyond IDO and tryptophan depletion. Cancer Res. 2012; 72(21):5435-40. DOI: 10.1158/0008-5472.CAN-12-0569. View

19.

Rohrig U, Majjigapu S, Vogel P, Zoete V, Michielin O . Challenges in the Discovery of Indoleamine 2,3-Dioxygenase 1 (IDO1) Inhibitors. J Med Chem. 2015; 58(24):9421-37. DOI: 10.1021/acs.jmedchem.5b00326. View

20.

Prendergast G, Smith C, Thomas S, Mandik-Nayak L, Laury-Kleintop L, Metz R . Indoleamine 2,3-dioxygenase pathways of pathogenic inflammation and immune escape in cancer. Cancer Immunol Immunother. 2014; 63(7):721-35. PMC: 4384696. DOI: 10.1007/s00262-014-1549-4. View