Discovery of Amino-cyclobutarene-derived Indoleamine-2,3-dioxygenase 1 (IDO1) Inhibitors for Cancer Immunotherapy
| Autor: | Theodore A. Martinot, Xavier Fradera, Meredeth A. McGowan, Wensheng Yu, Heidi Ferguson, Purakattle J Biju, H. Zhou, Nicolas Solban, Qinglin Pu, Yongxin Han, Xiao Wang, Kun Liu, Ravi Kurukulasuriya, Yu-hong Lam, Abdelghani Achab, Karin M. Otte, Michael J. Ardolino, Amy C. Doty, Charles A. Lesburg, J. Richard Miller, Yongqi Deng, Mangeng Cheng, Hongjun Zhang, Ian Knemeyer, Nunzio Sciammetta, David Jonathan Bennett |
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| Rok vydání: | 2019 |
| Předmět: |
Standard of care
Combination therapy 010405 organic chemistry Chemistry Drug candidate medicine.medical_treatment Immune checkpoint inhibitors Organic Chemistry Computational biology Metabolic stability 01 natural sciences Biochemistry 0104 chemical sciences 010404 medicinal & biomolecular chemistry Overall response rate Cancer immunotherapy Drug Discovery medicine Indoleamine 2 3-dioxygenase |
| Zdroj: | ACS Med Chem Lett |
| ISSN: | 1948-5875 |
| DOI: | 10.1021/acsmedchemlett.9b00344 |
| Popis: | [Image: see text] Checkpoint inhibitors have demonstrated unprecedented efficacy and are evolving to become standard of care for certain types of cancers. However, low overall response rates often hamper the broad utility and potential of these breakthrough therapies. Combination therapy strategies are currently under intensive investigation in the clinic, including the combination of PD-1/PD-L1 agents with IDO1 inhibitors. Here, we report the discovery of a class of IDO1 heme-binding inhibitors featuring a unique amino-cyclobutarene motif, which was discovered through SBDD from a known and weakly active inhibitor. Subsequent optimization efforts focused on improving metabolic stability and were greatly accelerated by utilizing a robust S(N)Ar reaction of a facile nitro-furazan intermediate to quickly explore different polar side chains. As a culmination of these efforts, compound 16 was identified and demonstrated a favorable overall profile with superior potency and selectivity. Extensive studies confirmed the chemical stability and drug-like properties of compound 16, rendering it a potential drug candidate. |
| Databáze: | OpenAIRE |
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