Spiro-Oxindole Skeleton Compounds Are Efficient Inhibitors for Indoleamine 2,3-Dioxygenase 1: An Attractive Target for Tumor Immunotherapy
Indoleamine 2,3-dioxygenase 1 (IDO1) is an attractive heme enzyme for its significant function in cancer immunotherapy. Potent IDO1 inhibitors have been discovered for decades, whereas no clinical drugs are used for cancer treatment up to now. With the goal of developing medically valuable IDO inhib...
| Main Authors: | , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2022-04-01
|
| Series: | International Journal of Molecular Sciences |
| Subjects: | |
| Online Access: | https://www.mdpi.com/1422-0067/23/9/4668 |
| _version_ | 1797504655070068736 |
|---|---|
| author | Daojing Yan Jiakun Xu Xiang Wang Jiaxing Zhang Gang Zhao Yingwu Lin Xiangshi Tan |
| author_facet | Daojing Yan Jiakun Xu Xiang Wang Jiaxing Zhang Gang Zhao Yingwu Lin Xiangshi Tan |
| author_sort | Daojing Yan |
| collection | DOAJ |
| description | Indoleamine 2,3-dioxygenase 1 (IDO1) is an attractive heme enzyme for its significant function in cancer immunotherapy. Potent IDO1 inhibitors have been discovered for decades, whereas no clinical drugs are used for cancer treatment up to now. With the goal of developing medically valuable IDO inhibitors, we performed a systematic study of SAR405838 analogs with a spiro-oxindole skeleton in this study. Based on the expression and purification of human IDO1, the inhibitory activity of spiro-oxindole skeleton compounds to IDO1 was evaluated by IC<sub>50</sub> and <i>K</i><sub>i</sub> values. The results demonstrated that inhibitor <b>3</b> exhibited the highest IDO1 inhibitory activity with IC<sub>50</sub> at 7.9 μM among all inhibitors, which is ~six-fold of the positive control (4−PI). Moreover, inhibitor <b>3</b> was found to have the most effective inhibition of IDO1 in MCF-7 cancer cells without toxic effects. Molecular docking analysis revealed that the hydrophobic interaction stabilized the binding of inhibitor <b>3</b> to the IDO1 active site and made an explanation for the uncompetitive mode of inhibitors. Therefore, this study provides valuable insights into the screen of more potent IDO1 inhibitors for cancer immunotherapy. |
| first_indexed | 2024-03-10T04:07:28Z |
| format | Article |
| id | doaj.art-a6ecd4229171436fafd1c301b7f02301 |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-10T04:07:28Z |
| publishDate | 2022-04-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-a6ecd4229171436fafd1c301b7f023012023-11-23T08:20:33ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672022-04-01239466810.3390/ijms23094668Spiro-Oxindole Skeleton Compounds Are Efficient Inhibitors for Indoleamine 2,3-Dioxygenase 1: An Attractive Target for Tumor ImmunotherapyDaojing Yan0Jiakun Xu1Xiang Wang2Jiaxing Zhang3Gang Zhao4Yingwu Lin5Xiangshi Tan6Department of Chemistry, Fudan University, 2005 Songhu Road, Shanghai 200433, ChinaKey Laboratory of Sustainable Development of Polar Fisheries, Ministry of Agriculture and Rural Affairs, Yellow Sea Fisheries Research Institute, Chinese Academy of Fishery Sciences, Laboratory for Marine Drugs and Byproducts of Pilot National Laboratory for Marine Science and Technology, Qingdao 266071, ChinaDepartment of Chemistry, Fudan University, 2005 Songhu Road, Shanghai 200433, ChinaKey Laboratory of Synthetic Chemistry of Natural Substances, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Road, Shanghai 200032, ChinaKey Laboratory of Synthetic Chemistry of Natural Substances, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Road, Shanghai 200032, ChinaSchool of Chemistry and Chemical Engineering, University of South China, Hengyang 421001, ChinaDepartment of Chemistry, Fudan University, 2005 Songhu Road, Shanghai 200433, ChinaIndoleamine 2,3-dioxygenase 1 (IDO1) is an attractive heme enzyme for its significant function in cancer immunotherapy. Potent IDO1 inhibitors have been discovered for decades, whereas no clinical drugs are used for cancer treatment up to now. With the goal of developing medically valuable IDO inhibitors, we performed a systematic study of SAR405838 analogs with a spiro-oxindole skeleton in this study. Based on the expression and purification of human IDO1, the inhibitory activity of spiro-oxindole skeleton compounds to IDO1 was evaluated by IC<sub>50</sub> and <i>K</i><sub>i</sub> values. The results demonstrated that inhibitor <b>3</b> exhibited the highest IDO1 inhibitory activity with IC<sub>50</sub> at 7.9 μM among all inhibitors, which is ~six-fold of the positive control (4−PI). Moreover, inhibitor <b>3</b> was found to have the most effective inhibition of IDO1 in MCF-7 cancer cells without toxic effects. Molecular docking analysis revealed that the hydrophobic interaction stabilized the binding of inhibitor <b>3</b> to the IDO1 active site and made an explanation for the uncompetitive mode of inhibitors. Therefore, this study provides valuable insights into the screen of more potent IDO1 inhibitors for cancer immunotherapy.https://www.mdpi.com/1422-0067/23/9/4668indoleamine 2,3-dioxygenase 1metalloenzymehemeproteininhibitormolecular docking |
| spellingShingle | Daojing Yan Jiakun Xu Xiang Wang Jiaxing Zhang Gang Zhao Yingwu Lin Xiangshi Tan Spiro-Oxindole Skeleton Compounds Are Efficient Inhibitors for Indoleamine 2,3-Dioxygenase 1: An Attractive Target for Tumor Immunotherapy International Journal of Molecular Sciences indoleamine 2,3-dioxygenase 1 metalloenzyme hemeprotein inhibitor molecular docking |
| title | Spiro-Oxindole Skeleton Compounds Are Efficient Inhibitors for Indoleamine 2,3-Dioxygenase 1: An Attractive Target for Tumor Immunotherapy |
| title_full | Spiro-Oxindole Skeleton Compounds Are Efficient Inhibitors for Indoleamine 2,3-Dioxygenase 1: An Attractive Target for Tumor Immunotherapy |
| title_fullStr | Spiro-Oxindole Skeleton Compounds Are Efficient Inhibitors for Indoleamine 2,3-Dioxygenase 1: An Attractive Target for Tumor Immunotherapy |
| title_full_unstemmed | Spiro-Oxindole Skeleton Compounds Are Efficient Inhibitors for Indoleamine 2,3-Dioxygenase 1: An Attractive Target for Tumor Immunotherapy |
| title_short | Spiro-Oxindole Skeleton Compounds Are Efficient Inhibitors for Indoleamine 2,3-Dioxygenase 1: An Attractive Target for Tumor Immunotherapy |
| title_sort | spiro oxindole skeleton compounds are efficient inhibitors for indoleamine 2 3 dioxygenase 1 an attractive target for tumor immunotherapy |
| topic | indoleamine 2,3-dioxygenase 1 metalloenzyme hemeprotein inhibitor molecular docking |
| url | https://www.mdpi.com/1422-0067/23/9/4668 |
| work_keys_str_mv | AT daojingyan spirooxindoleskeletoncompoundsareefficientinhibitorsforindoleamine23dioxygenase1anattractivetargetfortumorimmunotherapy AT jiakunxu spirooxindoleskeletoncompoundsareefficientinhibitorsforindoleamine23dioxygenase1anattractivetargetfortumorimmunotherapy AT xiangwang spirooxindoleskeletoncompoundsareefficientinhibitorsforindoleamine23dioxygenase1anattractivetargetfortumorimmunotherapy AT jiaxingzhang spirooxindoleskeletoncompoundsareefficientinhibitorsforindoleamine23dioxygenase1anattractivetargetfortumorimmunotherapy AT gangzhao spirooxindoleskeletoncompoundsareefficientinhibitorsforindoleamine23dioxygenase1anattractivetargetfortumorimmunotherapy AT yingwulin spirooxindoleskeletoncompoundsareefficientinhibitorsforindoleamine23dioxygenase1anattractivetargetfortumorimmunotherapy AT xiangshitan spirooxindoleskeletoncompoundsareefficientinhibitorsforindoleamine23dioxygenase1anattractivetargetfortumorimmunotherapy |