Apo-Form Selective Inhibition of IDO for Tumor Immunotherapy.

Abstract

The pharmacological inhibition of IDO1 is considered an effective therapeutic approach for cancer treatment. However, the inadequate response of existing holo-IDO1 inhibitors and unclear biomarkers available in clinical practice limit the possibility of developing efficacious IDO1 inhibitors. In the current study, we aimed to elucidate the activity and mechanism of a potent 1H-pyrrole-2-carboxylic acid derivative (B37) targeting apo-IDO1 and to determine its role in tumor therapy. By competing with heme for binding to apo-IDO1, B37 potently inhibited IDO1 activity, with an IC50 of 22 pM assessed using a HeLa cell-based assay. The x-ray cocrystal structure of the inhibitor-enzyme complex showed that the B37-human IDO1 complex has strong hydrophobic interactions, which enhances its binding affinity, determined using isothermal titration calorimetry. Stronger noncovalent interactions, including π stacking and hydrogen bonds formed between B37 and apo-human IDO1, underlay the enthalpy-driven force for B37 for binding to the enzyme. These binding properties endowed B37 with potent antitumor efficacy, which was confirmed in a mouse colon cancer CT26 syngeneic model in BALB/c mice and in an azoxymethane/dextran sulfate sodium-induced colon carcinogenesis model in C57BL/6 mice by activating the host immune system. Moreover, the combination of B37 and anti-PD1 Ab synergistically inhibited tumor growth. These results suggested that B37 may serve as a unique candidate for apo-IDO1 inhibition-mediated tumor immunotherapy.

• Authors: Wen Liu, Yi Zou, Kaiming Li, Haiqing Zhong, Longbo Yu, Shushan Ge, Yisheng Lai, Xianchi Dong, Qiang Xu, Wenjie Guo
• Journal: Journal of immunology (Baltimore, Md. : 1950) (J Immunol) Vol. 209 Issue 1 Pg. 180-191 (07 01 2022) ISSN: 1550-6606 [Electronic] United States
• PMID: 35725271 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2022 by The American Association of Immunologists, Inc.

Chemical References

• Enzyme Inhibitors
• Indoleamine-Pyrrole 2,3,-Dioxygenase

Topics

• Animals
• Enzyme Inhibitors (pharmacology)
• HeLa Cells
• Humans
• Immunotherapy
• Indoleamine-Pyrrole 2,3,-Dioxygenase (metabolism)
• Mice
• Mice, Inbred BALB C
• Mice, Inbred C57BL