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Discovery of a potent apo-IDO1 inhibitor for cancer immunotherapy
  • +8
  • Wen Liu,
  • Yi Zou,
  • Kaiming Li,
  • Shushan Ge,
  • Haiqing Zhong,
  • Yuanyuna Wang,
  • Yue Hu,
  • Yisheng Lai,
  • Xianchi Dong,
  • Wenjie Guo,
  • Qiang Xu
Wen Liu
Nanjing University
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Yi Zou
China Pharmaceutical University
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Kaiming Li
Nanjing University
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Shushan Ge
China Pharmaceutical University
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Haiqing Zhong
Nanjing University
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Yuanyuna Wang
Nanjing Medical University
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Yue Hu
Nanjing University
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Yisheng Lai
Nanjing University
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Xianchi Dong
Nanjing University
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Wenjie Guo
Nanjing University
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Qiang Xu
Nanjing University
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Abstract

BACKGROUND AND PURPOSE Pharmacological inhibition of indoleamine-2,3-dioxygenase 1 activity is now considered to be a potential therapeutic tool for cancer therapy. However, the anti-cancer efficacy may be the biggest obstacle for the clinical application of current IDO1 inhibitors. EXPERIMENTAL APPROACHES HeLa cell-based IDO1/Kyn assay as well as recombinant IDO1 activity assay were used to determine the IDO1 enzyme activity. Interaction was examined by UV-visible spectra, isothermal titration calorimetry assay, cellular thermal shift assay and co-crystallization. Mouse colon cancer CT26 syngeneic model and azoxymethane/dextran sulfate sodium induced colon carcinogenesis model were employed to confirm the anti-tumor effect in vivo. KEY RESULTS B37 effectively and specifically inhibited IDO1 by targeting its heme-free conformation (apo-IDO1). By competing with heme for binding to apo-IDO1, B37 potently inhibited IDO1 activity with IC50 for 22 pM in the HeLa cell based assay. X-ray co-crystal structures of the inhibitor-enzyme complexes showed that unlike the hIDO1-BMS-986205 complex, the B37-hIDO1 complex displayed stronger hydrophobic interactions, which enhanced its binding affinity measured with ITC. Accordingly, stronger non-covalent interactions including π stacking and hydrogen bonds formed between B37 and apo-hIDO1 underlay the enthalpy-driven force for B37 to bind the enzyme. This binding model endowed B37 potent anti-tumor efficacy in mouse colon cancer CT26 syngeneic model and azoxymethane/dextran sulfate sodium induced colon carcinogenesis model by activating the host’s immune system. Moreover, the combination of B37 with a VEGFR2 inhibitor apatinib synergistically inhibited tumor growth. CONCLUSIONS AND IMPLICATIONS These results revealed that B37 may serve as a candidate for apo-IDO1 inhibition mediated immunotherapy.