Characterization of novel inhibition of indoleamine 2,3-dioxygenase by targeting its apo form.

Ortiz-Meoz, R. F.; Wang, L.; Matico, R.; Rutkowska, A.; De la Rosa, M.; Bedard, S.; Midgett, R.; Strohmer, K.; Thomson, D.; Zhang, C.; Guss, J.; Totoritis, R.; Consler, T.; Campobasso, N.; Taylor, D.; Lewis, T.; Weaver, K.; Seal, J.; Dunham, R.; Kazmierski, W.; Favre, D.; Bergamini, G.; Shewchuk, L.; Rendina, A.; Zhang, G.

doi:10.1101/324947

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bioRxiv · 10.1101/324947

Characterization of novel inhibition of indoleamine 2,3-dioxygenase by targeting its apo form.

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Abstract

Indoleamine-2,3-dioxygenase 1 (IDO1) is a heme-containing enzyme that catalyzes the rate-limiting step in the kynurenine pathway of tryptophan (TRP) metabolism. As an inflammation-induced immunoregulatory enzyme, pharmacological inhibition of IDO1 activity is currently being pursued as a potential therapeutic tool for the treatment of cancer and other disease states. As such, a detailed understanding of the mechanism of action of established and novel IDO1 inhibitors remains of great interest. Comparison of a newly-developed IDO1 inhibitor (GSK5628) to the existing best-in-class compound, epacadostat (Incyte), allows us to report on a unique inhibition mechanism for IDO1. Here, we demonstrate that GSK5628 inhibits IDO1 by competing with heme for binding to a heme-free conformation of the enzyme (apo-IDO1) while epacadostat coordinates its binding with the iron atom of the IDO1 heme cofactor. Comparison of these two compounds in cellular systems reveals a long-lasting inhibitory effect of GSK5628, undescribed for other known IDO1 inhibitors. Detailed characterization of this apo-binding mechanism for IDO1 inhibition may help design superior inhibitors or may confer a unique competitive advantage over other IDO1 inhibitors vis-a-vis specificity and pharmacokinetic parameters.

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Ortiz-Meoz, R. F., Wang, L., Matico, R., Rutkowska, A., De la Rosa, M., Bedard, S., Midgett, R., Strohmer, K., Thomson, D., Zhang, C., Guss, J., Totoritis, R., Consler, T., Campobasso, N., Taylor, D., Lewis, T., Weaver, K., Seal, J., Dunham, R., Kazmierski, W., Favre, D., Bergamini, G., Shewchuk, L., Rendina, A., Zhang, G.. 2018-05-17. Characterization of novel inhibition of indoleamine 2,3-dioxygenase by targeting its apo form.. https://doi.org/10.1101/324947

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