Abstract
There is great interest in developing small molecules agents capable of reversing tumor immune escape to restore the body’s immune system. As an immunosuppressive enzyme, indoleamine 2,3-dioxygenase 1 (IDO-1) is considered a promising target for oncology immunotherapy. Currently, none of IDO-1 inhibitors have been launched for clinical practice yet. Thus, the discovery of new IDO-1 inhibitors is still in great demand. Herein, a series of diverse ortho-naphthaquinone containing natural product derivatives were synthesized as novel IDO-1 inhibitors. Among them, 1-ene-3-ketone-17-hydroxyl derivative 12 exhibited significantly improved enzymatic and cellular inhibitory activity against IDO-1 when compared to initial lead compounds. Besides, the molecular docking study disclosed that the two most potent compounds 11 and 12 have more interactions within the binding pocket of IDO-1 via hydrogen-bonding, which may account for their higher IDO-1 inhibitory activity.
Highlights
Immune checkpoint blockades such as anti-PD-L1, anti-PD-1 [1], and anti-CTLA4 [2] have demonstrated attractive therapeutic effects in multiple clinical trials, this new modality often suffers from a low response rate at least due to the immune escape developed by tumors [3]
This reaction leads to a local decrease of L-Trp concentration, and generates a variety of catabolic products, which both account for the immunosuppressive effects of IDO-1 [6,7,8,9]
We disclosed our effort on the chemical o-naphthaquinone scaffold for IDO-1 inhibition
Summary
Immune checkpoint blockades such as anti-PD-L1 (programmed cell death-ligand 1), anti-PD-1 (programmed cell death protein 1) [1], and anti-CTLA4 (cytotoxic T-lymphocyte-associated protein 4) [2] have demonstrated attractive therapeutic effects in multiple clinical trials, this new modality often suffers from a low response rate at least due to the immune escape developed by tumors [3]. Indoleamine 2,3-dioxygenase 1 (IDO-1) is a monomeric heme-containing enzyme found in nonhepatic human tissues [4]. It catalyzes the oxidative cleavage of the pyrrole ring of L-tryptophan (L-Trp) in the first and rate-limiting step of the kynurenine pathway to produce N-formylkynurenine [5]. This reaction leads to a local decrease of L-Trp concentration, and generates a variety of catabolic products, which both account for the immunosuppressive effects of IDO-1 [6,7,8,9].
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