Identification of a Novel Pseudo‐Natural Product Type IV IDO1 Inhibitor Chemotype

Abstract

Natural product (NP)-inspired design principles provide invaluable guidance for bioactive compound discovery. Pseudo-natural products (PNPs) are de novo combinations of NP fragments to target biologically relevant chemical space not covered by NPs. We describe the design and synthesis of apoxidoles, a novel pseudo-NP class, whereby indole-and tetrahydropyridine fragments are linked in monopodal connectivity not found in nature. Apoxidoles are efficiently accessible by an enantioselective [4+2] annulation reaction. Biological evaluation revealed that apoxidoles define a new potent type IV inhibitor chemotype of indoleamine 2,3-dioxygenase 1 (IDO1), a heme-containing enzyme considered a target for the treatment of neurodegeneration, autoimmunity and cancer. Apoxidoles target apo-IDO1, prevent heme binding and induce unique amino acid positioning as revealed by crystal structure analysis. Novel type IV apo-IDO1 inhibitors are in high demand, and apoxidoles may provide new opportunities for chemical biology and medicinal chemistry research.

Complexity‐to‐Diversity and Pseudo‐Natural Product Strategies as Powerful Platforms for Deciphering Next‐Generation Therapeutics

“…Interestingly, its enantiomer, the apoxidole ( R,S ) 115 b was not active against IDO1. Cell‐based investigations confirmed that apoxidole 115 a inhibits IDO1 by competing with heme via binding to a heme‐free conformation of the apo‐IDO1 [116] …”

“…Cell-based investigations confirmed that apoxidole 115 a inhibits IDO1 by competing with heme via binding to a hemefree conformation of the apo-IDO1. [116]…”

Prediction of IDO1 Inhibitors by a Fingerprint‐Based Stacking Ensemble Model Named IDO1Stack

“…Then we stratified the data according to an 8 : 2 ratio into a training set and a test set. Moreover, the external validation set included 222 compounds collected from multiple literature [16][17][18][19][20][21][22][23][24][25][26][27][28][29][30] in 2021-2023 in order to evaluate the generalization performance of the model. The number of IDO1 inhibitors and noninhibitors in each data set was listed in Table 1.…”

“…In this work, inhibitor data were collected from the PubChem database [33] and several literature in 2021-2023, [16][17][18][19][20][21][22][23][24][25][26][27][28][29][30] essentially covering the currently known IDO1 inhibitors. For compounds collected from the PubChem database, we first removed compounds with no activity values or no literature support, and ensured that the remaining compounds were assigned one of the following activity value types: IC 50 , EC 50 , K d , K i .…”

Synthetic Matching of Complex Monoterpene Indole Alkaloid Chemical Space

“…[7][8][9] According to this design principle, NPs are deconstructed into fragments and recombined in arrangements that are not found in Nature to afford scaffolds that are NP-like but are not accessible via known biosynthetic pathways. The pseudo-NPs may inherit the biological relevance of NPs, however, their structures are not yet linked to bioactivity which may lead to the identification of unexpected [10][11][12] or unprecedented bioactivities. [13] We describe the design and synthesis of a focused pseudo-NP collection comprised of two classes representing unprecedented scaffolds that occupy similar biologically relevant chemical space as MIA NPs (Figure 1b).…”