Belén Lucas

Targeted protein degradation modulates protein function beyond the inhibition of enzyme activity or protein–protein interactions. Most degrader drugs function by directly mediating the proximity between a neosubstrate and a hijacked E3 ligase. Here we identify pseudo-natural products derived from (−)-myrtanol, termed iDegs, that inhibit and induce degradation of the immunomodulatory enzyme indoleamine-2,3-dioxygenase 1 (IDO1) by a distinct mechanism. iDegs boost IDO1 ubiquitination and degradation by the cullin-RING E3 ligase CRL2 ^KLHDC3 , which we identified to natively mediate ubiquitin-mediated degradation of IDO1. Therefore, iDegs increase IDO1 turnover using the native proteolytic pathway. In contrast to clinically explored IDO1 inhibitors, iDegs reduce the formation of kynurenine by both inhibition and induced degradation of the enzyme and thus also modulate the non-enzymatic functions of IDO1. This unique mechanism of action may open up alternative therapeutic opportunities for the treatment of cancer beyond classical inhibition of IDO1.

Terpenoid alkaloids are derived from the fusion of structurally diverse terpenoid‐ and alkaloid moieties. The biologically relevant chemical space defined by this unique natural product (NP) class may be explored beyond the limitations of biosynthetic pathways by means of the pseudo natural product (PNP) principle, i.e., by combination of NP fragments in different arrangements. We describe the design, synthesis and structural evolution of a monoterpene–pyrrolidine PNP collection obtained by functionalization and combination of bicyclic monoterpenes with pyrrolidine alkaloid‐derived fragments. Diverse fusion strategies led to the discovery of (‐)‐myrtenal‐pyrrolidine PNPs that are indoleamine‐2,3‐dioxygenase 1 (IDO1) inhibitors and degraders, termed iDegs. Structural fine‐tuning modulated both degradation and inhibition potencies. Co‐crystallization revealed that iDegs induce unprecedented changes in the C‐terminus of IDO1 which promote degradation. iDegs inhibited tumor growth in SKOV‐3 tumor‐bearing mice and led to prolonged survival, which promises to inspire novel medicinal chemistry programs aimed at IDO1 in different diseases.

Terpenoid alkaloids are derived from the fusion of structurally diverse terpenoid‐ and alkaloid moieties. The biologically relevant chemical space defined by this unique natural product (NP) class may be explored beyond the limitations of biosynthetic pathways by means of the pseudo natural product (PNP) principle, i.e., by combination of NP fragments in different arrangements. We describe the design, synthesis and structural evolution of a monoterpene–pyrrolidine PNP collection obtained by functionalization and combination of bicyclic monoterpenes with pyrrolidine alkaloid‐derived fragments. Diverse fusion strategies led to the discovery of (‐)‐myrtenal‐pyrrolidine PNPs that are indoleamine‐2,3‐dioxygenase 1 (IDO1) inhibitors and degraders, termed iDegs. Structural fine‐tuning modulated both degradation and inhibition potencies. Co‐crystallization revealed that iDegs induce unprecedented changes in the C‐terminus of IDO1 which promote degradation. iDegs inhibited tumor growth in SKOV‐3 tumor‐bearing mice and led to prolonged survival, which promises to inspire novel medicinal chemistry programs aimed at IDO1 in different diseases.