DNA-Encoded Library Technology-Based Discovery, Lead Optimization, and Prodrug Strategy toward Structurally Unique Indoleamine 2,3-Dioxygenase-1 (IDO1) Inhibitors

Abstract

We report the discovery of a novel indoleamine 2,3-dioxygenase-1 (IDO1) inhibitor class through the affinity selection of a previously unreported indole-based DNA-encoded library (DEL). The DEL exemplar, spiro-chromane 1, had moderate IDO1 potency but high in vivo clearance. Series optimization quickly afforded a potent, low in vivo clearance lead 11. Although amorphous 11 was highly bio-available, crystalline 11 was poorly soluble and suffered disappointingly low bio-availability because of solubility-limited absorption. A prodrug approach was deployed and proved effective in discovering the highly bio-available phosphonooxymethyl 31, which rapidly converted to 11 in vivo. Obtaining crystalline 31 proved problematic, however; thus salt screening was performed in an attempt to circumvent this obstacle and successfully delivered greatly soluble and bio-available crystalline tris-salt 32. IDO1 inhibitor 32 is characterized by a low calculated human dose, best-in-class potential, and an unusual inhibition mode by binding the IDO1 heme-free (apo) form.

AncPhore: A versatile tool for anchor pharmacophore steered drug discovery with applications in discovery of new inhibitors targeting metallo-β-lactamases and indoleamine/tryptophan 2,3-dioxygenases

“…These enzymes are first and rate-limiting enzymes of the kynurenine pathway, and implicated in neurodegenerative diseases and tumoral immune resistance; in particular, IDO1 and TDO have been demonstrated as important targets for cancer immunotherapy 23 , 24 , 25 , 26 . Although a number of IDO1 and TDO inhibitors have been reported and several inhibitors are in preclinical development 26 , 27 , 28 , 29 , discovery of new inhibitor chemotypes is still desirable at present. By comprehensive analysis of all reported complex structures for IDO1/TDO and the catalytic mechanisms of the tryptophan substrate ( Fig.…”

“…The human IDO1 (residues 12–403) and TDO (residues 19–388) 26 , 27 , 28 were cloned into pET28a vectors for expression with N-terminally His 6 -Tagged proteins. IDO1/TDO were overexpressed in E. coli Transetta (DE3) cells at 37 °C using LB medium supplied with 1 mmol/L 5-ALA and 30 μmol/L hemin chloride in a shaker at 200 rpm.…”

Discovery of a potent apo-IDO1 inhibitor for cancer immunotherapy

“…On the other hand, the failure of epacadostat drive scientists to explore new action mode on IDO1 and several best-in-class inhibitors are being developed. As IDO1 is a heme-containing enzyme, inhibitors which exclude the heme from the enzyme showed high potency such as BMS-986205, GSK5628 and a recently compound developed by DNA-Encoded Library Technology (Ortiz-Meoz et al, 2018b;Pham & Yeh, 2018) , (Kazmierski et al, 2020). By competing with heme for binding to a heme-free conformation of IDO1, these kinds of inhibitors showed generally remarkable efficacy and suicide inhibition activity on IDO1.…”

Design, synthesis and evaluation of tryptophan analogues as tool compounds to study IDO1 activity

“…No such change is observed on incubating 17 with IDO1, ruling out this mechanism of inhibition (see ESI, † Appendix 3.9). 62 …”