7RRB
IDO1 IN COMPLEX WITH COMPOUND 9
Summary for 7RRB
| Entry DOI | 10.2210/pdb7rrb/pdb |
| Descriptor | Indoleamine 2,3-dioxygenase 1, 3-[4-(6-cyclopropylpyridin-3-yl)phenyl]-N-(4-fluorophenyl)oxetane-3-carboxamide (3 entities in total) |
| Functional Keywords | indoleamine dioxygenase, heme, inhibitor, oxidoreductase |
| Biological source | Homo sapiens (Human) |
| Total number of polymer chains | 2 |
| Total formula weight | 89487.07 |
| Authors | Lesburg, C.A. (deposition date: 2021-08-09, release date: 2022-03-16, Last modification date: 2024-10-23) |
| Primary citation | Li, D.,Sloman, D.L.,Achab, A.,Zhou, H.,McGowan, M.A.,White, C.,Gibeau, C.,Zhang, H.,Pu, Q.,Bharathan, I.,Hopkins, B.,Liu, K.,Ferguson, H.,Fradera, X.,Lesburg, C.A.,Martinot, T.A.,Qi, J.,Song, Z.J.,Yin, J.,Zhang, H.,Song, L.,Wan, B.,DAddio, S.,Solban, N.,Miller, J.R.,Zamlynny, B.,Bass, A.,Freeland, E.,Ykoruk, B.,Hilliard, C.,Ferraro, J.,Zhai, J.,Knemeyer, I.,Otte, K.M.,Vincent, S.,Sciammetta, N.,Pasternak, A.,Bennett, D.J.,Han, Y. Oxetane Promise Delivered: Discovery of Long-Acting IDO1 Inhibitors Suitable for Q3W Oral or Parenteral Dosing. J.Med.Chem., 65:6001-6016, 2022 Cited by PubMed Abstract: 3,3-Disubstituted oxetanes have been utilized as bioisosteres for gem-dimethyl and cyclobutane functionalities. We report the discovery of a novel class of oxetane indole-amine 2,3-dioxygenase (IDO1) inhibitors suitable for Q3W (once every 3 weeks) oral and parenteral dosing. A diamide class of IDO inhibitors was discovered through an automated ligand identification system (ALIS). Installation of an oxetane and fluorophenyl dramatically improved the potency. Identification of a biaryl moiety as an unconventional amide isostere addressed the metabolic liability of amide hydrolysis. Metabolism identification (Met-ID)-guided target design and the introduction of polarity resulted in the discovery of potent IDO inhibitors with excellent pharmacokinetic (PK) profiles in multiple species. To enable rapid synthesis of the key oxetane intermediate, a novel oxetane ring cyclization was also developed, as well as optimization of a literature route on kg scale. These IDO inhibitors may enable unambiguous proof-of-concept testing for the IDO1 inhibition mechanism for oncology. PubMed: 35239336DOI: 10.1021/acs.jmedchem.1c01670 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.69 Å) |
Structure validation
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