6UCG
Retinoic acid receptor-related orphan receptor (ROR) gamma in complex with allosteric compound 28
Summary for 6UCG
| Entry DOI | 10.2210/pdb6ucg/pdb |
| Related | 5C4T |
| Descriptor | Nuclear receptor ROR-gamma, (3S,4R)-1-[1-(2-chloro-6-cyclopropylbenzene-1-carbonyl)-4-fluoro-1H-indazol-3-yl]-3-hydroxypiperidine-4-carboxylic acid (3 entities in total) |
| Functional Keywords | ror gamma t, allosteric, nuclear receptor, transcription |
| Biological source | Homo sapiens (Human) |
| Total number of polymer chains | 1 |
| Total formula weight | 28642.55 |
| Authors | Palte, R.L.,Parthasarathy, G. (deposition date: 2019-09-16, release date: 2020-03-04, Last modification date: 2024-03-13) |
| Primary citation | Zhang, H.,Lapointe, B.T.,Anthony, N.,Azevedo, R.,Cals, J.,Correll, C.C.,Daniels, M.,Deshmukh, S.,van Eenenaam, H.,Ferguson, H.,Hegde, L.G.,Karstens, W.J.,Maclean, J.,Miller, J.R.,Moy, L.Y.,Simov, V.,Nagpal, S.,Oubrie, A.,Palte, R.L.,Parthasarathy, G.,Sciammetta, N.,van der Stelt, M.,Woodhouse, J.D.,Trotter, B.W.,Barr, K. Discovery ofN-(Indazol-3-yl)piperidine-4-carboxylic Acids as ROR gamma t Allosteric Inhibitors for Autoimmune Diseases. Acs Med.Chem.Lett., 11:114-119, 2020 Cited by PubMed Abstract: The clinical success of anti-IL-17 monoclonal antibodies (i.e., Cosentyx and Taltz) has validated Th17 pathway modulation for the treatment of autoimmune diseases. The nuclear hormone receptor RORγt is a master regulator of Th17 cells and affects the production of a host of cytokines, including IL-17A, IL-17F, IL-22, IL-26, and GM-CSF. Substantial interest has been spurred across both academia and industry to seek small molecules suitable for RORγt inhibition. A variety of RORγt inhibitors have been reported in the past few years, the majority of which are orthosteric binders. Here we disclose the discovery and optimization of a class of inhibitors, which bind differently to an allosteric binding pocket. Starting from a weakly active hit , a tool compound was quickly identified that demonstrated superior potency, selectivity, and off-target profile. Further optimization focused on improving metabolic stability. Replacing the benzoic acid moiety with piperidinyl carboxylate, modifying the 4-aza-indazole core in to 4-F-indazole, and incorporating a key hydroxyl group led to the discovery of , which possesses exquisite potency and selectivity, as well as an improved pharmacokinetic profile suitable for oral dosing. PubMed: 32071676DOI: 10.1021/acsmedchemlett.9b00431 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.87 Å) |
Structure validation
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