Optimizing a Weakly Binding Fragment into a Potent RORγt Inverse Agonist with Efficacy in an in Vivo Inflammation Model

Carcache, David A.; Vulpetti, Anna; Kallen, Joerg; Mattes, Henri; Orain, David; Stringer, Rowan; Vangrevelinghe, Eric; Wolf, Romain M.; Kaupmann, Klemens; Ottl, Johannes; Dawson, Janet; Cooke, Nigel G.; Hoegenauer, Klemens; Billich, Andreas; Wagner, Juergen; Guntermann, Christine; Hintermann, Samuel

doi:10.1021/acs.jmedchem.8b00529

Cited by 24 publications

(13 citation statements)

References 25 publications

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“…Compound 15 was prepared according to the general procedure described for 11. Flash column chromatography eluent: petroleum ether/EtOAc = 5/1; yield, 65%; yellow solid; 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.17 (17). 16 (100 mg, 0.17 mmol) was dissolved in THF (5 mL) and 2 mol/L NaOH aqueous solution (5 mL).…”

Section: Journal Of Medicinal Chemistrymentioning

confidence: 99%

Discovery and Characterization of XY101, a Potent, Selective, and Orally Bioavailable RORγ Inverse Agonist for Treatment of Castration-Resistant Prostate Cancer

Zhang

Xue

et al. 2019

J. Med. Chem.

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We report the design, optimization, and biological evaluation of nuclear receptor RORγ inverse agonists as therapeutic agents for prostate cancer treatment. The most potent compound 27 (designated as XY101) exhibited cellular activity with an IC50 value of 30 nM in a cell-based reporter gene assay with good selectivity against other nuclear receptor subtypes. The cocrystal structure of 27 in complex with the RORγ ligand binding domain provided a solid structural basis for its antagonistic mechanism. 27 potently inhibited cell growth, colony formation, and the expression of AR, AR-V7, and PSA. 27 also exhibited good metabolic stability and a pharmacokinetic profile with oral bioavailability of 59% and a half-life of 7.3 h. Notably, 27 demonstrated promising therapeutic effects with significant tumor growth inhibition in a prostate cancer xenograft model in mice. The potent, selective, metabolically stable, and orally available RORγ inverse agonists represent a new class of compounds as potential therapeutics against prostate cancer.

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Section: Journal Of Medicinal Chemistrymentioning

confidence: 99%

Discovery and Characterization of XY101, a Potent, Selective, and Orally Bioavailable RORγ Inverse Agonist for Treatment of Castration-Resistant Prostate Cancer

Zhang

Xue

et al. 2019

J. Med. Chem.

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“…Efforts to discover orally bioavailable inverse agonists of RORγt, as an alternative to antibody treatment, have generated a variety of different structural classes. Indeed, a diverse range of chemical structures has been reported as RORγt inhibitors by many research groups. − Recent clinical candidates from these efforts include VTP-43742, GNE-3500, AZD-0284, GSK805, T0901317, and GSK2981278 (Figure ). − Among them, GSK2981278 was developed in a phase II study for the topical treatment of psoriasis, but recently, the clinical development of this compound was halted. − GSK2981278 has potent in vitro RORγt inverse agonistic activity in a binding inhibitory assay and in a RORγt reporter gene assay (Table ).…”

Section: Introductionmentioning

confidence: 99%

“…Compound 17 was converted to 18 by methylation. The reaction of 18 with (2,4dimethoxyphenyl) methenamine(19) yielded compound 20. Compound 20 was deprotected using trifluoroacetic acid (TFA) to provide 21.…”

mentioning

confidence: 99%

Discovery of Chromane-6-Sulfonamide Derivative as a Potent, Selective, and Orally Available Novel Retinoic Acid Receptor-Related Orphan Receptor γt Inverse Agonist

Chen

Su²,

Qiu³

et al. 2021

J. Med. Chem.

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is a proinflammatory cytokine that plays a dominant role in inflammation, autoimmunity, and host defense. RORγt is a key transcription factor mediating T helper 17 (Th17) cell differentiation and IL-17 production, which is able to activate CD8 + T cells and elicit antitumor efficacy. A series of sulfonamide derivatives as novel RORγt inverse agonists were designed and synthesized. Using GSK2981278 (phase II) as a starting point, we engineered structural modifications that significantly improved the activity and pharmacokinetic profile. In animal studies, oral administration of compound d3 showed a robust and dosedependent inhibition of the IL-17A cytokine expression in a mouse imiquimod-induced skin inflammation model. Docking analysis of the binding mode revealed that the compound d3 occupied the active pocket suitably. Thus, compound d3 was selected as a clinical compound for the treatment of Th17-driven autoimmune diseases.

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“…In the absence of ligand, RORgt is in an active conformation, capable of recruiting coactivators. From a structural point of view, His 479 , Tyr 502 , and Phe 506 triplets have been identified as the primary structural elements responsible for stabilizing H12 and anchoring RORgt in the active conformation, allowing coactivator interactions (Williams et al, 2003;Carcache et al, 2018;Schnute et al, 2018). Agonist compounds stabilize the active conformation either directly or indirectly and it has been shown that a putative natural ligand like 25-hydroxy-cholesterol stabilizes H12 indirectly through a water-mediated hydrogen bond between His 479 and Tyr 502 Fig.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of Interleukin-23–Mediated Inflammation with a Novel Small Molecule Inverse Agonist of RORγt

Gauld

Jacquet

Gauvin

et al. 2019

J Pharmacol Exp Ther

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Blockade of interleukin (IL)-23 or IL-17 with biologics is clinically validated as a treatment of psoriasis. However, the clinical impact of targeting other nodes within the IL-23/IL-17 pathway, especially with small molecules, is less defined. We report on a novel small molecule inverse agonist of retinoid acid-related orphan receptor (ROR) gt and its efficacy in preclinical models of psoriasis and arthritis. 1-(2,4-Dichloro-3-((1,4-dimethyl-6-(trifluoromethyl)-1H-indol-2-yl)methyl)benzoyl)piperidine-4carboxylic acid (A-9758) was optimized from material identified from a high-throughput screening campaign. A-9758 is selective for RORgt and exhibits robust potency against IL-17A release both in vitro and in vivo. In vivo, we also show that IL-23 is sufficient to drive the accumulation of RORgt 1 cells, and inhibition of RORgt significantly attenuates IL-23-driven psoriasiform dermatitis. Therapeutic treatment with A-9758 (i.e., delivered during active disease) was also effective in blocking skin and joint inflammation. Finally, A-9758 exhibited efficacy in an ex vivo human whole blood assay, suggesting small molecule inverse agonists of RORgt could be efficacious in human IL-17-related diseases. SIGNIFICANCE STATEMENT Using a novel small molecule inverse agonist, and preclinical assays, we show that RORgt is a viable target for the inhibition of RORgt/Th17-driven diseases such as psoriasis. Preclinical models of psoriasis show that inhibition of RORgt blocks both the accumulation and effector function of IL-17-producing T cells.

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Optimizing a Weakly Binding Fragment into a Potent RORγt Inverse Agonist with Efficacy in an in Vivo Inflammation Model

Cited by 24 publications

References 25 publications

Discovery and Characterization of XY101, a Potent, Selective, and Orally Bioavailable RORγ Inverse Agonist for Treatment of Castration-Resistant Prostate Cancer

Discovery and Characterization of XY101, a Potent, Selective, and Orally Bioavailable RORγ Inverse Agonist for Treatment of Castration-Resistant Prostate Cancer

Discovery of Chromane-6-Sulfonamide Derivative as a Potent, Selective, and Orally Available Novel Retinoic Acid Receptor-Related Orphan Receptor γt Inverse Agonist

Inhibition of Interleukin-23–Mediated Inflammation with a Novel Small Molecule Inverse Agonist of RORγt

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