The retinoic acid receptor-related orphan receptor γ (RORγ) is a ligand-dependent transcription factor of the nuclear receptor super family that underpins metabolic activity, immune function, and cancer progression. Despite being a valuable drug target in health and disease, our understanding of the ligand-dependent activities of RORγ is far from complete. Like most nuclear receptors, RORγ must recruit coregulatory protein to enact the RORγ target gene program.
View Article and Find Full Text PDFNeuropsychopharmacology
January 2020
There is increasing interest in developing drugs that act at α4β2 nicotinic acetylcholine receptors (nAChRs) to treat alcohol use disorder. The smoking cessation agent varenicline, a partial agonist of α4β2 nAChRs, reduces alcohol intake, but its use can be limited by side effects at high therapeutic doses. There are two stoichiometric forms of α4β2 nAChRs, (α4)(β2) and (α4)(β2).
View Article and Find Full Text PDFNicotinic acetylcholine receptor (nAChR) ligands that lack agonist activity but enhance activation in the presence of an agonist are called positive allosteric modulators (PAMs). nAChR PAMs have therapeutic potential for the treatment of nicotine addiction and several neuropsychiatric disorders. PAMs need to be selectively targeted toward certain nAChR subtypes to tap this potential.
View Article and Find Full Text PDFBackground: Despite a massive industry endeavor to develop RORγ-modulators for autoimmune disorders, there has been no indication of efforts to target the close family member RORα for similar indications. This may be due to the misconception that RORα is redundant to RORγ, or the inherent difficulty in cultivating tractable starting points for RORα. RORα-selective modulators would be useful tools to interrogate the biology of this understudied orphan nuclear receptor.
View Article and Find Full Text PDFRORγt is well recognized as the lineage-defining transcription factor for T helper 17 (T17) cell development. However, the cell-intrinsic mechanisms that negatively regulate T17 cell development and autoimmunity remain poorly understood. Here, we demonstrate that the transcriptional repressor REV-ERBα is exclusively expressed in T17 cells, competes with RORγt for their shared DNA consensus sequence, and negatively regulates T17 cell development via repression of genes traditionally characterized as RORγt dependent, including Il17a.
View Article and Find Full Text PDFWe sought to develop RORβ-selective probe molecules in order to investigate the function of the receptor in vitro and in vivo and its role in the pathophysiology of disease. To accomplish this, we modified a potent dual RORβ/RORγ inverse agonist from the primary literature with the goal of improving selectivity for RORβ vs RORγ. Truncation of the Western portion of the molecule ablated activity at RORγ and led to a potent series of RORβ modulators.
View Article and Find Full Text PDFNuclear factor κB (NF-κB) is a transcription factor important for regulating innate and adaptive immunity, cellular proliferation, apoptosis, and senescence. Dysregulation of NF-κB and its upstream regulator IκB kinase (IKK) contributes to the pathogenesis of multiple inflammatory and degenerative diseases as well as cancer. An 11-amino acid peptide containing the NF-κB essential modulator (NEMO)-binding domain (NBD) derived from the C-terminus of β subunit of IKK, functions as a highly selective inhibitor of the IKK complex by disrupting the association of IKKβ and the IKKγ subunit NEMO.
View Article and Find Full Text PDFHerein we report the design and synthesis of a series of simple phenol amide ERRγ agonists based on a hydrazone lead molecule. Our structure activity relationship studies in this series revealed the phenol portion of the molecule to be required for activity. Attempts to replace the hydrazone with more suitable chemotypes led to a simple amide as a viable alternative.
View Article and Find Full Text PDFCrystallography has identified stearic acid, ALRT 1550 and ATRA as ligands that bind RORβ, however, none of these molecules represent good starting points to develop optimized small molecule modulators. Recently, Compound 1 was identified as a potent dual RORβ and RORγ inverse agonist with no activity towards RORα (Fig. 1).
View Article and Find Full Text PDFAn efficient route for the synthesis of enantiopure 3,3-difluoroproline on multigram-scale is described herein. The deoxofluorination can be achieved with DAST on the corresponding racemic pyrrolidinone in good yield. Resolution of the racemate by crystallization with D- and L-tyrosine hydrazide provides both enantiomers of 3,3-difluoroproline in high yield and ee%.
View Article and Find Full Text PDFThe nuclear retinoic acid receptor-related orphan receptor γ (RORγ; NR1F3) is a key regulator of inflammatory gene programs involved in T helper 17 (T 17) cell proliferation. As such, synthetic small-molecule repressors (inverse agonists) targeting RORγ have been extensively studied for their potential as therapeutic agents for various autoimmune diseases. Alternatively, enhancing T 17 cell proliferation through activation (agonism) of RORγ may boost an immune response, thereby offering a potentially new approach in cancer immunotherapy.
View Article and Find Full Text PDFA series of dipeptides were designed as potential agonists of the human KiSS1-derived peptide receptor (hGPR54). While the sequence Arg-Trp-NH was the most efficient in terms of affinity, we established a convergent synthetic strategy to optimize the N terminus. Using two successive Sonogashira cross-coupling reactions on a solid-supported peptide, we were able to introduce various alkynes at the N terminus to afford compounds with sub-micromolar affinities for hGPR54.
View Article and Find Full Text PDFThe T cell specific RORγ isoform RORγt has been shown to be the key lineage-defining transcription factor to initiate the differentiation program of TH17 and TC17 cells, cells that have demonstrated antitumor efficacy. RORγt controls gene networks that enhance immunity including increased IL17 production and decreased immune suppression. Both synthetic and putative endogenous agonists of RORγt have been shown to increase the basal activity of RORγt enhancing TH17 cell proliferation.
View Article and Find Full Text PDFMammalian RF-amide peptides including RF-amide-related peptides-1 and -3, neuropeptides AF and FF, Prolactin releasing peptides, Kisspeptins and RFa peptides are currently considered endogenous peptides for the GPCRs NPFF1R, NPFF2R, GPR10, GPR54 and GPR103, respectively. While NPFF1R and NPFF2R displayed high affinity for all the RF-amide peptides, GPR10, GPR54 and GPR103 only bind their cognate ligands. Through a systematic and sequential N-terminus deletion and benzoylation of either RF-amide neuropeptide (RFRP-3, NPFF, Kp-10, PrRP20, and 26RFa), we report the corresponding impact on affinity and activity towards all the RF-amide receptors (NPFF1R, NPFF2R, GPR10, GPR54 and GPR103).
View Article and Find Full Text PDFStarting from commercially available 2-chloro-3-hydroxypyridine, a new route leading to the first protypical pentaarylpyridine bearing five different substituents is reported. This strategy involves a set of five sequential but fully regiocontrolled Suzuki-Miyaura reactions and highlights the 2-OBn pyridine protecting group as a key intermediate. The 2-OBn group played a double role: (i) it allowed additional bromination at position 5 and (ii) it could afford the reactive OTf species for the last C-arylation step at the less hindered 2 position of the tetraarylpyridine.
View Article and Find Full Text PDFThe reaction of 3-azidopropanoic acid with the carbodiimide-based coupling reagent DIC leads to a six-membered-ring intermediate acting as a versatile precursor to a diverse set of aza heterocycles, including mono-, bi-, and tricyclic compounds.
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