Identification of an allosteric binding site for RORγt inhibition

Scheepstra, Marcel; Leysen, S.; Almen, Geert C. van; Miller, J. Richard; Piesvaux, Jennifer; Kutilek, Victoria; Eenennaam, Hans van; Zhang, Hongjun; Barr, Kenneth; Nagpal, Sunil; Soisson, S.M.; Kornienko, Maria; Wiley, Kristen; Elsen, Nathaniel L.; Sharma, Sujata; Correll, Craig C.; Trotter, B. Wesley; Stelt, Mario van der; Oubrie, Arthur; Ottmann, C.; Parthasarathy, Gopal; Brunsveld, Luc

doi:10.1038/ncomms9833

Cited by 101 publications

(184 citation statements)

References 45 publications

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“…SR1078 was also shown to have direct interaction with RORγt via thermal shift assay as measured by Circular Dichroism (CD) 17 . The lack of potency in displacing the radiolabeled orthosteric inverse agonist T0901317 is likely due to SR1078 binding in the recently described allosteric pocket on RORγt 20 . Initial SAR of the benzamide ring suggests that substituents are tolerated at the ortho-position leading to SR0987 (Fig.…”

Section: Resultsmentioning

confidence: 99%

Synthetic RORγt Agonists Enhance Protective Immunity

et al. 2016

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The 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 anti-tumor 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. Here we show that activation of RORγt using synthetic agonists drives proliferation of TH17 cells while decreasing levels of the immune checkpoint protein PD-1, a mechanism that should enhance anti-tumor immunity while blunting tumor associated adaptive immune resistance. Interestingly, putative endogenous agonists drive proliferation of TH17 cells but do not repress PD-1. These findings suggest that synthetic agonists of RORγt should activate TC17/TH17 cells (with concomitant reduction in the Tregs population), repress PD-1, and produce IL17 in situ (a factor associated with good prognosis in cancer). Enhanced immunity and blockage of immune checkpoints has transformed cancer treatment, thus such a molecule would provide a unique approach for the treatment of cancer.

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Section: Resultsmentioning

confidence: 99%

Synthetic RORγt Agonists Enhance Protective Immunity

et al. 2016

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“…Given that activation of RORgtc ontrolsg ene programst hat enhancei mmunity,i ncrease IL17 production, and decrease immune suppression, [18,19] this NR has become ah igh-priority targetf or numerous pharmaceutical companies over the past decade. [20][21][22][23][24][25] Significant efforts to developsmall molecules that exhibit selectivei nverse agonist(repressive) activity against RORg for the treatment of autoimmune diseases has ultimately resulted in severalc linicalc andidates. [26,27] Ap lethora of diverse chemical scaffolds have been published that bind to the RORg oxysterol orthosteric site such as SR2211, [28] indole 1, [21] triazole 2, [22] and biaryl amide 3 [23] (Figure 1).…”

Section: Introductionmentioning

confidence: 99%

N‐Arylsulfonyl Indolines as Retinoic Acid Receptor‐Related Orphan Receptor γ (RORγ) Agonists

et al. 2016

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The nuclear receptor RORγ (NR1F3) is a key regulator of inflammatory gene programs involved in T helper 17 (TH17) 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 TH17 cell proliferation through activation (agonism) of RORγ may boost an immune response thus offering a potentially new approach in cancer immunotherapy. Here we describe the development of N-arylsulfonyl indolines as RORγ agonists. Structure-activity studies reveal a critical linker region in these molecules as the major determinant for agonism. Hydrogen/deuterium exchange coupled to mass spectrometry (HDX-MS) analysis of RORγ-ligand complexes help rationalize the observed results.

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“…Following these promising preclinical results, several clinical trials with oral and topical RORγ inhibitors such as: VTP-43742, GSK2981278, ABBV-553, ARN-6039 and AZD-0284 have been started in psoriasis, MS, RA and uveitis patients (NCT02555709; NCT03004846; NCT03145948; NCT02976831). While several other inhibitors are still at the preclinical stage, an antagonist that inhibits RORγt with an allosteric mechanism, which could lead to increased selectivity, has also been reported to have promising in vitro activity [131]. …”

Section: Targeting Transcription Factors: the New Frontier?mentioning

confidence: 99%

Small molecules to the rescue: Inhibition of cytokine signaling in immune-mediated diseases

Gadina

Gazaniga

Vian

et al. 2017

Journal of Autoimmunity

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Cytokines are small, secreted proteins associated with the maintenance of immune homeostasis but also implicated with the pathogenesis of several autoimmune and inflammatory diseases. Biologic agents blocking cytokines or their receptors have revolutionized the treatment of such pathologies. Nonetheless, some patients fail to respond to these drugs or do not achieve complete remission. The signal transduction originating from membrane-bound cytokine receptors is an intricate network of events that lead to gene expression and ultimately regulate cellular functionality. Our understanding of the intracellular actions that molecules such as interleukins, inteferons (IFNs) and tumor necrosis factor (TNF) set into motion has greatly increased in the past few years, making it possible to interfere with cytokines’ signaling cascades. The Janus kinase (JAK)/signal transducer and activator of transcription (STAT), the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB), the mitogen activated protein kinase (MAPK) and the Phosphatidylinositol-3’-kinases (PI3K) pathways have all been intensively studied and key steps as well as molecules have been identified. These research efforts have led to the development of a new generation of small molecule inhibitors. Drugs capable of blocking JAK enzymatic activity or interfering with the proteasome-mediated degradation of intermediates in the NF-kB pathway have already entered the clinical arena confirming the validity of this approach. In this review, we have recapitulated the biochemical events downstream of cytokine receptors and discussed some of the drugs which have already been successfully utilized in the clinic. Moreover, we have highlighted some of the new molecules that are currently being developed for the treatment of immune-mediated pathologies and malignancies.

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Identification of an allosteric binding site for RORγt inhibition

Cited by 101 publications

References 45 publications

Synthetic RORγt Agonists Enhance Protective Immunity

Synthetic RORγt Agonists Enhance Protective Immunity

N‐Arylsulfonyl Indolines as Retinoic Acid Receptor‐Related Orphan Receptor γ (RORγ) Agonists

Small molecules to the rescue: Inhibition of cytokine signaling in immune-mediated diseases

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