Discovery of BMS-986251: A Clinically Viable, Potent, and Selective RORγt Inverse Agonist

Cherney, Robert J.; Cornelius, Lyndon; Srivastava, Anurag S.; Weigelt, Carolyn A.; Marcoux, David; Duan, James J.‐W.; Shi, Qing; Batt, Douglas G.; Liu, Qingjie; Yip, Shiuhang; Wu, Dauh‐Rurng; Ruzanov, Max; Sack, John S.; Khan, Javed; Wang, Jinhong; Yarde, Melissa; Cvijic, Mary Ellen; Mathur, Arvind; Li, Sha; Shuster, David J.; Khandelwal, Purnima; Borowski, Virna; Xie, Jenny; Obermeier, Mary; Fura, Aberra; Stefanski, Kevin; Cornelius, Georgia; Tino, Joseph A.; Macor, John E.; Salter–Cid, Luisa; Denton, Rex; Zhao, Qihong; Carter, Percy H.; Dhar, T. G. Murali

doi:10.1021/acsmedchemlett.0c00063

Cited by 36 publications

(32 citation statements)

References 30 publications

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“…Compared to structure 2 (Figure ), the side chain amide nitrogen in the new series (compounds 3 – 7 ) is sterically hindered because it is attached to the tricyclic core, which could potentially alter or slow down metabolic processes such as N-dealkylation. Because the reverse amide series was a logical extension from our earlier tricyclic pyrrolidine series where the nitrogen atom was a part of the ring system, as illustrated in 1 , , a number of side chains studied earlier were re-examined here. Molecular modeling studies revealed that the trajectory of the side chains in both tricyclic pyrrolidine and reverse amide series point toward the RORγt polar pocket, consisting of a network of residues including Glu286, Leu287, Arg364, and Arg367.…”

Section: Results and Discussionmentioning

confidence: 99%

“…As part of the screening process, we tested all newly synthesized compounds in both the GaL4-Luc reporter assay (GAL4) and a physiologically relevant IL-17-stimulated human whole blood (hWB) assay. Because the hWB EC 50 of 1 was 24 nM, 21 we required the EC 50 cutoff value of newly synthesized compounds to be ≤50 nM for further profiling. To assess MetStab, we measured the percent of parent remaining (% rem) following incubation with human, mouse, and rat liver microsomes, aiming for >90% recovery in these assays (Table 1).…”

Section: ■ Results and Discussionmentioning

confidence: 99%

“…Detailed biological experimental procedures, animal studies, and assay conditions used in this study can be found in our recent publications, refs . and .…”

Section: Methodsmentioning

confidence: 99%

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Tricyclic-Carbocyclic RORγt Inverse Agonists—Discovery of BMS-986313

et al. 2021

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SAR efforts directed at identifying RORγt inverse agonists structurally different from our clinical compound 1 (BMS-986251) led to tricyclic-carbocyclic analogues represented by 3−7 and culminated in the identification of 3d (BMS-986313), with structural differences distinct from 1. The X-ray co-crystal structure of 3d with the ligand binding domain of RORγt revealed several key interactions, which are different from 1. The in vitro and in vivo PK profiles of 3d are described. In addition, we demonstrate robust efficacy of 3d in two preclinical models of psoriasisthe IMQ-induced skin lesion model and the IL-23-induced acanthosis model. The efficacy seen with 3d in these models is comparable to the results observed with 1.

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Section: Results and Discussionmentioning

confidence: 99%

Section: ■ Results and Discussionmentioning

confidence: 99%

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Tricyclic-Carbocyclic RORγt Inverse Agonists—Discovery of BMS-986313

et al. 2021

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“…These findings suggest the potential utility of ROR modulators as anti-diabetic and anti-obesity agents. On the other hand, multiple selective RORγ Inhibitors reduce T-helper cell 17 (Th17) responses as well as production of the proinflammatory cytokine IL-17, indicating the therapeutic potential of these molecules for autoimmune diseases, including rheumatoid arthritis, multiple sclerosis, psoriasis, and inflammatory bowel disease (Cyr et al, 2016;Pandya et al, 2018;Cherney et al, 2020;Harcken et al, 2021;Meijer et al, 2021). Pharmacological inhibition of RORγ also exerts potent anti-tumor activity in in vitro and/or in vivo models of castration-resistant prostate cancer (J.…”

Section: Modulating Casein Kinases (Cks)mentioning

confidence: 99%

Circadian Rhythms, Disease and Chronotherapy

2021

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Circadian clocks are biological timing mechanisms that generate 24-h rhythms of physiology and behavior, exemplified by cycles of sleep/wake, hormone release, and metabolism. The adaptive value of clocks is evident when internal body clocks and daily environmental cycles are mismatched, such as in the case of shift work and jet lag or even mistimed eating, all of which are associated with physiological disruption and disease. Studies with animal and human models have also unraveled an important role of functional circadian clocks in modulating cellular and organismal responses to physiological cues (ex., food intake, exercise), pathological insults (e.g. virus and parasite infections), and medical interventions (e.g. medication). With growing knowledge of the molecular and cellular mechanisms underlying circadian physiology and pathophysiology, it is becoming possible to target circadian rhythms for disease prevention and treatment. In this review, we discuss recent advances in circadian research and the potential for therapeutic applications that take patient circadian rhythms into account in treating disease.

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“…We think that a statistical analysis of extensive structural information where one collectively examines protein-ligand contact interaction patterns may provide insight into this challenge. For this work, we studied 136 RORγ structures: 132 with one ligand (or ligand fragments) bound (100+ distinct ligands) from X-ray crystallography experiments ( Jin et al, 2010 ; Fujita-Sato et al, 2011 ; Fauber et al, 2013 ; Fauber et al, 2014 ; van Niel et al, 2014 ; Yang et al, 2014 ; Chao et al, 2015 ; Muegge et al, 2015 ; René et al, 2015 ; Santori et al, 2015 ; Scheepstra et al, 2015 ; Wang et al, 2015b ; Wang et al, 2015c ; Enyedy et al, 2016 ; Hirata et al, 2016 ; Hintermann et al, 2016 ; Marcotte et al, 2016 ; Olsson et al, 2016 ; Ouvry et al, 2016 ; Xue et al, 2016 ; Kallen et al, 2017 ; Kummer et al, 2017 ; Li et al, 2017 ; Noguchi et al, 2017 ; Carcache et al, 2018 ; Fukase et al, 2018 ; Gege et al, 2018 ; Gong et al, 2018 ; Kono et al, 2018 ; Narjes et al, 2018 ; Noguchi et al, 2018 ; Sasaki et al, 2018 ; Schnute et al, 2018 ; Shirai et al, 2018 ; Wang et al, 2018 ; Amaudrut et al, 2019 ; Duan et al, 2019 ; Hoegenauer et al, 2019 ; Kotoku et al, 2019 ; Lu et al, 2019 ; Marcoux et al, 2019 ; Sato et al, 2019 ; Strutzenberg et al, 2019 ; Tanis et al, 2019 ; von Berg et al, 2019 ; Yukawa et al, 2019 ; Zhang et al, 2019 ; Cherney et al, 2020 ; Duan et al, 2020 ; Gege et al, 2020 ; Harikrishnan et al, 2020 ; Jiang et al, 2020 ; Liu et al, 2020 ; Meijer et al, 2020 ;…”

Section: Introductionmentioning

confidence: 99%

Statistical Analysis of Protein-Ligand Interaction Patterns in Nuclear Receptor RORγ

Pham

Cheng²,

López³

et al. 2022

Front. Mol. Biosci.

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The receptor RORγ belongs to the nuclear receptor superfamily that senses small signaling molecules and regulates at the gene transcription level. Since RORγ has a high basal activity and plays an important role in immune responses, inhibitors targeting this receptor have been a focus for many studies. The receptor-ligand interaction is complex, and often subtle differences in ligand structure can determine its role as an inverse agonist or an agonist. We examined more than 130 existing RORγ crystal structures that have the same receptor complexed with different ligands. We reported the features of receptor-ligand interaction patterns and the differences between agonist and inverse agonist binding. Specific changes in the contact interaction map are identified to distinguish active and inactive conformations. Further statistical analysis of the contact interaction patterns using principal component analysis reveals a dominant mode which separates allosteric binding vs. canonical binding and a second mode which may indicate active vs. inactive structures. We also studied the nature of constitutive activity by performing a 100-ns computer simulation of apo RORγ. Using constitutively active nuclear receptor CAR as a comparison, we identified a group of conserved contacts that have similar contact strength between the two receptors. These conserved contact interactions, especially a couple key contacts in H11–H12 interaction, can be considered essential to the constitutive activity of RORγ. These protein-ligand and internal protein contact interactions can be useful in the development of new drugs that direct receptor activity.

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Discovery of BMS-986251: A Clinically Viable, Potent, and Selective RORγt Inverse Agonist

Cited by 36 publications

References 30 publications

Tricyclic-Carbocyclic RORγt Inverse Agonists—Discovery of BMS-986313

Tricyclic-Carbocyclic RORγt Inverse Agonists—Discovery of BMS-986313

Circadian Rhythms, Disease and Chronotherapy

Statistical Analysis of Protein-Ligand Interaction Patterns in Nuclear Receptor RORγ

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