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Dive into the research topics where Mi Ra Chang is active.

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Featured researches published by Mi Ra Chang.


Structure | 2012

Ligand and Receptor Dynamics Contribute to the Mechanism of Graded PPARγ Agonism

Travis S. Hughes; Michael J. Chalmers; Scott Novick; Dana S. Kuruvilla; Mi Ra Chang; Theodore M. Kamenecka; Mark Rance; Bruce A. Johnson; Thomas P. Burris; Patrick R. Griffin; Douglas J. Kojetin

Ligand binding to proteins is not a static process, but rather involves a number of complex dynamic transitions. A flexible ligand can change conformation upon binding its target. The conformation and dynamics of a protein can change to facilitate ligand binding. The conformation of the ligand, however, is generally presumed to have one primary binding mode, shifting the protein conformational ensemble from one state to another. We report solution nuclear magnetic resonance (NMR) studies that reveal peroxisome proliferator-activated receptor γ (PPARγ) modulators can sample multiple binding modes manifesting in multiple receptor conformations in slow conformational exchange. Our NMR, hydrogen/deuterium exchange and docking studies reveal that ligand-induced receptor stabilization and binding mode occupancy correlate with the graded agonist response of the ligand. Our results suggest that ligand and receptor dynamics affect the graded transcriptional output of PPARγ modulators.


ACS Chemical Biology | 2012

Identification of SR2211: a potent synthetic RORγ-selective modulator.

Naresh Kumar; Brent Lyda; Mi Ra Chang; Janelle L. Lauer; Laura A. Solt; Thomas P. Burris; Theodore M. Kamenecka; Patrick R. Griffin

Nuclear receptors (NRs) are ligand-regulated transcription factors that display canonical domain structure with highly conserved DNA-binding and ligand-binding domains. The identification of the endogenous ligands for several receptors remains elusive or is controversial, and thus these receptors are classified as orphans. One such orphan receptor is the retinoic acid receptor-related orphan receptor γ (RORγ). An isoform of RORγ, RORγt, has been shown to be essential for the expression of Interleukin 17 (IL-17) and the differentiation of Th17 cells. Th17 cells have been implicated in the pathology of several autoimmune diseases, including multiple sclerosis (MS) and rheumatoid arthritis (RA). Genetic ablation of RORγ alone or in combination with RORα in mice led to impaired Th17 differentiation and protected the mice from development of experimental autoimmune encephalomyelitis (EAE), a mouse model of MS. Here we describe SR2211, a selective RORγ modulator that potently inhibits production of IL-17 in cells.


Cell Metabolism | 2014

The Therapeutic Potential of Nuclear Receptor Modulators for Treatment of Metabolic Disorders: PPARγ, RORs, and Rev-erbs

David Marciano; Mi Ra Chang; Cesar A. Corzo; Devrishi Goswami; Vinh Q. Lam; Bruce D. Pascal; Patrick R. Griffin

Nuclear receptors (NRs) play central roles in metabolic syndrome, making them attractive drug targets despite the challenge of achieving functional selectivity. For instance, members of the thiazolidinedione class of insulin sensitizers offer robust efficacy but have been limited due to adverse effects linked to activation of genes not involved in insulin sensitization. Studies reviewed here provide strategies for targeting subsets of PPARγ target genes, enabling development of next-generation modulators with improved therapeutic index. Additionally, emerging evidence suggests that targeting the NRs ROR and Rev-erb holds promise for treating metabolic syndrome based on their involvement in circadian rhythm and metabolism.


Arthritis & Rheumatism | 2014

Pharmacologic Repression of Retinoic Acid Receptor–Related Orphan Nuclear Receptor γ Is Therapeutic in the Collagen-Induced Arthritis Experimental Model

Mi Ra Chang; Brent Lyda; Theodore M. Kamenecka; Patrick R. Griffin

The nuclear receptor retinoic acid receptor–related orphan nuclear receptor γ (RORγ; T cell–specific isoform RORγt) is a key regulator of Th17 cell differentiation, controlling the production of the inflammatory cytokine interleukin‐17 (IL‐17). Lipopolysaccharide (LPS) stimulation of monocytes leads to the induction of RORγ. We previously showed that the potent and selective inverse agonist of RORγ, SR2211, was effective at suppressing IL‐17 production in EL4 cells. The aim of this study was to examine the effects of SR2211 treatment on proinflammatory cytokine expression in LPS‐stimulated RAW 264.7 cells as well as on joint inflammation in vivo in mice with collagen‐induced arthritis (CIA).


MedChemComm | 2013

Synthetic modulators of the retinoic acid receptor-related orphan receptors

Theodore M. Kamenecka; Brent Lyda; Mi Ra Chang; Patrick R. Griffin

Nuclear receptors (NR) are ligand-regulated transcription factors that control the expression of target genes involved in a range of physiological processes such as development, metabolism, and immunity. The retinoic acid receptor-related orphan receptors alpha, beta, and gamma (RORA, RORB, and RORC) comprise a distinct subfamily of nuclear receptors and are considered ‘orphan’ receptors, as they have no known generally agreed upon endogenous ligands, although these receptors do bind to and are modulated by oxysterols. Several recent reports have highlighted the potential role for RORs in human disease, and more importantly, studies have demonstrated that these receptors can be modulated by exogenous synthetic ligands. The identification of potent and selective ROR ligands will allow for a better understanding of the roles of the ROR receptors in human disease, and potentially pave the way for development of novel therapeutics. Here we review the current status of synthetic ligand development from both the primary and patent literature.


ACS Chemical Biology | 2016

Synthetic RORγt Agonists Enhance Protective Immunity

Mi Ra Chang; Venkatasubramanian Dharmarajan; Christelle Doebelin; Ruben D. Garcia-Ordonez; Scott Novick; Dana S. Kuruvilla; Theodore M. Kamenecka; Patrick R. Griffin

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 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. 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 antitumor 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.


ACS Chemical Biology | 2016

SR2067 Reveals a Unique Kinetic and Structural Signature for PPARγ Partial Agonism

Laura M. van Marrewijk; Steven W. Polyak; Marcel Hijnen; Dana S. Kuruvilla; Mi Ra Chang; Youseung Shin; Theodore M. Kamenecka; Patrick R. Griffin; John B. Bruning

Synthetic full agonists of PPARγ have been prescribed for the treatment of diabetes due to their ability to regulate glucose homeostasis and insulin sensitization. While the use of full agonists of PPARγ has been hampered due to severe side effects, partial agonists have shown promise due to their decreased incidence of such side effects in preclinical models. No kinetic information has been forthcoming in regard to the mechanism of full versus partial agonism of PPARγ to date. Here, we describe the discovery of a partial agonist, SR2067. A co-crystal structure obtained at 2.2 Å resolution demonstrates that interactions with the β-sheet are driven exclusively via hydrophobic interactions mediated through a naphthalene group, an observation that is unique from other partial agonists. Surface plasmon resonance revealed that SR2067 binds to the receptor with higher affinity (KD = 513 nM) as compared to that of full agonist rosiglitazone, yet it has a much slower off rate compared to that of rosiglitazone.


Molecular Pharmacology | 2015

Antiobesity Effect of a Small Molecule Repressor of RORγ.

Mi Ra Chang; Yuanjun He; Tanya M. Khan; Dana S. Kuruvilla; Ruben D. Garcia-Ordonez; Cesar A. Corzo; Thaddeus J. Unger; David W. White; Susan Khan; Li Lin; Michael D. Cameron; Theodore M. Kamenecka; Patrick R. Griffin

The orphan nuclear receptor RORγ is a key regulator for T helper 17 (TH17) cell differentiation, which regulates metabolic and circadian rhythm genes in peripheral tissues. Previously, it was shown that the small molecule inverse agonist of RORγ SR1555 [1-(4-((4′-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-[1,1′-biphenyl]-4-yl)methyl)piperazin-1-yl) ethanone] suppressed TH17 differentiation and stimulated induced T regulatory (iTreg) cells. Here, we show that treatment of cultured pre-adipocyctes with SR1555 represses the expression of RORγ while leading to increased expression of FGF21 and adipoQ. Chronic administration of SR1555 to obese diabetic mice resulted in a modest reduction in food intake accompanied with significant reduction in fat mass, resulting in reduced body weight and improved insulin sensitivity. Analysis ex vivo of treated mice demonstrates that SR1555 induced expression of the thermogenic gene program in fat depots. Further studies in cultured cells showed that SR1555 inhibited activation of hormone-sensitive lipase and increased fatty acid oxidation. Combined, these results suggest that pharmacological repression of RORγ may represent a strategy for treatment of obesity by increasing thermogenesis and fatty acid oxidation, while inhibition of hormone-sensitive lipase activity results in a reduction of serum free fatty acids, leading to improved peripheral insulin sensitivity.


Molecular Pharmacology | 2015

Antiproliferation Activity of a Small Molecule Repressor of Liver Receptor Homolog 1

Cesar A. Corzo; Yelenis Mari; Mi Ra Chang; Tanya M. Khan; Dana S. Kuruvilla; Philippe Nuhant; Naresh Kumar; Graham M. West; Derek R. Duckett; William R. Roush; Patrick R. Griffin

The orphan nuclear receptor liver receptor homolog 1 (LRH-1; NR5A2) is a potent regulator of cholesterol metabolism and bile acid homeostasis. Recently, LRH-1 has been shown to play an important role in intestinal inflammation and in the progression of estrogen receptor positive and negative breast cancers and pancreatic cancer. Structural studies have revealed that LRH-1 can bind phospholipids and the dietary phospholipid dilauroylphosphatidylcholine activates LRH-1 activity in rodents. Here we characterize the activity of a novel synthetic nonphospholipid small molecule repressor of LRH-1, SR1848 (6-[4-(3-chlorophenyl)piperazin-1-yl]-3-cyclohexyl-1H-pyrimidine-2,4-dione). In cotransfection studies, SR1848 reduced LRH-1-dependent expression of a reporter gene and in cells that endogenously express LRH-1 dose dependently reduced the expression of cyclin-D1 and -E1, resulting in inhibition of cell proliferation. The cellular effects of SR1848 treatment are recapitulated after transfection of cells with small-interfering RNA targeting LRH-1. Immunocytochemistry analysis shows that SR1848 induces rapid translocation of nuclear LRH-1 to the cytoplasm. Combined, these results suggest that SR1848 is a functional repressor of LRH-1 that impacts expression of genes involved in proliferation in LRH-1–expressing cancers. Thus, SR1848 represents a novel chemical scaffold for the development of therapies targeting malignancies driven by LRH-1.


Current Topics in Microbiology and Immunology | 2014

RORs in autoimmune disease.

Mi Ra Chang; Hugh Rosen; Patrick R. Griffin

The retinoic acid receptor-related orphan receptor (ROR) subfamily of nuclear receptors are transcription factors involved in the maintenance of circadian rhythm and are essential for proper immune function. The T cell-specific isoform, RORγt, is required for T helper 17 cells (TH17) development and it has been implicated in the pathogenesis of autoimmune diseases including multiple sclerosis and rheumatoid arthritis. Thus, pharmacological repression of RORγt may provide a strategy for therapeutic intervention in autoimmune disorders. This chapter provides a summary of the current status for target validation and development of new chemical entities targeting RORγt.

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Brent Lyda

Scripps Research Institute

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Hugh Rosen

California Institute of Technology

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Naresh Kumar

Scripps Research Institute

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Jill Ferguson

Scripps Research Institute

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Pasha Khan

Scripps Research Institute

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