SR2067 reveals a unique kinetic and structural signature for PPARγ partial agonism

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

doi:10.1021/acschembio.5b00580

Title: SR2067 reveals a unique kinetic and structural signature for PPARγ partial agonism

Journal Article · Wed Nov 18 00:00:00 EST 2015 · ACS Chemical Biology

DOI:https://doi.org/10.1021/acschembio.5b00580· OSTI ID:1345039

van Marrewijk, Laura M. ^[1]; Polyak, Steven W. ^[1]; Hijnen, Marcel ^[2]; Kuruvilla, Dana ^[3]; Chang, Mi Ra ^[3]; Shin, Youseung ^[3]; Kamenecka, Theodore M. ^[3]; Griffin, Patrick R. ^[3]; Bruning, John B. ^[1]

The Univ. of Adelaide, Adelaide, SA (Australia)
GE Healthcare Life Sciences ANZ, Melbourne, VIC (Australia)
The Scripps Research Inst., Jupiter, FL (United States)

Here, 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. In this paper, 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. Finally, surface plasmon resonance revealed that SR2067 binds to the receptor with higher affinity (K_D = 513 nM) as compared to that of full agonist rosiglitazone, yet it has a much slower off rate compared to that of rosiglitazone.

View Accepted Manuscript (DOE)

Cite

Export

Save

Research Organization:: Scripps Research Inst., Jupiter, FL (United States)

Sponsoring Organization:: USDOE Office of Science (SC), Basic Energy Sciences (BES); USDOE Office of Science (SC), Biological and Environmental Research (BER)

Grant/Contract Number:: AC02-76SF00515

OSTI ID:: 1345039

Journal Information:: ACS Chemical Biology, Vol. 11, Issue 1; ISSN 1554-8929

Publisher:: American Chemical Society (ACS)Copyright Statement

Country of Publication:: United States

Language:: English

Citation Metrics:

Cited by: 28 works

Citation information provided by
Web of Science

References (44)

Activation of a member of the steroid hormone receptor superfamily by peroxisome proliferators Issemann, Isabelle; Green, Stephen Nature, Vol. 347, Issue 6294 https://doi.org/10.1038/347645a0	journal	October 1990
Fat and Beyond: The Diverse Biology of PPARγ Tontonoz, Peter; Spiegelman, Bruce M. Annual Review of Biochemistry, Vol. 77, Issue 1 https://doi.org/10.1146/annurev.biochem.77.061307.091829	journal	June 2008
The peroxisome proliferator-activated receptor interacts with the retinoid X receptor in vivo Miyata, Kenji S.; McCaw, Shannon E.; Marcus, Sandra L. Gene, Vol. 148, Issue 2 https://doi.org/10.1016/0378-1119(94)90707-2	journal	October 1994
PPAR ligands: Potential therapies for metabolic syndrome Akiyama, Taro E.; Meinke, Peter T.; Berger, Joel P. Current Diabetes Reports, Vol. 5, Issue 1 https://doi.org/10.1007/s11892-005-0067-3	journal	January 2005
Thiazolidinediones and PPARγ agonists: time for a reassessment Cariou, Bertrand; Charbonnel, Bernard; Staels, Bart Trends in Endocrinology & Metabolism, Vol. 23, Issue 5 https://doi.org/10.1016/j.tem.2012.03.001	journal	May 2012
Clinical trials with thiazolidinediones in subjects with Type 2 diabetes – is pioglitazone any different from rosiglitazone? Doggrell, Sheila A. Expert Opinion on Pharmacotherapy, Vol. 9, Issue 3 https://doi.org/10.1517/14656566.9.3.405	journal	January 2008
How safe is the use of thiazolidinediones in clinical practice? Rizos, Cv; Elisaf, Moses; Mikhailidis, Dp Expert Opinion on Drug Safety, Vol. 8, Issue 1 https://doi.org/10.1517/14740330802597821	journal	November 2008
Effect of Rosiglitazone on the Risk of Myocardial Infarction and Death from Cardiovascular Causes Nissen, Steven E.; Wolski, Kathy New England Journal of Medicine, Vol. 356, Issue 24 https://doi.org/10.1056/NEJMoa072761	journal	June 2007
Anti-diabetic drugs inhibit obesity-linked phosphorylation of PPARγ by Cdk5 Choi, Jang Hyun; Banks, Alexander S.; Estall, Jennifer L. Nature, Vol. 466, Issue 7305 https://doi.org/10.1038/nature09291	journal	July 2010
Antidiabetic actions of a non-agonist PPARγ ligand blocking Cdk5-mediated phosphorylation Choi, Jang Hyun; Banks, Alexander S.; Kamenecka, Theodore M. Nature, Vol. 477, Issue 7365 https://doi.org/10.1038/nature10383	journal	September 2011
Structure of the intact PPAR-γ–RXR-α nuclear receptor complex on DNA Chandra, Vikas; Huang, Pengxiang; Hamuro, Yoshitomo Nature, Vol. 456, Issue 7220 https://doi.org/10.1038/nature07413	journal	November 2008
Transcription coactivators for peroxisome proliferator-activated receptors Yu, S.; Reddy, J. Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids, Vol. 1771, Issue 8 https://doi.org/10.1016/j.bbalip.2007.01.008	journal	August 2007
Ligand binding and co-activator assembly of the peroxisome proliferator-activated receptor-γ Nolte, Robert T.; Wisely, G. Bruce; Westin, Stefan Nature, Vol. 395, Issue 6698 https://doi.org/10.1038/25931	journal	September 1998
INT131: A Selective Modulator of PPARγ Motani, Alykhan; Wang, Zhulun; Weiszmann, Jennifer Journal of Molecular Biology, Vol. 386, Issue 5 https://doi.org/10.1016/j.jmb.2009.01.025	journal	March 2009
Selective peroxisome proliferator-activated receptor γ (PPARγ) modulation as a strategy for safer therapeutic PPARγ activation Higgins, Linda Slanec; DePaoli, Alex M. The American Journal of Clinical Nutrition, Vol. 91, Issue 1 https://doi.org/10.3945/ajcn.2009.28449E	journal	November 2009
Distinct Properties and Advantages of a Novel Peroxisome Proliferator-Activated Protein γ Selective Modulator Berger, Joel P.; Petro, Ann E.; Macnaul, Karen L. Molecular Endocrinology, Vol. 17, Issue 4 https://doi.org/10.1210/me.2002-0217	journal	April 2003
A peroxisome proliferator-activated receptor ligand inhibits adipocyte differentiation Oberfield, J. L.; Collins, J. L.; Holmes, C. P. Proceedings of the National Academy of Sciences, Vol. 96, Issue 11 https://doi.org/10.1073/pnas.96.11.6102	journal	May 1999
Selective PPARγ modulator INT131 normalizes insulin signaling defects and improves bone mass in diet-induced obese mice Lee, Dae Ho; Huang, Hu; Choi, Kangduk American Journal of Physiology-Endocrinology and Metabolism, Vol. 302, Issue 5 https://doi.org/10.1152/ajpendo.00569.2011	journal	March 2012
Pharmacological characteristics of a novel nonthiazolidinedione insulin sensitizer, FK614 Minoura, Hideaki; Takeshita, Shigeru; Ita, Makoto European Journal of Pharmacology, Vol. 494, Issue 2-3 https://doi.org/10.1016/j.ejphar.2004.04.038	journal	June 2004
Effect of PPAR- Activation and Inhibition on Glucose-Stimulated Insulin Release in INS-1e Cells Santini, E.; Fallahi, P.; Ferrari, S. M. Diabetes, Vol. 53, Issue Supplement 3 https://doi.org/10.2337/diabetes.53.suppl_3.S79	journal	November 2004
An ERK/Cdk5 axis controls the diabetogenic actions of PPARγ Banks, Alexander S.; McAllister, Fiona E.; Camporez, João Paulo G. Nature, Vol. 517, Issue 7534 https://doi.org/10.1038/nature13887	journal	November 2014
Discovery of GSK1997132B a novel centrally penetrant benzimidazole PPARγ partial agonist Sime, Mairi; Allan, Amanda C.; Chapman, Paul Bioorganic & Medicinal Chemistry Letters, Vol. 21, Issue 18 https://doi.org/10.1016/j.bmcl.2011.06.088	journal	September 2011
Synthesis and biological activities of novel indole derivatives as potent and selective PPARγ modulators Lamotte, Yann; Martres, Paul; Faucher, Nicolas Bioorganic & Medicinal Chemistry Letters, Vol. 20, Issue 4 https://doi.org/10.1016/j.bmcl.2009.12.107	journal	February 2010
Structural basis for telmisartan-mediated partial activation of PPAR gamma Amano, Yasushi; Yamaguchi, Tomohiko; Ohno, Kazuki Hypertension Research, Vol. 35, Issue 7 https://doi.org/10.1038/hr.2012.17	journal	February 2012
Discovery of INT131: A selective PPARγ modulator that enhances insulin sensitivity Taygerly, Joshua P.; McGee, Lawrence R.; Rubenstein, Steven M. Bioorganic & Medicinal Chemistry, Vol. 21, Issue 4 https://doi.org/10.1016/j.bmc.2012.11.058	journal	February 2013
Pharmacological repression of PPARγ promotes osteogenesis Marciano, David P.; Kuruvilla, Dana S.; Boregowda, Siddaraju V. Nature Communications, Vol. 6, Issue 1 https://doi.org/10.1038/ncomms8443	journal	June 2015
Partial Agonists Activate PPARγ Using a Helix 12 Independent Mechanism Bruning, John B.; Chalmers, Michael J.; Prasad, Swati Structure, Vol. 15, Issue 10 https://doi.org/10.1016/j.str.2007.07.014	journal	October 2007
Label-free kinetic binding data as a decisive element in drug discovery Andersson, Karl; Karlsson, Robert; Löfås, Stefan Expert Opinion on Drug Discovery, Vol. 1, Issue 5 https://doi.org/10.1517/17460441.1.5.439	journal	October 2006
Drug–target residence time and its implications for lead optimization Copeland, Robert A.; Pompliano, David L.; Meek, Thomas D. Nature Reviews Drug Discovery, Vol. 5, Issue 9 https://doi.org/10.1038/nrd2082	journal	August 2006
Tiotropium (SPIRIVA™): Mechanistical considerations and clinical profile in obstructive lung disease Disse, Bernd; Speck, Georg A.; Rominger, Karl Ludwig Life Sciences, Vol. 64, Issue 6-7 https://doi.org/10.1016/S0024-3205(98)00588-8	journal	January 1999
Tc17 CD8 T Cells: Functional Plasticity and Subset Diversity Yen, Hung-Rong; Harris, Timothy J.; Wada, Satoshi The Journal of Immunology, Vol. 183, Issue 11 https://doi.org/10.4049/jimmunol.0900368	journal	November 2009
The Dipeptide H-Trp-Glu-OH Shows Highly Antagonistic Activity against PPARγ: Bioassay with Molecular Modeling Simulation Ye, Fei; Zhang, Zhen-Shan; Luo, Hai-Bin ChemBioChem, Vol. 7, Issue 1 https://doi.org/10.1002/cbic.200500186	journal	November 2005
Structure-Based Drug Design of a Novel Family of PPARγ Partial Agonists: Virtual Screening, X-ray Crystallography, and in Vitro/in Vivo Biological Activities Lu, I-Lin; Huang, Chien-Fu; Peng, Yi-Hui Journal of Medicinal Chemistry, Vol. 49, Issue 9 https://doi.org/10.1021/jm051129s	journal	April 2006
Substituents at the naphthalene C3 position of (−)-Cercosporamide derivatives significantly affect the maximal efficacy as PPARγ partial agonists Furukawa, Akihiro; Arita, Tsuyoshi; Fukuzaki, Takehiro Bioorganic & Medicinal Chemistry Letters, Vol. 22, Issue 3 https://doi.org/10.1016/j.bmcl.2011.12.066	journal	February 2012
Crystal Structure of the Peroxisome Proliferator-Activated Receptor γ (PPARγ) Ligand Binding Domain Complexed with a Novel Partial Agonist: A New Region of the Hydrophobic Pocket Could Be Exploited for Drug Design Montanari, Roberta; Saccoccia, Fulvio; Scotti, Elena Journal of Medicinal Chemistry, Vol. 51, Issue 24 https://doi.org/10.1021/jm800733h	journal	November 2008
The Differential Interactions of Peroxisome Proliferator-Activated Receptor γ Ligands with Tyr473 Is a Physical Basis for Their Unique Biological Activities Einstein, Monica; Akiyama, Taro E.; Castriota, Gino A. Molecular Pharmacology, Vol. 73, Issue 1 https://doi.org/10.1124/mol.107.041202	journal	October 2007
A Novel Partial Agonist of Peroxisome Proliferator-Activated Receptor-γ (PPARγ) Recruits PPARγ-Coactivator-1α, Prevents Triglyceride Accumulation, and Potentiates Insulin Signaling in Vitro Burgermeister, Elke; Schnoebelen, Astride; Flament, Angele Molecular Endocrinology, Vol. 20, Issue 4 https://doi.org/10.1210/me.2005-0171	journal	April 2006
Pharmacology and in Vitro Profiling of a Novel Peroxisome Proliferator-Activated Receptor .GAMMA. Ligand, Cerco-A Wakabayashi, Kenji; Hayashi, Shinko; Matsui, Yumi Biological and Pharmaceutical Bulletin, Vol. 34, Issue 7 https://doi.org/10.1248/bpb.34.1094	journal	January 2011
[20] Processing of X-ray diffraction data collected in oscillation mode Otwinowski, Zbyszek; Minor, Wladek Macromolecular Crystallography Part A, 307-326 https://doi.org/10.1016/S0076-6879(97)76066-X	book	January 1997
Phaser crystallographic software McCoy, Airlie J.; Grosse-Kunstleve, Ralf W.; Adams, Paul D. Journal of Applied Crystallography, Vol. 40, Issue 4 https://doi.org/10.1107/S0021889807021206	journal	July 2007
Automated Structure Solution with the PHENIX Suite Zwart, Peter H.; Afonine, Pavel V.; Grosse-Kunstleve, Ralf W. Methods in Molecular Biology https://doi.org/10.1007/978-1-60327-058-8_28	book	January 2008
Features and development of Coot Emsley, P.; Lohkamp, B.; Scott, W. G. Acta Crystallographica Section D Biological Crystallography, Vol. 66, Issue 4 https://doi.org/10.1107/S0907444910007493	journal	March 2010
MolProbity : all-atom structure validation for macromolecular crystallography Chen, Vincent B.; Arendall, W. Bryan; Headd, Jeffrey J. Acta Crystallographica Section D Biological Crystallography, Vol. 66, Issue 1 https://doi.org/10.1107/S0907444909042073	journal	December 2009
Averaged kick maps: less noise, more signal…and probably less bias Pražnikar, Jure; Afonine, Pavel V.; Gunčar, Gregor Acta Crystallographica Section D Biological Crystallography, Vol. 65, Issue 9 https://doi.org/10.1107/S0907444909021933	journal	August 2009

Cited By (8)

Structural basis for PPAR partial or full activation revealed by a novel ligand binding mode Capelli, Davide; Cerchia, Carmen; Montanari, Roberta Scientific Reports, Vol. 6, Issue 1 https://doi.org/10.1038/srep34792	journal	October 2016
Identification of novel PPARα/γ dual agonists by virtual screening, ADMET prediction and molecular dynamics simulations Liu, Xin; Jing, Zhi; Jia, Wen-Qing Journal of Biomolecular Structure and Dynamics, Vol. 36, Issue 11 https://doi.org/10.1080/07391102.2017.1373706	journal	September 2017
Investigations on Binding Pattern of Kinase Inhibitors with PPAR γ : Molecular Docking, Molecular Dynamic Simulations, and Free Energy Calculation Studies Mazumder, Mohit; Ponnan, Prija; Das, Umashankar PPAR Research, Vol. 2017 https://doi.org/10.1155/2017/6397836	journal	January 2017
Deep Docking - a Deep Learning Approach for Virtual Screening of Big Chemical Datasets Gentile, Francesco; Agrawal, Vibudh; Hsing, Michael ACS Central Science https://doi.org/10.1101/2019.12.15.877316	journal	December 2019
Type II diabetes mellitus and obesity: Common links, existing therapeutics and future developments Banerjee, Subhadeep; Talukdar, Indrani; Banerjee, Arnab Journal of Biosciences, Vol. 44, Issue 6 https://doi.org/10.1007/s12038-019-9962-7	journal	November 2019
PPARγ in Complex with an Antagonist and Inverse Agonist: a Tumble and Trap Mechanism of the Activation Helix Frkic, Rebecca L.; Marshall, Andrew C.; Blayo, Anne-Laure iScience, Vol. 5 https://doi.org/10.1016/j.isci.2018.06.012	journal	July 2018
Dihydrosanguinarine Enhances Glucose Uptake in Mouse 3T3-L1 Cells Chow, Yit-Lai; Iwata, Yuko; Sato, Fumihiko ACS Omega, Vol. 2, Issue 10 https://doi.org/10.1021/acsomega.7b01134	journal	October 2017
Structural and Dynamic Elucidation of a Non-acid PPARγ Partial Agonist: SR1988 Frkic, Rebecca L.; Chua, Benjamin S.; Shin, Youseung Nuclear Receptor Research, Vol. 5 https://doi.org/10.11131/2018/101350	journal	January 2018

Similar Records

PPARγ partial agonist GQ-16 strongly represses a subset of genes in 3T3-L1 adipocytes

Journal Article · Fri Aug 28 00:00:00 EDT 2015 · Biochemical and Biophysical Research Communications · OSTI ID:1345039

Milton, Flora Aparecida; Cvoro, Aleksandra; Amato, Angelica A.; +6 more

A novel natural Nrf2 activator with PPARγ-agonist (monascin) attenuates the toxicity of methylglyoxal and hyperglycemia

Journal Article · Fri Nov 01 00:00:00 EDT 2013 · Toxicology and Applied Pharmacology · OSTI ID:1345039

Hsu, Wei-Hsuan; Lee, Bao-Hong; Chang, Yu-Ying; +2 more

Identification of a novel selective PPAR$γ$ ligand with a unique binding mode and improved therapeutic profile in vitro

Journal Article · Fri Jan 27 00:00:00 EST 2017 · Scientific Reports · OSTI ID:1345039

Yi, Wei; Shi, Jingjing; Zhao, Guanguan; +4 more

Related Subjects

59 BASIC BIOLOGICAL SCIENCES
37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY

Title: SR2067 reveals a unique kinetic and structural signature for PPARγ partial agonism

Citation Formats

References (44)

Cited By (8)

Similar Records

Related Subjects