WO2021041749A1 - Brown Adipose Tissue Myosin II Activators for Metabolic Therapy - Google Patents
Brown Adipose Tissue Myosin II Activators for Metabolic TherapyDownload PDFInfo
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- WO2021041749A1 WO2021041749A1PCT/US2020/048301US2020048301WWO2021041749A1WO 2021041749 A1WO2021041749 A1WO 2021041749A1US 2020048301 WUS2020048301 WUS 2020048301WWO 2021041749 A1WO2021041749 A1WO 2021041749A1
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- myh4
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/498—Pyrazines or piperazines ortho- and peri-condensed with carbocyclic ring systems, e.g. quinoxaline, phenazine
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
Definitions
- Brown adipose tissueacts as a thermoregulator by uncoupling oxidative phosphorylation through uncoupling protein 1 (UCP1) and holds the promise of enhancing energy expenditure for the treatment of metabolic diseases.
- Adrenergic signalingis viewed as a key regulator of thermogenesis and UCP1 expression in BAT, while also operating as a potent contractile stimulator in muscle.
- PPARgammanuclear transcription factors
- BATUpon adrenergic stimulation, BAT utilizes key components of muscular contractile machinery, specifically the actomyosin network, to generate tensional responses. Furthermore, during differentiation, brown and beige adipocytes have a unique type II myosin (MyH) expression pattern. Disruption of the actomyosin network using type II myosin inhibitors such as blebbistatin or 2,3BDM results in a decrease in brown adipose function. See, Tharp et ah, 2018, Cell Metabolism 27, 602-615.
- MyHtype II myosin
- the inventionprovides therapeutic methods and pharmaceutical compositions for treating obesity and obesity-associated disorders such as type-2 diabetes, cardiovascular disease, and non-alcoholic fatty liver disease with an activator of type II myosin.
- the inventionprovides a method of treating obesity or an obesity-related disease comprising: administering to a person in need thereof a type II myosin activator, and optionally detecting a resultant improvement in the obesity or an obesity-related disease.
- the inventionprovides a method of stimulating respiration in brown or beige adipocytes comprising contacting the adipocytes with a type II myosin activator, and optionally detecting a resultant increased respiration of the adipocytes.
- the activatorbinds MyH4
- the activatorbinds MyHl 1 ;
- the activatoris selected from Table 1;
- the activatoris selected from Table 2; and/or [013] the activator is selected from Myh4_#35, Myh4_#43, Myh4_#55, Myh4_#63 and Myhl 1 _2153.
- the inventionprovides a pharmaceutical composition for treating obesity or obesity-associated disorders such as type-2 diabetes, cardiovascular disease, and non-alcoholic fatty liver disease, comprising an adipocyte a type II myosin activator and a different anti obesity or anti-obesity related disorder medicament, preferably in a combined unit dosage.
- the medicamentis selected from:
- a medicament for inhibiting weight gainsuch as a food intake inhibitor or a food absorption inhibitor
- a medicament for inhibiting weight gainsuch as Orlistat, Sibutramine, Lorcaserin, Rimonabant, Metformin , Exenatide , Pramlintide, phentermine/topiramate; and [019] a medicament for reducing serum LDL, cholesterol, LDL-c, or triglycerides, such as atorvastatin (Lipitor), fluvastatin (Lescol), lovastatin (Altoprev, Mevacor), pravastatin (Pravachol), rosuvastatin (Crestor), simvastatin (Zocor), cholestyramine (Prevalite, Questran), colesevelam (Welchol), colestipol (Colestid), ezetimibe (Zetia), ezetimibe-simvastatin (Vytorin), fenofibrate (Lofibra, TriCor), gemfibrozil (Lopid), Niacin (Nia
- the activatorbinds MyH4
- the activatorbinds MyHl 1 ;
- the activatoris selected from Table 1;
- the activatoris selected from Table 2; and/or
- the activatoris selected from Myh4_#8, Myh4_#15, Myh4_#35, Myh4_#43, Myh4_#55, Myh4_#63 and Myhl 1 2153.
- Figs.lA-lFAdrenergic Induction of Tension in Brown Adipocytes. From ‘ Actomyosin-Mediated Tension Orchestrates Uncoupled Respiration in Adipose Tissues.
- A.Single-cell measurements of isoproterenol -induced stiffness in cultured brown adipocytes.
- DStorage modulus of intact BAT from mice housed at 23 ° C or exposed to 24 H of 4 ° C.
- ECellular respiration in brown adipocytes treated with 1 mM isoproterenol, IOOmM blebbistatin, or 1 mM isoproterenol and IOOmM blebbistatin.
- FRelative gene expression of brown adipocytes treated with 1 mM isoproterenol, IOOmM blebbistatin, or 1 mM isoproterenol and IOOmM blebbistatin.
- Figs. 2A-2DType II MyH4 Targeted UCP1 Induction.
- ARelative UCP1 expression from brown adipocytes treated with 1 mM isoproterenol and IOmM MyH4 activator for ⁇ 24 H. (Consolidation of the positive compounds from 92 compounds tested).
- BRelative UCP1 expression of brown adipocytes treated with IOmM Myh4 activator for ⁇ 24 H.
- CTime course of UCP1 induction in brown adipocytes treated with IOmM of MyH4 compound #55.
- DDose titration of the relative UCP1 expression of brown adipocytes treated with MyH4 compound #55 alone for ⁇ 24 H.
- Figs. 3A-3DType II MyHl 1 Targeted UCP1 Induction.
- ARelative UCP1 expression from brown adipocytes treated with 1 mM isoproterenol and IOmM MyHl 1 activator for ⁇ 24 H. (Consolidation of the positive compounds from 74 compounds tested).
- BRelative UCP1 expression of brown adipocytes treated with IOmM MyHl 1 activator for ⁇ 24 H.
- CUCP1 protein from brown adipocytes treated with or without MyHl 1 compound #2153 for 24 H, gel.
- Figs. 4A-CCellular Respiration in Brown and Beige Adipocytes.
- ACellular Respiration of brown adipocytes treated for 1 H with 10mM MyH4 compound #35 and with 1 mM of isoproterenol.
- B/CCellular respiration of human derived ZenBio cell line differentiated to beige adipocytes treated overnight with 10mM MyH4 compound #43 and with or without 1 mM of isoproterenol.
- sBAT cells(brown adipocyte cell line) were treated overnight with lOuM of either Myh 4 activator #8, #55, or #15 and luM of isoproterenol for 24 hours. 24 hours post treatment, a mitochondrial stress test was done to determine cellular respiration using a Seahorse XFe24 Analyzer. Oligomycin, FCCP, Rotenone, and Antimycin were injected at lOuM nal to determine basal, uncoupled, and maximal respiration. Cells were harvested with RIPA and cellular respiration was normalized to protein content.
- C57BL/6J(Jackson laboratory, Bar Harbor ME).
- C57BL/6Jis an inbred strain susceptible to diet-induced obesity, type 2 diabetes, and atherosclerosis.
- IP injection1, 10 and 100 mg/kg compound in saline, administered weekly over two months; oral: 20, 100 and 500 mg/kg compound mixed with food and fed continuously for 2 months.
- Active Type II myosin activatorMyH4 activators.
- sBATpositive mitochondrial stress test for cellular respiration, see e.g. Fig.5; Ob/Ob: reduced weight in B6.Cg-Lepob/J mice, supra; HFD: lower weight gain in high fat diet C57BL/6J mice, supra. Active compounds provide significant (p ⁇ 05, +++) at at least one graduated dose.
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- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
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- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
Description
Brown Adipose Tissue Myosin II Activators for Metabolic Therapy
This invention was made with government support under Grant Number DK118940 awarded by the National Institutes of Health. The government has certain rights in the invention.
[001] Introduction
[002] Brown adipose tissue (BAT), acts as a thermoregulator by uncoupling oxidative phosphorylation through uncoupling protein 1 (UCP1) and holds the promise of enhancing energy expenditure for the treatment of metabolic diseases. Adrenergic signaling is viewed as a key regulator of thermogenesis and UCP1 expression in BAT, while also operating as a potent contractile stimulator in muscle. However, current approaches for treating obesity -related disease by relying on activation of B-adrenergic receptors or nuclear transcription factors (PPARgamma) activators (rosiglitazone) have been fraught with severe side-effects.
[003] Upon adrenergic stimulation, BAT utilizes key components of muscular contractile machinery, specifically the actomyosin network, to generate tensional responses. Furthermore, during differentiation, brown and beige adipocytes have a unique type II myosin (MyH) expression pattern. Disruption of the actomyosin network using type II myosin inhibitors such as blebbistatin or 2,3BDM results in a decrease in brown adipose function. See, Tharp et ah, 2018, Cell Metabolism 27, 602-615.
[004] Summary of the Invention
[005] The invention provides therapeutic methods and pharmaceutical compositions for treating obesity and obesity-associated disorders such as type-2 diabetes, cardiovascular disease, and non-alcoholic fatty liver disease with an activator of type II myosin.
[006] In an aspect the invention provides a method of treating obesity or an obesity-related disease comprising: administering to a person in need thereof a type II myosin activator, and optionally detecting a resultant improvement in the obesity or an obesity-related disease.
[007] In an aspect the invention provides a method of stimulating respiration in brown or beige adipocytes comprising contacting the adipocytes with a type II myosin activator, and optionally detecting a resultant increased respiration of the adipocytes.
[008] In embodiments:
[009] the activator binds MyH4;
[010] the activator binds MyHl 1 ;
[Oil] the activator is selected from Table 1;
[012] the activator is selected from Table 2; and/or [013] the activator is selected from Myh4_#35, Myh4_#43, Myh4_#55, Myh4_#63 and Myhl 1 _2153.
[014] In an aspect the invention provides a pharmaceutical composition for treating obesity or obesity-associated disorders such as type-2 diabetes, cardiovascular disease, and non-alcoholic fatty liver disease, comprising an adipocyte a type II myosin activator and a different anti obesity or anti-obesity related disorder medicament, preferably in a combined unit dosage.
[015] In embodiments:
[016] the medicament is selected from:
[017] a medicament for inhibiting weight gain such as a food intake inhibitor or a food absorption inhibitor;
[018] a medicament for inhibiting weight gain such as Orlistat, Sibutramine, Lorcaserin, Rimonabant, Metformin , Exenatide , Pramlintide, phentermine/topiramate; and [019] a medicament for reducing serum LDL, cholesterol, LDL-c, or triglycerides, such as atorvastatin (Lipitor), fluvastatin (Lescol), lovastatin (Altoprev, Mevacor), pravastatin (Pravachol), rosuvastatin (Crestor), simvastatin (Zocor), cholestyramine (Prevalite, Questran), colesevelam (Welchol), colestipol (Colestid), ezetimibe (Zetia), ezetimibe-simvastatin (Vytorin), fenofibrate (Lofibra, TriCor), gemfibrozil (Lopid), Niacin (Niaspan), Omega-3 fatty acid (Lovaza);
[020] the activator binds MyH4;
[021] the activator binds MyHl 1 ;
[022] the activator is selected from Table 1;
[023] the activator is selected from Table 2; and/or
[024] the activator is selected from Myh4_#8, Myh4_#15, Myh4_#35, Myh4_#43, Myh4_#55, Myh4_#63 and Myhl 1 2153.
[025] The invention encompasses all combinations of the particular embodiments recited herein, as if each combination had been laboriously recited.
[026] Brief Description of the Drawings
[027] Figs.lA-lF: Adrenergic Induction of Tension in Brown Adipocytes. From ‘ Actomyosin-Mediated Tension Orchestrates Uncoupled Respiration in Adipose Tissues. A. Single-cell measurements of isoproterenol -induced stiffness in cultured brown adipocytes. B: BAT explant response to isoproterenol treatment (100 mM). C: AFM assessment of cellular stiffness across a monolayer of fully differentiated brown adipocytes 30min after treatment with 1 mM isoproterenol and lOOpM blebbistatin. D: Storage modulus of intact BAT from mice housed at 23°C or exposed to 24 H of 4°C. E: Cellular respiration in brown adipocytes treated with 1 mM isoproterenol, IOOmM blebbistatin, or 1 mM isoproterenol and IOOmM blebbistatin. F: Relative gene expression of brown adipocytes treated with 1 mM isoproterenol, IOOmM blebbistatin, or 1 mM isoproterenol and IOOmM blebbistatin.
[028] Figs. 2A-2D: Type II MyH4 Targeted UCP1 Induction. A: Relative UCP1 expression from brown adipocytes treated with 1 mM isoproterenol and IOmM MyH4 activator for ~24 H. (Consolidation of the positive compounds from 92 compounds tested). B: Relative UCP1 expression of brown adipocytes treated with IOmM Myh4 activator for ~24 H. C: Time course of UCP1 induction in brown adipocytes treated with IOmM of MyH4 compound #55. D: Dose titration of the relative UCP1 expression of brown adipocytes treated with MyH4 compound #55 alone for ~24 H.
[029] Figs. 3A-3D: Type II MyHl 1 Targeted UCP1 Induction. A: Relative UCP1 expression from brown adipocytes treated with 1 mM isoproterenol and IOmM MyHl 1 activator for ~24 H. (Consolidation of the positive compounds from 74 compounds tested). B: Relative UCP1 expression of brown adipocytes treated with IOmM MyHl 1 activator for ~24 H. C: UCP1 protein from brown adipocytes treated with or without MyHl 1 compound #2153 for 24 H, gel.
D. UCP1 protein from brown adipocytes treated with or without MyHl 1 compound #2153 for 24 H, bar graph.
[030] Figs. 4A-C: Cellular Respiration in Brown and Beige Adipocytes. A. Cellular Respiration of brown adipocytes treated for 1 H with 10mM MyH4 compound #35 and with 1 mM of isoproterenol. B/C: Cellular respiration of human derived ZenBio cell line differentiated to beige adipocytes treated overnight with 10mM MyH4 compound #43 and with or without 1 mM of isoproterenol.
[031] Fig. 5. sBAT cells (brown adipocyte cell line) were treated overnight with lOuM of either Myh 4 activator #8, #55, or #15 and luM of isoproterenol for 24 hours. 24 hours post treatment, a mitochondrial stress test was done to determine cellular respiration using a Seahorse XFe24 Analyzer. Oligomycin, FCCP, Rotenone, and Antimycin were injected at lOuM nal to determine basal, uncoupled, and maximal respiration. Cells were harvested with RIPA and cellular respiration was normalized to protein content.
[032] Description of Particular Embodiments of the Invention
[033] Unless contraindicated or noted otherwise, in these descriptions and throughout this specification, the terms “a” and “an” mean one or more, the term “or” means and/or. The examples and embodiments described herein are for illustrative purposes only and that various modifications or changes in light thereof will be suggested to persons skilled in the art and are to be included within the spirit and purview of this application and scope of the appended claims. All publications, patents, and patent applications cited herein, including citations therein, are hereby incorporated by reference in their entirety for all purposes.
[034] We disclose therapeutic methods and pharmaceutical compositions for treating obesity and obesity-associated disorders with an activator of type II myosin. We report that we can stimulate brown and beige adipose tissue by increasing myosin activity. We used a convolutional neural network for structure-based drug discovery, including the development of homology models to target Myosin proteins and 166 compounds we predicted to bind to either MyH4 or MyHl 1. We report that increasing the ATPase activity of the myosin isoforms results in an increase in brown and beige adipose function, including respiration, as a result of increased UCP1 expression and cellular respiration, and that Myosin II activators show the ability to increase the expression of uncoupling protein 1 (UCP1), a pivotal determinant of uncoupled respiration, in murine and human brown and beige cells.
[035] Animal models of human obesity and obesity-associated disesase. After demonstrating that the compounds are effective to stimulate respiration in brown adipocytes, we applied the activators to two animal models of human obesity and obesity related disorders (such as type-2 diabetes, cardiovascular disease, and non-alcoholic fatty liver disease) to demonstrate these compounds may be used to treat human obesity and obesity associated disorders [036] B6.Cg-Lepob/J (Jackson laboratory, Bar Harbor ME). Mice homozygous for the obese spontaneous mutation, Lepob (commonly referred to as ob or ob/ob), exhibit obesity, hyperphagia, transient hyperglycemia, glucose intolerance, and elevated plasma insulin. Obesity is characterized by an increase in the number and size of adipocytes. Although hyperphagia contributes to the obesity, homozygotes gain excess weight and deposit excess fat even when restricted to a diet sufficient for normal weight maintenance in lean mice.
[037] C57BL/6J(Jackson laboratory, Bar Harbor ME). C57BL/6J is an inbred strain susceptible to diet-induced obesity, type 2 diabetes, and atherosclerosis. Hu et al. Cell Metab. 2018 Sep 4;28(3):415-431.e4; Takahashi et al. JNutr Sci Vitaminol (Tokyo). 1999 Oct;45(5):583-93.
[038] High Fat Diet: D 12492; Rodent Diet With 60 kcal% Fat, fed continuously, two months
[039] Administration. Both oral and intraperitoneal (IP) injection routes were established at graduating dosages: IP injection: 1, 10 and 100 mg/kg compound in saline, administered weekly over two months; oral: 20, 100 and 500 mg/kg compound mixed with food and fed continuously for 2 months.
[040] Table 1. Active Type II myosin activator: MyH4 activators. sBAT: positive mitochondrial stress test for cellular respiration, see e.g. Fig.5; Ob/Ob: reduced weight in B6.Cg-Lepob/J mice, supra; HFD: lower weight gain in high fat diet C57BL/6J mice, supra. Active compounds provide significant (p< 05, +++) at at least one graduated dose.
[041] Table 2. Active Type II myosin activator: MyHll activators sBAT: positive mitochondrial stress test for cellular respiration, see e.g. Fig.5; Ob/Ob: reduced weight in
B6.Cg-Lepob/J mice, supra; HFD: lower weight gain in high fat diet C57BL/6J mice, supra. Active compounds provide significant (p< 05, +++) results at at least one graduated dose.
Claims
1. A method of stimulating respiration in brown or beige adipocytes, the method comprising contacting the adipocytes with a type II myosin activator.
2. The method of claim 1 wherein the method comprises treating obesity or an obesity-related disease by administering to a person in need thereof a type II myosin activator, wherein the adipocytes are in situ in the person.
3. A method of treating obesity or an obesity-related disease by administering to a person in need thereof a type II myosin activator.
4. The method of claim 1, 2 or 3 wherein the activator binds MyH4.
5. The method of claim 1, 2 or 3 wherein the activator binds MyHl 1.
6. The method of claim 1, 2 or 3 wherein the activator is selected from Table 1.
7. The method of claim 1, 2 or 3 wherein the activator is selected from Table 2.
8. The method of claim 1, 2 or 3 wherein the activator is selected from Myh4_#8, Myh4_#15, Myh4_#35, Myh4_#43, Myh4_#55, and Myh4_#63:
9. The method of claim 1, 2 or 3 wherein the activator is Myhl 1 2153:
Myhl 1 _2153: N-(benzo[d][l,3]dioxol-5-ylmethyl)-4-(6-(2-methoxyphenoxy)pyrimidin-4- yl)benzamide.
10. The method of claim 1 further comprising the step of detecting a resultant increased respiration of the adipocytes.
11. The method of claim 2 or 3 further comprising the step of detecting a resultant improvement in the obesity or obesity-related disease.
12. A pharmaceutical composition for treating obesity or obesity-associated disorders such as type-2 diabetes, cardiovascular disease, and non-alcoholic fatty liver disease, comprising an adipocyte a type II myosin activator and a different anti -obesity or anti-obesity related disorder medicament.
13. The composition of claim 12 formulated in a combined unit dosage.
14. The composition of claim 12 or 13 wherein the medicament is selected from: a medicament for inhibiting weight gain such as a food intake inhibitor or a food absorption inhibitor; a medicament for inhibiting weight gain such as Orlistat, Sibutramine, Lorcaserin, Rimonabant, Metformin , Exenatide , Pramlintide, phentermine/topiramate; and a medicament for reducing serum LDL, cholesterol, LDL-c, or triglycerides, such as atorvastatin (Lipitor), fluvastatin (Lescol), lovastatin (Altoprev, Mevacor), pravastatin (Pravachol), rosuvastatin (Crestor), simvastatin (Zocor), cholestyramine (Prevalite, Questran), colesevelam (Welchol), colestipol (Colestid), ezetimibe (Zetia), ezetimibe-simvastatin (Vytorin), fenofibrate (Lofibra, TriCor), gemfibrozil (Lopid), Niacin (Niaspan), Omega-3 fatty acid (Lovaza).
15. The composition of claim 12, 13 or 14 wherein the activator binds MyH4.
16. The composition of claim 12, 13 or 14 wherein the activator binds MyHl 1.
17. The composition of claim 12, 13 or 14 wherein the activator is selected from Table 1.
18. The composition of claim 12, 13 or 14 wherein the activator is selected from Table 2.
19. The composition of claim 12, 13 or 14 wherein the activator is selected from Myh4_#8,
Myh4_# l 5, Myh4_#35, Myh4_#43, Myh4_#55, and Myh4_#63
20. The composition of claim 12, 13 or 14 wherein the activator is Myhl 1 2153.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
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| US201962892523P | 2019-08-27 | 2019-08-27 | |
| US62/892,523 | 2019-08-27 |
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| WO2021041749A1true WO2021041749A1 (en) | 2021-03-04 |
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2012065057A2 (en)* | 2010-11-12 | 2012-05-18 | Exelixis, Inc. | Phosphatidylinositol 3-kinase inhibitors and methods of their use |
| US20150164861A1 (en)* | 2010-08-20 | 2015-06-18 | Amira Pharmaceuticals, Inc. | Autotaxin inhibitors and uses thereof |
| US20160311764A1 (en)* | 2013-12-16 | 2016-10-27 | The Johns Hopkins University | Activators of myosin ii for modulating cell mechanics |
- 2020
- 2020-08-27WOPCT/US2020/048301patent/WO2021041749A1/ennot_activeCeased
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20150164861A1 (en)* | 2010-08-20 | 2015-06-18 | Amira Pharmaceuticals, Inc. | Autotaxin inhibitors and uses thereof |
| WO2012065057A2 (en)* | 2010-11-12 | 2012-05-18 | Exelixis, Inc. | Phosphatidylinositol 3-kinase inhibitors and methods of their use |
| US20160311764A1 (en)* | 2013-12-16 | 2016-10-27 | The Johns Hopkins University | Activators of myosin ii for modulating cell mechanics |
Non-Patent Citations (2)
| Title |
|---|
| DATABASE PUBCHEM compound [online] 28 May 2009 (2009-05-28), "3-Chloro-N-[3-({[6-(1H-pyrazol-1-yl)pyridin-3-yl]methyl}amino)quinoxalin-2-yl]benzene-1-sulfonamide", XP055801392, retrieved from NCBI Database accession no. 26034697* |
| THARP KEVIN M; KANG MICHAEL S; TIMBLIN GREG A; DEMPERSMIER JON; DEMPSEY GARRET E; ZUSHIN PETER-JAMES H; BENAVIDES JAIME; CHOI CATH: "Actomyosin-Mediated Tension Orchestrates Uncoupled Respiration in Adipose Tissues", CELL METABOLISM, vol. 27, 6 March 2018 (2018-03-06), pages 602 - 615, XP085357907, DOI: 10.1016/j.cmet.2018.02.005* |
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