MK-5046
目录号 : GC19413
MK-5046是一种强效，具有选择性和口服活性的Bombesin受体亚型3（BRS-3）激动剂，对hBRS-3的IC50和EC50值分别为27nM和25nM。
Cas No.:1022152-70-0
Sample solution is provided at 25 µL, 10mM.
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MK-5046 is a potent, selective, and orally active Bombesin receptor subtype 3 (BRS-3) agonist, with IC50 and EC50 values of 27nM and 25nM, respectively, for human BRS-3[1]. BRS-3 is an orphan G protein-coupled receptor (GPCR) that plays an important role in regulating energy homeostasis, glucose metabolism, and insulin secretion[2]. MK-5046 is commonly used in the treatment of obesity and in studies of BRS-3-related signaling pathways[3,4].
In vitro, treatment of BRS-3-H1299 cells with MK-5046 (0.01, 0.1, 1μM) for 5min dose-dependently and significantly increased HER2 tyrosine phosphorylation (PY1248-HER2) and ERK phosphorylation (P-ERK)[5]. Treatment of serum-starved H1299-BRS3 cells with MK-5046 (10nM) for 24h significantly enhanced cell migration, an effect that could be reversed by the BRS-3 antagonist Bantag-1 or the Hippo pathway inhibitor Verteporfin[6].
In vivo, subcutaneous administration of MK-5046 (5, 25, 50mg/kg/day) for 14 days in diet-induced obesity (DIO) mice resulted in dose-dependent body weight reduction, with a maximum weight loss of approximately 9%[7]. Intravenous administration of MK-5046 (1mg/kg) in anesthetized wild-type mice significantly increased interscapular brown adipose tissue temperature and core body temperature[8].
References:
[1] SEBHAT I K, FRANKLIN C, LO M M C, et al. Discovery of MK-5046, a potent, selective bombesin receptor subtype-3 agonist for the treatment of obesity[J]. ACS Medicinal Chemistry Letters, 2011, 2(1): 43-47.
[2] FENG Y, GUAN X M, LI J, et al. Bombesin receptor subtype-3 (BRS-3) regulates glucose-stimulated insulin secretion in pancreatic islets across multiple species[J]. Endocrinology, 2011, 152(11): 4106-4115.
[3] GONZÁLEZ N, MORENO P, JENSEN R T. Bombesin receptor subtype 3 as a potential target for obesity and diabetes[J]. Expert Opinion on Therapeutic Targets, 2015, 19(9): 1153-1170.
[4] REITMAN M L, DISHY V, MOREAU A, et al. Pharmacokinetics and pharmacodynamics of MK-5046, a bombesin receptor subtype-3 (BRS-3) agonist, in healthy patients[J]. The Journal of Clinical Pharmacology, 2012, 52(9): 1306-1316.
[5] MOODY T W, RAMOS-ALVAREZ I, MANTEY S A, et al. Bombesin receptor subtype-3 regulates tumor growth by HER2 tyrosine phosphorylation in a reactive oxygen species-dependent manner in lung cancer cells[J]. Targets, 2025, 3(1): 7.
[6] GUO M, ZHANG Y, WU L, et al. Dynamic phosphoproteomics of BRS3 activation reveals the Hippo signaling pathway for cell migration[J]. Journal of Proteome Research, 2023, 22(7): 2364-2376.
[7] GUAN X M, METZGER J M, YANG L, et al. Antiobesity effect of MK-5046, a novel bombesin receptor subtype-3 agonist[J]. The Journal of Pharmacology and Experimental Therapeutics, 2011, 336(2): 356-364.
[8] LATEEF D M, ABREU-VIEIRA G, XIAO C, et al. Regulation of body temperature and brown adipose tissue thermogenesis by bombesin receptor subtype-3[J]. American Journal of Physiology-Endocrinology and Metabolism, 2014, 306(6): E681-E687.
MK-5046是一种强效，具有选择性和口服活性的Bombesin受体亚型3（BRS-3）激动剂，对hBRS-3的IC50和EC50值分别为27nM和25nM[1]。BRS-3是一种孤儿型G蛋白偶联受体（GPCR），在调控能量稳态、葡萄糖代谢和胰岛素分泌中发挥重要作用[2]。MK-5046通常用于肥胖的治疗和BRS-3相关信号通路的研究[3,4]。
在体外，MK-5046（0.01, 0.1, 1μM）处理BRS-3-H1299细胞5min，剂量依赖性地显著增加了HER2酪氨酸磷酸化（PY1248-HER2）和ERK磷酸化（P-ERK）[5]。MK-5046（10nM）处理血清饥饿的H1299-BRS3细胞24h，显著增强了细胞的迁移能力，但该效应可被Bantag-1或Hippo通路抑制剂Verteporfin所逆转[6]。
在体内，MK-5046（5, 25, 50mg/kg/day）通过皮下注射处理饮食诱导肥胖（DIO）小鼠14天，剂量依赖性地引起了小鼠体重下降，最大减重约9%[7]。MK-5046（1mg/kg）通过静脉注射处理麻醉的野生型小鼠，显著增加了肩胛间棕色脂肪组织的温度和体温[8]。
| Cell experiment [1]: | |
Cell lines | Starved H1299-BRS3 cells |
Preparation Method | 5 × 104 starved cells were plated into the top chamber with FBS-free medium, while a medium containing 10% FBS and drugs was added to the external chamber as a chemoattractant. The starved cells were treated with MK-5046 (10nM), or MK-5046 and Bantag-1, or MK-5046 and Verteporfin for 24h. After incubation, 0.5% crystal violet was used to stain the cells. The upper layer cells that did not pass through the membrane were erased, while the cells that passed through were counted under an Echo Revolve Upside-Down integrated fluorescence microscope. |
Reaction Conditions | 10nM; 24h |
Applications | Treatment with MK-5046 (10nM) significantly enhanced cell migration, but this effect could be reversed by the Bantag-1 or Hippo pathway inhibitor Verteporfin. |
| Animal experiment [2]: | |
Animal models | Diet-induced obesity (DIO) mice |
Preparation Method | DIO mice received continuous subcutaneous infusion of MK-5046 at doses of 5, 25, or 50mg/kg/day for 14 days. Body weight was monitored daily throughout the study period. |
Dosage form | 5, 25, 50mg/kg/day; 14 days; s.c. |
Applications | Treatment with MK-5046 (5, 25, 50mg/kg/day) induced a dose-dependent decrease in body weight in mice, with a maximum weight loss of approximately 9%. |
References: | |
| Cas No. | 1022152-70-0 | SDF | |
| Canonical SMILES | O[C@](CC1=NC(CC2(C(F)(F)F)CC2)=CN1)(C(F)(F)F)C3=CC=C(N4C=CC=N4)C=C3 | ||
| 分子式 | C20H18F6N4O | 分子量 | 444.37 |
| 溶解度 | Soluble in DMSO | 储存条件 | Store at -20°C |
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| 制备储备液 | |||
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1 mg | 5 mg | 10 mg |
| 1 mM | 2.2504 mL | 11.2519 mL | 22.5038 mL |
| 5 mM | 450.1 μL | 2.2504 mL | 4.5008 mL |
| 10 mM | 225 μL | 1.1252 mL | 2.2504 mL |
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| 给药剂量 | mg/kg |  |
动物平均体重 | g | |
每只动物给药体积 | ul | |
动物数量 | 只 |
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| % DMSO % % Tween 80 % saline | ||||||||||
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工作液浓度： mg/ml；
DMSO母液配制方法： mg 药物溶于 μL DMSO溶液（母液浓度 mg/mL，
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2.
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