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]。