MK-5046 / Merck (MSD) - LARVOL DELTA

Divergent activation patterns of BRS3 revealed by two Chinese herb-derived agonists. (PubMed, Acta Pharm Sin B) - "Recent structural studies have elucidated BRS3 signaling mechanisms using synthetic ligands, including BA1 and MK-5046...Although both compounds bind to the orthosteric pocket, they differentially engage the interaction network of BRS3, as demonstrated by mutagenesis studies assessing calcium mobilization and inositol phosphate 1 (IP1) accumulation. These findings enhance our understanding of BRS3 activation and provide valuable insights into the development of small-molecule BRS3 modulators with therapeutic potential."

Journal • GRP-10

Bombesin Receptor Subtype-3 Regulates Tumor Growth by HER2 Tyrosine Phosphorylation in a Reactive Oxygen Species-Dependent Manner in Lung Cancer Cells. (PubMed, Targets (Basel)) - "The increase in HER2/ERK phosphorylation caused by MK-5046 was inhibited by ROS inhibitors, N-acetylcysteine and Tiron (superoxide-scavenger). These results indicate that in lung cancer cells activation of BRS-3 regulates HER2-transactivation in ROS-dependent manner which can mediate tumor growth. These results raise the possibility that the use of HER2-inhibiting compounds alone or in combination with other agents, could be a novel approach in the treatment of these tumors."

Journal • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • EGFR • GRP-10 • HER-2

Structural insights into ligand recognition, selectivity, and activation of bombesin receptor subtype-3. (PubMed, Cell Rep) - "We present two cryogenic electron microscopy (cryo-EM) structures of BRS3 in complex with the heterotrimeric Gq protein in its active states: one bound to the pan-BnR agonist BA1 and the other bound to the synthetic BRS3-specific agonist MK-5046...Examination of conserved micro-switches suggests a shared activation mechanism among BnRs. Our findings shed light on BRS3's ligand selectivity and signaling mechanisms, paving the way for exploring its therapeutic potential for diabetes, obesity, and related metabolic disorders."

Journal • Diabetes • Genetic Disorders • Metabolic Disorders • Obesity • GRP-10

Dynamic Phosphoproteomics of BRS3 Activation Reveals the Hippo Signaling Pathway for Cell Migration. (PubMed, J Proteome Res) - "The lung cancer cell line H1299-BRS3 was treated with MK-5046, an agonist of BRS3, for different durations...Verification experiments demonstrated that downregulation of the Hippo signaling pathway caused by BRS3 activation could induce the dephosphorylation and nucleus localization of the Yes-associated protein (YAP), and its association with cell migration was further confirmed by kinase inhibition. Our data collectively demonstrate that BRS3 activation contributes to cell migration through downregulation of the Hippo signaling pathway."

Journal • Lung Cancer • Oncology • Solid Tumor • GRP-10

The non-peptide agonist, MK-5046, functions as an allosteric agonist for the Bombesin receptor subtype-3 (BRS-3). (PubMed, J Pharmacol Exp Ther) - "No allosteric ligands exist for any of the mammalian Bombesin receptor (BnR) family. Here we provide evidence for the first such example of a BnR allosteric ligand by showing MK-5046, a nonpeptide agonist for the BRS-3 receptor, is functioning as an allosteric agonist."

Journal • Gastrointestinal Disorder • GRP-10

Bombesin-like receptor 3 neurons regulate body temperature, heart rate and food intake (Neuroscience 2017) - "...Nucleus-targeted MK-5046 injections in the DMH, but not in the PVH, raised BAT temperature...Taken together, the results suggest that the food intake suppression and thermogenic effects of Brs3 activation are mediated by different subsets of Brs3-expressing neurons. Specifically, DMHBrs3 neurons can increase energy expenditure, body temperature and heart rate, and PVHBrs3 neurons can suppress food intake"

CNS Disorders

DIFFERENT CLASSES OF NONPEPTIDE AGONISTS HAVE A DIFFERENT MOLECULAR BASIS FOR THEIR AFFINITY/SELECTIVITY FOR THE HUMAN BOMBESIN RECEPTOR SUBTYPE-3, HBRS-3 (DDW 2020) - "Aim: To determine the molecular basis for the affinity/selectivity of members from two classes of BRS3 nonpeptide agonists; the chiral diazepine 9G and MK-5046... These results show that the molecular pharmacophore for these two nonpeptide BRS3 agonists is markedly different. Although both interact with the extracellular loop two or EC3, the exact determinants are markedly different in this and other receptor regions. The definition of these different areas will allow a detailed exploration of the exact molecular/chemical determinants of these agonists high BRS3 affinity/selectivity"

GRP-10

Bombesin Receptor Subtype-3 in Human Diseases. (PubMed, Arch Med Res) - "However, several agonists and antagonists have been synthesized which facilitate its characterization, (D-Tyr6, β-Ala11, Phe13, Nle14) Bn-(6-14) and MK-5046 are agonists, whereas ML-18 and Bantag-1 are antagonists. With the development of several selective, high-affinity BRS-3 agonists and antagonists, recent studies provided some insights into the biological effects of BRS-3 in several disease states including lung cancer, obesity, diabetes mellitus, asthma, and kidney diseases."

Journal • Review

BRS3 in both MC4R- and SIM1-expressing neurons regulates energy homeostasis in mice. (PubMed, Mol Metab) - "BRS3 in both MC4R- and SIM1-expressing neurons contributes to regulation of body weight/adiposity, insulin sensitivity, food intake, and body temperature."

Journal • GRP-10