RET IN 1

RET-IN-1 is a RET kinase inhibitor with IC50 values of 1 nM for RET (WT), 7 nM for RET (V804M), and 101 nM for RET (G810R).

RETligand-1 is a target protein ligand that specifically interacts with RET and can be utilized in the synthesis of the PROTAC LDD39.

RET Ligand-Linker Conjugate-1 consists of a complex formed by a RET ligand and a linker, which can be utilized in the synthesis of QZ2135.

RET/TRKA-IN-1 (Compound 13) is a dual inhibitor targeting RET with an IC50 of 0.375 µM and TRKA. It reduces cell viability of LC-2 and KM12, with GI50 values of 0.72 and 0.25 µM respectively. RET/TRKA-IN-1 also induces cell cycle arrest at the G1 phase.

RET V804M-IN-1 (RETV804M kinase inhibitor) is a wt-RET -selective RETV804M kinase inhibitors(IC50 = 20 nM).

RET-IN-12 is a RET inhibitor capable of acting on RET(WT) (IC50: 0.3 nM) and RET(V804M) (IC50: 1 nM).

Secretin (1-6) is the N-terminal part of secretin. It can produce vitro glucose-dependent insulin release induced by secretin.

RET-IN-15 is an inhibitor of rearrangement kinase (RET) during transfection and can be used in cancer research.

RET-IN-14 is a potent inhibitor of RET, capable of acting on RET (WT) (IC50 < 0.51 nM), RET (G810R) (IC50: 9.3 nM), RET (V804M) (IC50: 1.3 nM), BTK (C481S) (IC50: 9.2 nM) and BTK (C481S) (IC50 : 15 nM). RET-IN-14 exhibits potential for tumor studies.

RET-IN-11 is a potent and selective RET inhibitor that acts on RET (IC50: 6.20 nM) and RETV804M (IC50: 18.68 nM). RET-IN-11 induces apoptosis and exhibits anti-proliferative and migratory effects in LC-2/ad cells.

RET-IN-10 is a potent inhibitor of RET, with RET loss-of-function mutations linked to congenital megacolon and gain-of-function mutations associated with various human tumors. RET-IN-10 has demonstrated research potential in cancer diseases.

RET-IN-19 is a potent inhibitor of RET and exhibits anticancer effects on RET-wt (IC50: 6.8 nM) and RET V804M (IC50: 13.51 nM).RET-IN-19 can be used to study non-small cell lung cancer (NSCLC).

RET-IN-17 is a potent inhibitor of RET with potential applications in studies of pain associated with IBS and other gastrointestinal disorders, as well as cancers with constitutive RET kinase activity.

RET-IN-13, a quinoline-based compound, effectively inhibits the RET kinase, demonstrating IC50 values of 0.5 nM for RET (WT) and 0.9 nM for RET (V804M). It holds promise for research into tumors and intestinal diseases associated with abnormal RET activation.

RET-IN-16 is a potent, selective inhibitor of RET, exhibiting IC50 values of 3.98 nM for RET(WT), 8.42 nM for RET(M918T), 15.05 nM for RET(V804L), 7.86 nM for RET(V804M), 5.43 nM for RET-CCDC6, and 8.86 nM for RET-KIF5B, indicating its high efficacy across different RET mutations. It possesses anticancer properties.

Orexin A (human, rat, mouse) acetate (Hypocretin-1) is an excitatory neuropeptide with analgesic properties. It activates Orexin-1 (OX1R) and Orexin-2 (OX2R) receptors, used for studying neurodegenerative diseases.

rac-Hesperetin-13C-D3 the 13C and deuterated compound of rac-Hesperetin (T12667). rac-Hesperetin has a CAS number of 69097-99-0. (Rac)-Hesperetin is the racemate form of of Hesperetin. Hesperetin is a natural flavanone compound, and it exhibits potent inhibitory effects against human UGT activity, making it a broad-spectrum inhibitor. Furthermore, Hesperetin induces apoptosis through the activation of p38 MAPK.

Orexin A-13C18,15N3 (human, rat, mouse) ((Hypocretin-1-13C18,15N3 (human, rat, mouse)) TFA) is a compound labeled with 13C and 15N, and it is a form of Orexin A (human, rat, mouse). Orexin A, also known as Hypocretin-1, is a 33 amino acid excitatory neuropeptide involved in various central and peripheral processes. It binds to and activates two G protein-coupled receptors: the Orexin-1 receptor (OX1R) and Orexin-2 receptor (OX2R), playing a crucial role in regulating feeding behavior. Orexin A is also an active molecule with potent antinociceptive and anti-hyperalgesic properties.

Orexin A-13C6,15N (human, rat, mouse) (also known as Hypocretin-1-13C6,15N (human, rat, mouse)) TFA is an isotopically labeled version of Orexin A (human, rat, mouse). This 33-amino acid excitatory neuropeptide is involved in various central and peripheral processes. It binds to and activates two G protein-coupled receptors, the Orexin-1 receptor (OX1R) and the Orexin-2 receptor (OX2R), playing a crucial role in regulating feeding behavior. Additionally, Orexin A (human, rat, mouse) is an effective agent against nociception and hyperalgesia.

Multi-kinase-IN-5 (compound 15c) is a multi-kinase inhibitory agent that demonstrates significant inhibition of a range of protein kinases, including RET (69%), KIT (31%), cMet (62%), VEGFR1 (40%), VEGFR2 (73%), FGFR1 (74%), PDGFR (59%), and BRAF (74%). Its IC50 values are 1.287 μM for FGFR1, 0.117 μM for VEGFR, and 1.185 μM for RET kinases, indicating its potency [1].

Vandetanib Fumarate is an orally available tyrosine kinase inhibitor. Vandetanib Fumarate works by blocking RET (REarranged during Transfection), vascular endothelial growth factor receptor (VEGFR-2, VEGFR-3), and epidermal growth factor receptor and to a

QZ2135 (compound 20) is a PROTAC degrader that specifically targets RET and exhibits antitumor activity in vivo within a Ba/F3-KIF5B-RET-G810C xenograft mouse model. The compound demonstrates degradation activity with DC50 values of 4.7 nM (WT), 17.2 nM (V804M), and 73.8 nM (G810C) when targeting KIF5B-RET. QZ2135 is composed of the target protein ligand (red part) RETligand-3, the E3 ligase ligand (blue part) Lenalidomide-F, and the PROTAC Linker (black part) 7-Iodohept-1-yne, wherein the target protein ligand combined with the linker forms the conjugate RETLigand-Linker Conjugate-1.

APS03118 is an orally effective, potent, and highly selective RET inhibitor. It broadly inhibits RET fusions and various mutations (including G810, V804, L730, and Y806 variants), with IC50 values generally below 1 nM (0.0952 nM for the wild type; mutation IC50s range from 0.00438 to 5.72 nM), demonstrating significant inhibitory activity against RETG810 mutations. APS03118 effectively suppresses the entire RET signaling pathway, including RET, Shc, and ERK1/2, and shows more than 20-fold selectivity over most off-target kinases, excluding FLT3 and YES. In vivo, APS03118 induces complete tumor regression in KIF5B-RET and CCDC6-RET V804M PDX mouse models and significantly extends survival in intracranial CCDC6-RET metastatic mouse models. This compound is applicable for research on RET-driven cancers resistant to selective RET inhibitors (SRI).

Ganglioside GM1is a monosialylated ganglioside and the prototypic ganglioside for those containing one sialic acid residue.1,2It is found in a large variety of cells, including immune cells and neurons, and is enriched in lipid rafts in the cell membrane.3It associates with growth factor receptors, including TrkA, TrkB, and the GDNF receptor complex containing Ret and GFRα, and is required for TrkA expression on the cell surface. Ganglioside GM1interacts with other proteins to increase calcium influx, affecting various calcium-dependent processes, including inducing neuronal outgrowth during differentiation. Ganglioside GM1acts as a receptor for cholera toxin, which binds to its oligosaccharide group, facilitating toxin cell entry into epithelial cells of the jejunum.4,5Similarly, it is bound by the heat-labile enterotoxin fromE. coliin the pathogenesis of traveler's diarrhea.6Ganglioside GM1gangliosidosis, characterized by a deficiency in GM1-β-galactosidase, the enzyme that degrades ganglioside GM1, leads to accumulation of the gangliosides GM1and GA1in neurons and can be fatal in infants.1Levels of ganglioside GM1are decreased in the substantia nigra pars compacta in postmortem brain from patients with Parkinson's disease.3Ganglioside GM1mixture contains a mixture of ovine ganglioside GM1molecular species with primarily C18:0 fatty acyl chain lengths, among various others. [Matreya, LLC. Catalog No. 1544] 1.Kolter, T.Ganglioside biochemistryISRN Biochem.506160(2012) 2.Mocchetti, I.Exogenous gangliosides, neuronal plasticity and repair, and the neurotrophinsCell Mol. Life Sci.62(19-20)2283-2294(2005) 3.Ledeen, R.W., and Wu, G.The multi-tasked life of GM1 ganglioside, a true factotum of natureTrends Biochem. Sci.40(7)407-418(2015) 4.Turnbull, W.B., Precious, B.L., and Homans, S.W.Dissecting the cholera toxin-ganglioside GM1 interaction by isothermal titration calorimetryJ. Am. Chem. Soc.126(4)1047-1054(2004) 5.Blank, N., Schiller, M., Krienke, S., et al.Cholera toxin binds to lipid rafts but has a limited specificity for ganglioside GM1Immunol. Cell Biol.85(5)378-382(2007) 6.Minke, W.E., Roach, C., Hol, W.G., et al.Structure-based exploration of the ganglioside GM1 binding sites of Escherichia coli heat-labile enterotoxin and cholera toxin for the discovery of receptor antagonistsBiochemistry38(18)5684-5692(1999)