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).

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

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

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-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-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-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-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.

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.

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].

TRK II-IN-1 is a potent type II inhibitor of tropomyosin receptor kinases (TRK), with IC50 values of 3.3, 6.4, 4.3, and 9.4 nM against TRKA, TRKB, TRKC, and the mutant TRKA G667C, respectively. It also exhibits IC50 values of 1.3 nM against FLT3, 9.9 nM against RET, and 71.1 nM against VEGFR2. TRK II-IN-1 primarily serves as a research tool for studying TRK-driven cancers [1].

RET-IN-24 (Compound 26) is a selective RET tyrosine kinase inhibitor with demonstrated antitumor activity [1].

RET-IN-25 (compound 6b) is an anticancer RET kinase inhibitor effective against medullary thyroid carcinoma (MTC), with half-maximal inhibitory concentrations (IC50s) of 3.6 μM at 3 days and 3.0 μM at 6 days in TT(C634R) MTC [1].

NSC194598, a p53 DNA-binding inhibitor, demonstrates an in vitro IC50 of 180 nM and an in vivo range of 2-40 μM. It disrupts the transcriptional activation of the mutated RET gene in human medullary thyroid carcinoma TT cells and is utilized in research investigating acute toxicity in normal tissues due to radiation and chemotherapy [1] [2].

RET-IN-22 (compound 17b) is a potent, selective, and orally active inhibitor of RET, exhibiting IC50 values of 20.9 nM for wild-type RET and 18.3 nM for RET-V804M. It demonstrates a highly selective inhibition profile across a broad spectrum of kinases, with notable specificity over EGFR and VEGFR2, and is implicated in exerting anticancer effects [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

PLM-101 is an anticancer compound orally active against acute myeloid leukemia by targeting FLT3 and RET. It impedes RET function, promoting autophagic breakdown of FLT3, and suppresses the PI3K and Ras ERK pathways, contributing to its anti-leukemic effects. The compound's antitumor efficacy is demonstrated in both a mouse MV4-11 flank xenograft model (doses of 3 and 10 mg kg; po) and an allogeneic xenograft mouse model (dose of 40 mg kg; po) [1].

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)

RET-IN-26 (compound D5) is a kinase inhibitor that selectively targets the RET protein with an IC50 value of 0.33 μM [1].

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.

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.

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