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RMC-4550 Sale

目录号 : GC33044

A SHP-2 inhibitor

RMC-4550 Chemical Structure

Cas No.:2172651-73-7

规格 价格 库存 购买数量
10mM (in 1mL DMSO)
¥2,673.00
现货
5mg
¥2,430.00
现货
10mg
¥3,690.00
现货
50mg
¥9,900.00
现货
100mg
¥14,977.00
现货

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产品文档

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产品描述

RMC-4550 is an inhibitor of Src homology region 2 domain-containing phosphatase 2 (SHP-2; IC50 = 1.55 nM).1 It is selective for SHP-2 over a panel of 14 additional protein phosphatases and a panel of 468 protein kinases at 10 ?M. It inhibits tumor ERK phosphorylation in a KYSE-520 human esophageal cancer xenograft model in a dose-dependent manner.

1.Koltun, E.S., Aay, N., Buckl, A., et al.RMC-4550, an allosteric inhibitor of SHP2: Synthesis, structure, and anti-tumor activityCancer Res.78(13 Suppl.)(2018)

Chemical Properties

Cas No. 2172651-73-7 SDF
Canonical SMILES ClC1=C(C(C2=NC(CO)=C(N=C2C)N3CCC4(CC3)CO[C@H]([C@H]4N)C)=CC=C1)Cl
分子式 C21H26Cl2N4O2 分子量 437.36
溶解度 DMSO : 125 mg/mL (285.81 mM) 储存条件 Store at -20°C
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1 mg 5 mg 10 mg
1 mM 2.2864 mL 11.4322 mL 22.8645 mL
5 mM 0.4573 mL 2.2864 mL 4.5729 mL
10 mM 0.2286 mL 1.1432 mL 2.2864 mL
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Research Update

Probing the acting mode and advantages of RMC-4550 as an Src-homology 2 domain-containing protein tyrosine phosphatase (SHP2) inhibitor at molecular level through molecular docking and molecular dynamics

J Biomol Struct Dyn 2020 Mar;38(5):1525-1538.PMID:31043123DOI:10.1080/07391102.2019.1613266.

The over-activation of Ras/mitogen-activated protein kinase (MAPK) signaling pathway associated with a variety of cancers is usually related with abnormal activation of Src-homology 2 domain-containing protein tyrosine phosphatase (SHP2). For this purpose, SHP2 has attracted extensive interest as a potential target for cancer treatment. RMC-4550, as a newly developed selective inhibitor of SHP2, possesses an overwhelming advantage over the previous generation inhibitor SHP099 in terms of in vitro activity. However, the binding mode of SHP2 with RMC-4550 and the reason for the high efficiency of RMC-4550 as SHP2 inhibitor at molecular level are still unclear. Therefore, in this study, the binding mode of RMC-4550 with SHP2 and the superiorities of RMC-4550 as inhibitor at binding affinity and dynamic interactive behavior with SHP2 were probed by molecular docking and molecular dynamics (MD) simulations. By comparing the results of molecular docking, it was found that SHP2 formed more tight interaction with RMC-4550 than that with SHP099. Subsequently, a series of post-dynamic analyses on three simulation trajectories (SHP2WT, SHP2SHP099 and SHP2RMC-4550) were performed and found that the SHP2 protein bound with RMC-4550 maintained a firmer interaction between N-Src-homology 2 (N-SH2) and PTP domain throughout the MD simulation, leading to a more stable protein conformation. The finding here provides new clues for the design of SHP2 inhibitor against the over-activation of Ras/MAPK pathway.Communicated by Ramaswamy H. Sarma.

Extensive preclinical validation of combined RMC-4550 and LY3214996 supports clinical investigation for KRAS mutant pancreatic cancer

Cell Rep Med 2022 Nov 15;3(11):100815.PMID:36384095DOI:10.1016/j.xcrm.2022.100815.

Over 90% of pancreatic cancers present mutations in KRAS, one of the most common oncogenic drivers overall. Currently, most KRAS mutant isoforms cannot be targeted directly. Moreover, targeting single RAS downstream effectors induces adaptive resistance mechanisms. We report here on the combined inhibition of SHP2, upstream of KRAS, using the allosteric inhibitor RMC-4550 and of ERK, downstream of KRAS, using LY3214996. This combination shows synergistic anti-cancer activity in vitro, superior disruption of the MAPK pathway, and increased apoptosis induction compared with single-agent treatments. In vivo, we demonstrate good tolerability and efficacy of the combination, with significant tumor regression in multiple pancreatic ductal adenocarcinoma (PDAC) mouse models. Finally, we show evidence that 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET) can be used to assess early drug responses in animal models. Based on these results, we will investigate this drug combination in the SHP2 and ERK inhibition in pancreatic cancer (SHERPA; ClinicalTrials.gov: NCT04916236) clinical trial, enrolling patients with KRAS-mutant PDAC.

RAS nucleotide cycling underlies the SHP2 phosphatase dependence of mutant BRAF-, NF1- and RAS-driven cancers

Nat Cell Biol 2018 Sep;20(9):1064-1073.PMID:30104724DOI:10.1038/s41556-018-0169-1.

Oncogenic alterations in the RAS/RAF/MEK/ERK pathway drive the growth of a wide spectrum of cancers. While BRAF and MEK inhibitors are efficacious against BRAFV600E-driven cancers, effective targeted therapies are lacking for most cancers driven by other pathway alterations, including non-V600E oncogenic BRAF, RAS GTPase-activating protein (GAP) NF1 (neurofibromin 1) loss and oncogenic KRAS. Here, we show that targeting the SHP2 phosphatase (encoded by PTPN11) with RMC-4550, a small-molecule allosteric inhibitor, is effective in human cancer models bearing RAS-GTP-dependent oncogenic BRAF (for example, class 3 BRAF mutants), NF1 loss or nucleotide-cycling oncogenic RAS (for example, KRASG12C). SHP2 inhibitor treatment decreases oncogenic RAS/RAF/MEK/ERK signalling and cancer growth by disrupting SOS1-mediated RAS-GTP loading. Our findings illuminate a critical function for SHP2 in promoting oncogenic RAS/MAPK pathway activation in cancers with RAS-GTP-dependent oncogenic BRAF, NF1 loss and nucleotide-cycling oncogenic KRAS. SHP2 inhibition is a promising molecular therapeutic strategy for patients with cancers bearing these oncogenic drivers.

Targeted Degradation of the Oncogenic Phosphatase SHP2

Biochemistry 2021 Aug 31;60(34):2593-2609.PMID:34411482DOI:10.1021/acs.biochem.1c00377.

SHP2 is a protein tyrosine phosphatase that plays a critical role in the full activation of the Ras-MAPK pathway upon stimulation of receptor tyrosine kinases, which are frequently amplified or mutationally activated in human cancer. In addition, activating mutations in SHP2 result in developmental disorders and hematologic malignancies. Several allosteric inhibitors have been developed for SHP2 and are currently in clinical trials. Here, we report the development and evaluation of a SHP2 PROTAC created by conjugating RMC-4550 with pomalidomide using a PEG linker. This molecule is highly selective for SHP2, induces degradation of SHP2 in leukemic cells at submicromolar concentrations, inhibits MAPK signaling, and suppresses cancer cell growth. SHP2 PROTACs serve as an alternative strategy for targeting ERK-dependent cancers and are useful tools alongside allosteric inhibitors for dissecting the mechanisms by which SHP2 exerts its oncogenic activity.

In situ modeling of acquired resistance to RTK/RAS pathway targeted therapies

bioRxiv 2023 Feb 3;2023.01.27.525958.PMID:36747633DOI:10.1101/2023.01.27.525958.

Intrinsic and acquired resistance limit the window of effectiveness for oncogene-targeted cancer therapies. Preclinical studies that identify synergistic combinations enhance therapeutic efficacy to target intrinsic resistance, however, methods to study acquired resistance in cell culture are lacking. Here, we describe a novel in situ resistance assay (ISRA), performed in a 96-well culture format, that models acquired resistance to RTK/RAS pathway targeted therapies. Using osimertinib resistance in EGFR-mutated lung adenocarcinoma (LUAD) as a model system, we show acquired resistance can be reliably modeled across cell lines using objectively defined osimertinib doses. Similar to patient populations, isolated osimertinib-resistant populations showed resistance via enhanced activation of multiple parallel RTKs so that individual RTK inhibitors did not re-sensitize cells to osimertinib. In contrast, inhibition of proximal RTK signaling using the SHP2 inhibitor RMC-4550 both re-sensitized resistant populations to osimertinib and prevented the development of osimertinib resistance as a primary therapy. Similar, objectively defined drug doses were used to model resistance to additional RTK/RAS pathway targeted therapies including the KRASG12C inhibitors adagrasib and sotorasib, the MEK inhibitor trametinib, and the farnesyl transferase inhibitor tipifarnib. These studies highlight the tractability of in situ resistance assays to model acquired resistance to targeted therapies and provide a framework for assessing the extent to which synergistic drug combinations can target acquired drug resistance.