RMC-4550口服活性的SHP2变构抑制剂（IC50=0.583nM）。
Cas No.:2172651-73-7
Sample solution is provided at 25 µL, 10mM.
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RMC-4550 is an orally active allosteric inhibitor of SHP2 (IC₅₀=0.583nM). RMC-4550 disrupts the SHP2/SOS1/GRB2 module by stabilizing the autoinhibited conformation of the wild-type SHP2 enzyme, thereby downregulating RAS-GTP levels and inhibiting the RAS/MAPK signaling pathway[1-2]. RMC-4550 can be used in research related to KRAS-mutant pancreatic cancer, lung cancer, and esophageal cancer, among others[3-4].
In vitro, FLT3-ITD-mutant AML cell lines (Molm-14, MV4-11) and KIT-mutant cell lines (SKNO-1) were treated with RMC-4550 (500nM) for 24-48 hours. RMC-4550 upregulated the expression of interferon-stimulated genes, including IFIT2, OAS1, and OASL, inhibited cell proliferation, induced apoptosis, and reduced RAS-GTP levels and ERK phosphorylation[5]. Treatment of neuroblastoma cell lines (CLB-GE, CLB-GA, CLB-BA, KELLY, and SK-N-AS) with RMC-4550 (0.1-1000nM) for 72 hours inhibited cell proliferation in a dose-dependent manner[6].
In vivo, Balb/c nude mice with subcutaneous RPMI-8226 cell-derived tumors were orally administered RMC-4550 (30mg/kg) once daily for 20 days. RMC-4550 significantly inhibited the growth of myeloma xenograft tumors[7]. C57BL/6J or nu/nu mice, which received orthotopic inoculation of LLC 46 NRAS KO or mKRC.1 cells into the left lung, were orally administered RMC-4550 (30mg/kg) once daily for 35 days. RMC-4550 monotherapy slightly slowed the growth of LLC 46 NRAS KO tumors, and its combination with MRTX-849 caused tumor regression; in mKRC.1 tumors, RMC-4550 monotherapy was ineffective, but its combination with MRTX-849 produced sustained tumor regression[8].
References:
[1] Nichols RJ, Haderk F, Stahlhut C, et al. 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.
[2] Frank KJ, Mulero-Sánchez A, Berninger A, et al. 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.
[3] Wang RR, Liu WS, Zhou L, et al. 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.
[4] Vemulapalli V, Donovan KA, Seegar TCM, et al. Targeted Degradation of the Oncogenic Phosphatase SHP2. Biochemistry. 2021 Aug 31;60(34):2593-2609.
[5] Popescu B, Stahlhut C, Tarver TC, et al. Allosteric SHP2 inhibition increases apoptotic dependency on BCL2 and synergizes with venetoclax in FLT3- and KIT-mutant AML. Cell Rep Med. 2023 Nov 21;4(11):101290.
[6] Uçkun E, Siaw JT, Guan J, et al. BioID-Screening Identifies PEAK1 and SHP2 as Components of the ALK Proximitome in Neuroblastoma Cells. J Mol Biol. 2021 Sep 17;433(19):167158.
[7] Zhou P, Xiao M, Li W, et al. SHP2 Inhibitors Show Anti-Myeloma Activity and Synergize With Bortezomib in the Treatment of Multiple Myeloma. Front Pharmacol. 2022 Apr 6;13:841308.
[8] Sisler DJ, Hinz TK, Le AT, et al. Evaluation of KRASG12C inhibitor responses in novel murine KRASG12C lung cancer cell line models. Front Oncol. 2023 Feb 8;13:1094123.
RMC-4550口服活性的SHP2变构抑制剂（IC50=0.583nM）。MC-4550通过稳定野生型SHP2酶的自抑制构象来破坏SHP2/SOS1/GRB2模块，从而下调RAS-GTP水平并抑制RAS/MAPK信号通路[1-2]。RMC-4550可用于KRAS突变胰腺癌、肺癌和食管癌等相关研究[3-4]。
在体外，RMC-4550（500nM）处理FLT3-ITD突变型AML细胞系（Molm-14、MV4-11）和KIT突变型细胞系（SKNO-1）24-48小时。RMC-4550上调包括IFIT2、OAS1、OASL在内的干扰素刺激基因表达，可抑制细胞增殖，诱导细胞凋亡，并降低RAS-GTP水平和ERK磷酸化[5]。RMC-4550（0.1-1000nM）处理CLB-GE、CLB-GA、CLB-BA、KELLY及SK-N-AS等神经母细胞瘤细胞72小时，可剂量依赖性地抑制细胞增殖[6]。
在体内，RMC-4550（30mg/kg）每日一次口服给药于皮下注射了RPMI-8226细胞并形成肿瘤的Balb/c裸鼠20天。RMC-4550显著抑制了异种移植骨髓瘤肿瘤的生长[7]。RMC-4550（30mg/kg）每日一次口服给药于通过左肺原位接种了LLC 46 NRAS KO或mKRC.1细胞的C57BL/6J小鼠或nu/nu小鼠35天。RMC-4550单药略微减缓了LLC 46 NRAS KO肿瘤的生长，与MRTX-849联合使用时引起了肿瘤萎缩；在mKRC.1肿瘤中，RMC-4550单药无效，但与MRTX-849联合产生了持久的肿瘤萎缩[8]。
| Cell experiment [1]: | |
Cell lines | Molm-14, MV4-11, Kasumi-1, and SKNO-1 (human acute myeloid leukemia cell lines with FLT3 or KIT mutations) |
Preparation Method | The indicated AML cell lines were cultured in RPMI-1640 medium supplemented with 10% fetal bovine serum (FBS) and 1% penicillin/streptomycin/L-glutamine. Kasumi-1 cells were cultured with 20% FBS. The culture medium for the SKNO-1 cell line was supplemented with human GM-CSF (10ng/mL). Cells were treated with the RMC-4550. |
Reaction Conditions | 500nM; 24-48h. |
Applications | RMC-4550 inhibited cell proliferation, impaired RAS GTP loading, and repressed downstream phosphorylation of ERK. RMC-4550 increased the expression of the pro-apoptotic protein BMF and decreased levels of the anti-apoptotic protein MCL1. Treatment with RMC-4550 increased apoptotic priming and dependency on BCL2. |
| Animal experiment [2]: | |
Animal models | Female Balb/c nude mice |
Preparation Method | Mice were subcutaneously injected with RPMI-8226 cells. When tumors reached approximately 100-130mm³, tumor-bearing mice were randomly divided into cohorts and received RMC-4550 (30mg/kg; p.o.) or vehicle for 35 days. |
Dosage form | 30mg/kg; p.o.; daily for 35 days. |
Applications | Oral administration of RMC-4550 reduced tumor size, growth, and weight in the xenograft mice compared to the vehicle-treated group. Tumor masses from the RMC-4550 treated mice exhibited increased expression of BAK, P21, and cleaved caspase-3, and decreased levels of p-SHP2 and p-ERK. |
References: | |
| 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 |
| General tips | 请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液；一旦配成溶液，请分装保存，避免反复冻融造成的产品失效。 储备液的保存方式和期限：-80°C 储存时，请在 6 个月内使用，-20°C 储存时，请在 1 个月内使用。 为了提高溶解度，请将管子加热至37℃，然后在超声波浴中震荡一段时间。 |
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| 制备储备液 | |||
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1 mg | 5 mg | 10 mg |
| 1 mM | 2.2864 mL | 11.4322 mL | 22.8645 mL |
| 5 mM | 457.3 μL | 2.2864 mL | 4.5729 mL |
| 10 mM | 228.6 μL | 1.1432 mL | 2.2864 mL |
| 第一步：请输入基本实验信息（考虑到实验过程中的损耗，建议多配一只动物的药量） | ||||||||||
| 给药剂量 | mg/kg |  |
动物平均体重 | g | |
每只动物给药体积 | ul | |
动物数量 | 只 |
| 第二步：请输入动物体内配方组成（配方适用于不溶于水的药物；不同批次药物配方比例不同，请联系GLPBIO为您提供正确的澄清溶液配方） | ||||||||||
| % DMSO % % Tween 80 % saline | ||||||||||
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计算结果:
工作液浓度： mg/ml；
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体内配方配制方法：取 μL DMSO母液，加入 μL PEG300，混匀澄清后加入μL Tween 80，混匀澄清后加入 μL saline，混匀澄清。
1. 首先保证母液是澄清的；
2.
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