RMC-6236是一种可逆的，GTP结合的RAS（ON）多选择性抑制剂。
Cas No.:2765081-21-6
Sample solution is provided at 25 µL, 10mM.
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RMC-6236 is a reversible, GTP-binding RAS (ON) multi-selective inhibitor. RMC-6236 inhibits the active, GTP-bound state of both mutant and wild-type canonical RAS isoforms and has broad therapeutic potential in cancers driven by the RAS signaling pathway. RMC-6236 acts by forming a ternary complex: it first binds cyclophilin A (CypA; Kd=55.3nM) to form a binary complex, which then associates with RAS proteins, including KRAS (wild-type, G12V, and G12D), with Kd values of 131, 364, and 154nM, respectively[1][2].
In vitro, RMC-6236 significantly inhibits the growth of RAS-mutant cancer cell lines harboring KRAS G12X and NRAS Q61X mutations, with EC50 values of 8 and 22nM, respectively[2]. Treatment of GP2D colorectal cancer cells with 10nM RMC-6236 for 4-48 hours did not sustain suppression of mTOR pathway activity, whereas combination with KO-2806 prevented its rebound[3].
In vivo, a single oral gavage dose of RMC-6236 at 10 or 25mg/kg reduced tumor Dual Specificity Phosphatase 6 (DUSP6) levels by more than 95% at 8 hours and maintained more than 90% inhibition at 24 hours; at 25mg/kg, it also sustained more than 80% inhibition of pERK levels at 24 hours post-dose in mouse xenograft models[2]. RMC-6236 administered orally at 10-25mg/kg once daily for 4 weeks showed dose-dependent antitumor activity in KRAS-mutant human tumor xenograft models, including Capan-2, NCI-H441, HPAC, and NCI-H358[2]. RMC-6236, administered orally at 25mg/kg once daily for 28 days, inhibited tumor growth in xenograft models of KRASG12C-mutant NCI-H2122 non-small cell lung cancer and KRASG12D-mutant GP2D colorectal cancer[3].
References:
[1] Long SA, Amparo AM, Goodhart G, Ahmad SA, Waters AM. Evaluation of KRAS inhibitor-directed therapies for pancreatic cancer treatment. Front Oncol. 2024;14:1402128.
[2] Jiang J, Jiang L, Maldonato BJ, et al. Translational and Therapeutic Evaluation of RAS-GTP Inhibition by RMC-6236 in RAS-Driven Cancers. Cancer Discov. 2024;14(6):994-1017.
[3] Patel H V, et al. The farnesyl transferase inhibitor KO-2806 re-sensitizes relapsing tumors to RAS inhibition. BioRxiv, 2024: 2024.12. 20.629824.
RMC-6236是一种可逆的，GTP结合的RAS（ON）多选择性抑制剂。RMC-6236能够抑制包括突变型和野生型在内的经典RAS亚型的活性（GTP结合）状态，并在由RAS信号通路驱动的癌症中具有广泛的治疗潜力。RMC-6236通过形成三元复合物发挥作用：其首先与环孢素蛋白A（CypA；Kd=55.3nM）结合形成二元复合物，随后与RAS蛋白结合，包括KRAS（野生型、G12V和G12D），其对应的Kd分别为131、364和154nM[1][2]。
体外实验中，RMC-6236能显著抑制RAS突变癌细胞系KRASG12X和NRASQ61X的生长，其EC50值分别为8和22nM[2]。用10nM的RMC-6236处理GP2D结直肠癌细胞4-48小时，未能持续抑制mTOR通路活性，而与KO-2806联合使用则可防止其活性反弹[3]。
体内实验中，在小鼠异种移植模型中，单次口服灌胃给予10或25mg/kg的RMC-6236，可在给药后8小时使肿瘤中双特异性磷酸酶（DUSP6）水平降低超过95%，并在24小时仍维持超过90%的抑制作用；在25mg/kg剂量下，其在给药后24 小时仍可维持超过 80%的pERK 水平抑制作用[2]。RMC-6236以10-25mg/kg剂量口服灌胃给药，每日一次，连续4周，在携带常见KRAS突变的人源肿瘤异种移植模型中（包括Capan-2、NCI-H441、HPAC和NCI-H358）均表现出剂量依赖性的抗肿瘤活性[2]。RMC-6236以25mg/kg剂量口服给药，每日一次，连续28天，在KRASG12C 突变的NCI-H2122非小细胞肺癌和KRASG12D突变的GP2D结直肠癌异种移植模型中抑制了肿瘤生长[3]。
| Cell experiment [1]: | |
Cell lines | GP2D cells |
Preparation Method | 10nM RMC-6236 for 0, 4, 24, or 48 hours in the presence or absence of 1μM KO-2806. Evaluate the expression of mTOR pathway proteins. |
Reaction Conditions | 10nM; 0-48h |
Applications | RMC-6236 was unable to durably inhibit mTOR activity, but the addition of KO-2806 controlled mTOR rebound. |
| Animal experiment [2]: | |
Animal models | Female BALB/c nude, NOD-SCID, and NMRI nu/nu mouse xenograft models. |
Preparation Method | RMC-6236 was prepared using formulation of 10/20/10/60 (%v/v/v/v) DMSO/PEG-400/Solutol HS15/water. A single dose of RMC-6236 was administered orally at either 3, 10, or 25mg/kg. Blood and tissues, including the tumor, brain, colon, ear skin, and muscle, were harvested at indicated time points. |
Dosage form | 3, 10, 25mg/kg; once; p.o. |
Applications | Dose-dependent blood and tumor exposure were observed following a single dose of RMC-6236 at 3, 10, or 25mg/kg. A single oral dose of 10 or 25mg/kg RMC-6236 was sufficient to achieve more than 95% inhibition (relative to vehicle control) of tumor DUSP6 levels at 8 hours after dose; the latter maintained >90% inhibition up to 24 hours after dose, diminishing thereafter in concordance with declining tumor RMC-6236 concentrations. |
References: | |
| Cas No. | 2765081-21-6 | SDF | |
| 化学名 | (1S,2S)-N-[(2R,14S,18S)-1-ethyl-18,19,20,21-tetrahydro-2-[2-[(1S)-1-methoxyethyl]-5-(4-methyl-1-piperazinyl)-3-pyridinyl]-25,25-dimethyl-15,22-dioxo-17H-5,3-([4,2]-endo-thiazolopropano[1,3]-endo-pyridazinomethanoxypropano)-1H-indol-14-yl]-2-methyl-cyclopropanecarboxamide | ||
| Canonical SMILES | O=C([C@H](CCC1)NN1C([C@H](CC2=NC3=CS2)NC([C@H]4C[C@@H]4C)=O)=O)OCC(C)(C)CC5=[C@@]([C@@]6=C([C@H](C)OC)N=CC(N7CCN(C)CC7)=C6)N(CC)C8=C5C=C3C=C8 | ||
| 分子式 | C44H58N8O5S | 分子量 | 811.1 |
| 溶解度 | DMSO: Sparingly soluble: 1-10 mg/ml,Ethanol: Sparingly soluble: 1-10 mg/ml | 储存条件 | -20°C |
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| 制备储备液 | |||
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1 mg | 5 mg | 10 mg |
| 1 mM | 1.2329 mL | 6.1645 mL | 12.3289 mL |
| 5 mM | 246.6 μL | 1.2329 mL | 2.4658 mL |
| 10 mM | 123.3 μL | 616.4 μL | 1.2329 mL |
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动物平均体重 | g | |
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动物数量 | 只 |
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| % DMSO % % Tween 80 % saline | ||||||||||
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2.
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