GLPBio

RMC-6236

Catalog No.: GC92066Purity:>99.00%
COASDSData Sheet
RMC-6236 is a reversible, GTP-binding RAS (ON) multi-selective inhibitor.

Products are for research use only. Not for human use. We do not sell to patients.

RMC-6236
Cas No.: 2765081-21-6
10mM (in 1mL DMSO)In Stock
$222.00
1
1mgIn Stock
$68.00
1
5mgIn Stock
$168.00
1
10mgIn Stock
$249.00
1
25mgIn Stock
$348.00
1
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Description

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.

Protocol

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:
[1] Patel H V, et al. The farnesyl transferase inhibitor KO-2806 re-sensitizes relapsing tumors to RAS inhibition. BioRxiv, 2024: 2024.12. 20.629824.
[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.

Product Documents

Purity:>99.00%Appearance:A solid
COASDSData Sheet

Chemical Properties

CAS No.
2765081-21-6
Chemical Name
(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
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
Molecular Formula
C44H58N8O5S
Molecular Weight
811.1
Solubility
DMSO: >100mg/ml
Storage
-20°C
General tips
Select a suitable solvent according to the product solubility data. Once prepared, aliquot the stock solution to avoid repeated freeze-thaw cycles.
Use stock solutions within 6 months when stored at -80°C or within 1 month when stored at -20°C.
To improve solubility, warm the tube to 37°C and sonicate it for an appropriate period.
Shipping Condition
Evaluation samples are shipped with blue ice. Other available sizes are shipped at room temperature or with blue ice upon request.

CalculatorsMolarity / Dilution / Molecular Weight / Unit Conversion / In Vivo Formulation / Solubility

g/mol

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