RMC-6236 | Daraxonrasib | CAS#2765081-21-6 | RAS inhibitor

MedKoo Cat#: 207192 | Name: RMC-6236

Description:

WARNING: This product is for research use only, not for human or veterinary use.

Daraxonrasib, also known as RMC-6236 and RAS-IN-2, is a potent and selective RAS(ON) inhibitor. RMC-6236 exhibits potent in vitro activity against RAS-driven cancer cell lines, particularly those harboring KRAS mutations at codon 12. In biochemical assays, RMC-6236 demonstrated low nanomolar EC₅₀ values for inhibiting the interaction between RAS-GTP and RAF, indicating strong binding affinity to both wild-type and mutant RAS proteins. In cellular assays, RMC-6236 effectively inhibited the viability of KRAS G12D-mutant pancreatic cancer cell lines, such as HPAC and Capan-2, with EC₅₀ values of 1.2 and 1.4 nmol/L, respectively. Treatment with RMC-6236 led to sustained suppression of downstream RAS signaling pathways, as evidenced by reduced phosphorylation of ERK (pERK) and S6 (pS6) proteins, and induced apoptosis in these cell lines. Furthermore, a comprehensive screening across 845 cancer cell lines revealed that those with KRAS G12X mutations were significantly more sensitive to RMC-6236, with a median EC₅₀ of 8 nmol/L, compared to cell lines with other oncogenic KRAS mutations.

Chemical Structure

RMC-6236

CAS#2765081-21-6

Theoretical Analysis

MedKoo Cat#: 207192

Name: RMC-6236

CAS#: 2765081-21-6

Chemical Formula: C44H58N8O5S

Exact Mass: 810.4251

Molecular Weight: 811.06

Elemental Analysis: C, 65.16; H, 7.21; N, 13.82; O, 9.86; S, 3.95

Price and Availability

Size	Price	Availability
5mg	USD 150.00	Ready to ship
10mg	USD 250.00	Ready to ship
25mg	USD 450.00	Ready to ship
100mg	USD 950.00	Ready to ship

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Related CAS #

2765091-21-0 (racemate) 2765081-21-6

Synonym

RMC-6236; RMC 6236; RMC6236; RAS-IN-2; RAS In 2; daraxonrasib;

IUPAC/Chemical Name

(1S,2S)-N-((63S,4S,Z)-11-ethyl-12-(2-((S)-1-methoxyethyl)-5-(4-methylpiperazin-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-61,62,63,64,65,66-hexahydro-11H-8-oxa-2(4,2)-thiazola-1(5,3)-indola-6(1,3)-pyridazinacycloundecaphane-4-yl)-2-methylcyclopropane-1-carboxamide

InChi Key

FVICRBSEYSHKFY-JYQNNKODSA-N

InChi Code

InChI=1S/C44H58N8O5S/c1-8-51-37-12-11-28-19-31(37)33(40(51)32-20-29(23-45-39(32)27(3)56-7)50-16-14-49(6)15-17-50)22-44(4,5)25-57-43(55)34-10-9-13-52(48-34)42(54)35(21-38-46-36(28)24-58-38)47-41(53)30-18-26(30)2/h11-12,19-20,23-24,26-27,30,34-35,48H,8-10,13-18,21-22,25H2,1-7H3,(H,47,53)/t26-,27-,30-,34-,35-/m0/s1

SMILES Code

CC(COC([C@H]1NN(C([C@H](CC2=NC3=CS2)NC([C@H]4C[C@@H]4C)=O)=O)CCC1)=O)(C)CC5=[C@@](N(CC)C6=C5C=C3C=C6)[C@@]7=C([C@H](C)OC)N=CC(N8CCN(C)CC8)=C7

Appearance

To be determined

Purity

>98% (or refer to the Certificate of Analysis)

Shipping Condition

Shipped under ambient temperature as non-hazardous chemical. This product is stable enough for a few weeks during ordinary shipping and time spent in Customs.

Storage Condition

Dry, dark and at 0 - 4 C for short term (days to weeks) or -20 C for long term (months to years).

Solubility

To be determined

Shelf Life

>2 years if stored properly

Drug Formulation

To be determined

Stock Solution Storage

0 - 4 C for short term (days to weeks), or -20 C for long term (months).

HS Tariff Code

2934.99.9001

More Info

KRAS is mutated in approximately 30% of cancers, and the most frequent mutations replace the glycine at position 12 (G12) with another amino acid in cancers such as pancreatic ductal adenocarcinoma (PDAC), non-small cell lung cancer (NSCLC), and colorectal cancer (CRC) RAS plays an important role in cell signaling, division and differentiation. Mutations of RAS may induce constitutive signal transduction leading to tumor cell growth, proliferation, invasion, and metastasis. (note the structure was from https://www.sohu.com/a/640171704_121124565).

Product Data

Product Data

Certificate of Analysis

View CoA: current batch, Lot#A24T11K04

QC Data

View QC data: current batch, Lot#A24T11K04

Safety Data Sheet (SDS)

View Safety Data Sheet (SDS)

Instruction

View handling instruction

Biological target:

RMC-6236 is a first-in-class, potent, oral RAS-selective tri-complex, RAS(MULTI)(ON) inhibitor with an attractive preclinical profile and is designed to treat cancers caused by multiple RAS variants.

In vitro activity:

Biochemical Potency: RMC-6236 effectively disrupts the RAS-RAF interaction across multiple RAS variants. The half-maximal effective concentration (EC₅₀) values for wild-type KRAS, NRAS, and HRAS are 85 nM, 66 nM, and 82 nM, respectively. For oncogenic RAS mutants, EC₅₀ values range from 28 to 220 nM. PMC.NCBI.NLM.NIH.GOV Cellular Activity: In cancer cell lines harboring KRAS mutations, RMC-6236 demonstrates potent growth inhibition. For example, in HPAC (KRAS G12D/WT, pancreatic ductal adenocarcinoma) and Capan-2 (KRAS G12V/WT, pancreatic ductal adenocarcinoma) cell lines, the half-maximal inhibitory concentration (IC₅₀) values are 1.2 nM and 1.4 nM, respectively. PMC.NCBI.NLM.NIH.GOV In a broader panel of 845 cancer cell lines, KRAS mutations significantly correlate with sensitivity to RMC-6236 (P = 1.19 × 10⁻³⁷). Notably, KRAS G12X and NRAS Q61X mutations are associated with increased sensitivity, whereas BRAF V600E mutations are linked to resistance. PMC.NCBI.NLM.NIH.GOV

In vivo activity:

Preliminary results from phase I trials evaluating RMC-6236 indicate that it is safe and shows promising signs of antitumor activity. Reference: Cancer Discov. 2023 Dec 12;13(12):OF7. https://pubmed.ncbi.nlm.nih.gov/37871268/

	Solvent	mg/mL	mM
Solubility
	DMSO	250.0	308.24

Note: There can be variations in solubility for the same chemical from different vendors or different batches from the same vendor. The following factors can affect the solubility of the same chemical: solvent used for crystallization, residual solvent content, polymorphism, salt versus free form, degree of hydration, solvent temperature. Please use the solubility data as a reference only. Warming and sonication will facilitate dissolving. Still have questions? Please contact our Technical Support scientists.

Preparing Stock Solutions

The following data is based on the product molecular weight 811.06 Batch specific molecular weights may vary from batch to batch due to the degree of hydration, which will affect the solvent volumes required to prepare stock solutions.

Concentration / Solvent Volume / Mass	1 mg	5 mg	10 mg
1 mM	1.15 mL	5.76 mL	11.51 mL
5 mM	0.23 mL	1.15 mL	2.3 mL
10 mM	0.12 mL	0.58 mL	1.15 mL
50 mM	0.02 mL	0.12 mL	0.23 mL

Formulation for in vivo study

Title	Description

Formulation protocol:

1. Jiang J, Jiang L, Maldonato BJ, Wang Y, Holderfield M, Aronchik I, Winters IP, Salman Z, Blaj C, Menard M, Brodbeck J, Chen Z, Wei X, Rosen MJ, Gindin Y, Lee BJ, Evans JW, Chang S, Wang Z, Seamon KJ, Parsons D, Cregg J, Marquez A, Tomlinson ACA, Yano JK, Knox JE, Quintana E, Aguirre AJ, Arbour KC, Reed A, Gustafson WC, Gill AL, Koltun ES, Wildes D, Smith JAM, Wang Z, Singh M. Translational and Therapeutic Evaluation of RAS-GTP Inhibition by RMC-6236 in RAS-Driven Cancers. Cancer Discov. 2024 Apr 9:OF1-OF24. doi: 10.1158/2159-8290.CD-24-0027. Epub ahead of print. PMID: 38593348. 2. Drugging RAS: Moving Beyond KRASG12C. Cancer Discov. 2023 Dec 12;13(12):OF7. doi: 10.1158/2159-8290.CD-ND2023-0010. PMID: 37871268.

In vitro protocol:

To be determined

In vivo protocol:

1: Mahadevan KK, Maldonado AS, Li B, Bickert AA, Perdyan A, Kumbhar SV, Piya S, Sockwell A, Morse SJ, Arian K, Sugimoto H, Shalapour S, Hong DS, Heffernan TP, Maitra A, Kalluri R. Inhibitors of oncogenic Kras specifically prime CTLA4 blockade to transcriptionally reprogram Tregs and overcome resistance to suppress pancreas cancer. bioRxiv [Preprint]. 2025 Mar 4:2025.02.28.640711. doi: 10.1101/2025.02.28.640711. PMID: 40093186; PMCID: PMC11908235. 2: Orlen MI, Vostrejs WP, Sor R, McDevitt JC, Kemp SB, Kim IK, Kramer AB, Tovbis Shifrin N, Markosyan N, Clendenin C, Singh M, Quintana E, Menard M, Vonderheide RH, Stanger BZ. T-cell dependency of tumor regressions and complete responses with RAS(ON) multi-selective inhibition in preclinical models of PDAC. Cancer Discov. 2025 Mar 7. doi: 10.1158/2159-8290.CD-24-1475. Epub ahead of print. PMID: 40057911. 3: Cregg J, Edwards AV, Chang S, Lee BJ, Knox JE, Tomlinson ACA, Marquez A, Liu Y, Freilich R, Aay N, Wang Y, Jiang L, Jiang J, Wang Z, Flagella M, Wildes D, Smith JAM, Singh M, Wang Z, Gill AL, Koltun ES. Discovery of Daraxonrasib (RMC-6236), a Potent and Orally Bioavailable RAS(ON) Multi-selective, Noncovalent Tri-complex Inhibitor for the Treatment of Patients with Multiple RAS-Addicted Cancers. J Med Chem. 2025 Mar 8. doi: 10.1021/acs.jmedchem.4c02314. Epub ahead of print. PMID: 40056080. 4: Sait SF, Tang KH, Angus SP, Brown R, Sun D, Xie X, Iltis C, Lien M, D Socci N, Bale TA, Davis C, Dixon SAH, Zhang C, Wade Clapp D, Neel BG, Parada LF. Hydroxychloroquine prevents resistance and potentiates the antitumor effect of SHP2 inhibition in NF1-associated malignant peripheral nerve sheath tumors. Proc Natl Acad Sci U S A. 2025 Jan 7;122(1):e2407745121. doi: 10.1073/pnas.2407745121. Epub 2024 Dec 30. PMID: 39793045; PMCID: PMC11725864. 5: Filis P, Salgkamis D, Matikas A, Zerdes I. Breakthrough in RAS targeting with pan-RAS(ON) inhibitors RMC-7977 and RMC-6236. Drug Discov Today. 2025 Jan;30(1):104250. doi: 10.1016/j.drudis.2024.104250. Epub 2024 Nov 24. PMID: 39586491. 6: Vanclooster P, Seghers S, Prenen H. State-of-the-art and upcoming trends in RAS-directed therapies in gastrointestinal malignancies. Curr Opin Oncol. 2024 Jul 1;36(4):313-319. doi: 10.1097/CCO.0000000000001042. Epub 2024 Apr 19. PMID: 38726828. 7: Jiang J, Jiang L, Maldonato BJ, Wang Y, Holderfield M, Aronchik I, Winters IP, Salman Z, Blaj C, Menard M, Brodbeck J, Chen Z, Wei X, Rosen MJ, Gindin Y, Lee BJ, Evans JW, Chang S, Wang Z, Seamon KJ, Parsons D, Cregg J, Marquez A, Tomlinson ACA, Yano JK, Knox JE, Quintana E, Aguirre AJ, Arbour KC, Reed A, Gustafson WC, Gill AL, Koltun ES, Wildes D, Smith JAM, Wang Z, Singh M. Translational and Therapeutic Evaluation of RAS-GTP Inhibition by RMC-6236 in RAS-Driven Cancers. Cancer Discov. 2024 Jun 3;14(6):994-1017. doi: 10.1158/2159-8290.CD-24-0027. PMID: 38593348; PMCID: PMC11149917. 8: Holderfield M, Lee BJ, Jiang J, Tomlinson A, Seamon KJ, Mira A, Patrucco E, Goodhart G, Dilly J, Gindin Y, Dinglasan N, Wang Y, Lai LP, Cai S, Jiang L, Nasholm N, Shifrin N, Blaj C, Shah H, Evans JW, Montazer N, Lai O, Shi J, Ahler E, Quintana E, Chang S, Salvador A, Marquez A, Cregg J, Liu Y, Milin A, Chen A, Ziv TB, Parsons D, Knox JE, Klomp JE, Roth J, Rees M, Ronan M, Cuevas-Navarro A, Hu F, Lito P, Santamaria D, Aguirre AJ, Waters AM, Der CJ, Ambrogio C, Wang Z, Gill AL, Koltun ES, Smith JAM, Wildes D, Singh M. Concurrent inhibition of oncogenic and wild-type RAS-GTP for cancer therapy. Nature. 2024 May;629(8013):919-926. doi: 10.1038/s41586-024-07205-6. Epub 2024 Apr 8. PMID: 38589574; PMCID: PMC11111408. 9: Drugging RAS: Moving Beyond KRASG12C. Cancer Discov. 2023 Dec 12;13(12):OF7. doi: 10.1158/2159-8290.CD-ND2023-0010. PMID: 37871268.