RMC-6236

Catalog No: 25074

CAS Number: 2765081-21-6

Purity: 98% Min.

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.

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Chemical Information

Name	RMC-6236
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
Synonyms	RMC-6236; RMC 6236; RMC6236; RAS-IN-2; RAS In 2; daraxonrasib;
Molecular Formula	C44H58N8O5S
Molecular Weight	811.06
Smile	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
InChiKey
InChi
CAS Number	2765081-21-6
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Formulation	Off-white solid
Purity	98% Min.
Storage	Dry, dark and at 0 - 4℃ for short term (days to weeks) or -20℃ for long term (months to years).
Solubility	Soluble in DMSO
Handling
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.
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Mechanism
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Animal study
Clinical study

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.

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RMC-6236

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