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daraxonrasib   Click here for help

GtoPdb Ligand ID: 13368

Synonyms: RAS Inhibitor A122 | RMC-6236 | RMC6236
Compound class: Synthetic organic
Comment: RMC-6236 is a macrocyclic, noncovalent (reversible) pan-RAS inhibitor [1-2]. It was developed using structure-guided design from the bacterial polyketide Sanglifehrin A. RMC-6236 forms a binary complex with the ubiquitously-expressed chaperone protein cyclophilin A. The binary complex has high affinity for RAS proteins, and interactions lead to the formation of an inhibitory tri-complex [4]. RMC-6236 has activity against active state (GTP-bound) mutant and wild-type RAS proteins. This mode of action is described as RAS(ON) inhibition, and is intended to target tumours with oncogenic RAS mutations beyond the common driver mutation KRASG12C [2]. The chemical structure of RMC-6236 is identical to that for the INN daraxonrasib (proposed list 132, Feb. 2025).
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Ligand Activity Visualisation Charts

These are box plot that provide a unique visualisation, summarising all the activity data for a ligand taken from ChEMBL and GtoPdb across multiple targets and species. Click on a plot to see the median, interquartile range, low and high data points. A value of zero indicates that no data are available. A separate chart is created for each target, and where possible the algorithm tries to merge ChEMBL and GtoPdb targets by matching them on name and UniProt accession, for each available species. However, please note that inconsistency in naming of targets may lead to data for the same target being reported across multiple charts.

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View interactive charts of activity data across species

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2D Structure
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2D Structure

An image of the ligand's 2D structure. For small molecules with SMILES these are drawn using the NCI/CADD Chemical Identifier Resolver. Click on the image to access the chemical structure search tool with the ligand pre-loaded in the structure editor. For other types of ligands, e.g. longer nucleotides and peptides, a manually drawn representation of the molecule may be provided.

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Physico-chemical Properties
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Physico-chemical Properties

Calculated molecular properties are available for small molecules and natural products (not peptides). Properties were generated using the Chemistry Development Kit (CDK) (Willighagen EL et al. Journal of Cheminformatics vol. 9:33. 2017, doi:10.1186/s13321-017-0220-4; https://cdk.github.io/). All properties were selected to enable the prediction of the Lipinski Rule-of-Five profile or ‘druglikeness’ for each ligand. For more info on each category see the help pages.

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Hydrogen bond acceptors 13
Hydrogen bond donors 2
Rotatable bonds 8
Topological polar surface area 156.71
Molecular weight 811.05
XLogP 5.08
No. Lipinski's rules broken 3

Generated using the Chemistry Development Kit (CDK) (Willighagen EL et al. Journal of Cheminformatics vol. 9:33. 2017, doi:10.1186/s13321-017-0220-4; https://cdk.github.io/)
SMILES / InChI / InChIKey
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SMILES / InChI / InChIKey

SMILES (Simplified Molecular Input Line Entry Specification) A specification for unambiguously describing the structure of chemical molecules using short ASCII strings. Canonical SMILES specify a unique representation of the 2D structure without chiral or isotopic specifications. Isomeric SMILES include chiral specification and isotopes.

Standard InChI (IUPAC International Chemical Identifier) and InChIKey InChI is a non-proprietary, standard, textual identifier for chemical substances designed to facilitate linking of information and database searching. An InChIKey is a simplified version of a full InChI, designed for easier web searching.

Generated using the Chemistry Development Kit (CDK) (Willighagen EL et al. Journal of Cheminformatics vol. 9:33. 2017, doi:10.1186/s13321-017-0220-4; https://cdk.github.io/)

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Canonical SMILES CCN1C2=C3C=C(C=C2)C4=CSC(=N4)C[C@@H](C(=O)N5CCC[C@@H](C(=O)OCC(C)(C)CC3=C1C6=C([C@H](C)OC)N=CC(=C6)N7CCN(C)CC7)N5)NC(=O)[C@H]8C[C@@H]8C
Isomeric SMILES CCN1C2=C3C=C(C=C2)C4=CSC(=N4)C[C@@H](C(=O)N5CCC[C@H](N5)C(=O)OCC(CC3=C1C6=C(N=CC(=C6)N7CCN(CC7)C)[C@H](C)OC)(C)C)NC(=O)[C@H]8C[C@@H]8C
InChI 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
InChI Key FVICRBSEYSHKFY-JYQNNKODSA-N

Generated using the Chemistry Development Kit (CDK) (Willighagen EL et al. Journal of Cheminformatics vol. 9:33. 2017, doi:10.1186/s13321-017-0220-4; https://cdk.github.io/)
References
1. Cregg J, Edwards AV, Chang S, Lee BJ, Knox JE, Tomlinson ACA, Marquez A, Liu Y, Freilich R, Aay N et al.. (2025)
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, 68 (6): 6064-6083. [PMID:40056080]
2. Jiang J, Jiang L, Maldonato BJ, Wang Y, Holderfield M, Aronchik I, Winters IP, Salman Z, Blaj C, Menard M et al.. (2024)
Translational and Therapeutic Evaluation of RAS-GTP Inhibition by RMC-6236 in RAS-Driven Cancers.
Cancer Discov, 14 (6): 994-1017. [PMID:38593348]
3. O’Reilly EM, Wainberg ZA, Hendifar AE, Borad MJ, Pietrantonio F, Pant S, Hammel P, Cremolini C, Manji GA, Oberstein PE et al.. (2026)
Daraxonrasib or Chemotherapy in Previously Treated Metastatic Pancreatic Cancer.
NEJM, Epub ahead of print. DOI: 10.1056/NEJMoa2605555
4. Schulze CJ, Seamon KJ, Zhao Y, Yang YC, Cregg J, Kim D, Tomlinson A, Choy TJ, Wang Z, Sang B et al.. (2023)
Chemical remodeling of a cellular chaperone to target the active state of mutant KRAS.
Science, 381 (6659): 794-799. [PMID:37590355]
5. Wolpin BM, Park W, Garrido-Laguna I, Spira A, Starodub A, Sommerhalder D, Punekar SR, Barve M, Pelster M, Herzberg B et al.. (2026)
Daraxonrasib in Previously Treated Advanced RAS-Mutated Pancreatic Cancer.
N Engl J Med, 394 (18): 1790-1802. [PMID:42090791]