9bg0

Tri-complex of Daraxonrasib (RMC-6236), NRAS WT, and CypA

spinqualitylabelsall models 9bg0, resolution 1.64Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 9bg0 is a 4 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 1.64Å Ligands: A1AHB, GNP, MG Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Disease RASN_HUMAN Defects in NRAS are a cause of juvenile myelomonocytic leukemia (JMML) [MIM:607785. JMML is a pediatric myelodysplastic syndrome that constitutes approximately 30% of childhood cases of myelodysplastic syndrome (MDS) and 2% of leukemia. Defects in NRAS are the cause of Noonan syndrome type 6 (NS6) [MIM:613224. A syndrome characterized by facial dysmorphic features such as hypertelorism, a downward eyeslant and low-set posteriorly rotated ears. Other features can include short stature, a short neck with webbing or redundancy of skin, cardiac anomalies, deafness, motor delay and variable intellectual deficits. Defects in NRAS are the cause of autoimmune lymphoproliferative syndrome type 4 (ALPS4) [MIM:614470. A disorder of apoptosis, characterized by chronic accumulation of non-malignant lymphocytes, defective lymphocyte apoptosis, and an increased risk for the development of hematologic malignancies. Function RASN_HUMAN Ras proteins bind GDP/GTP and possess intrinsic GTPase activity. Publication Abstract from PubMed Oncogenic RAS mutations are among the most common in human cancers. To target the active, GTP-bound state of RAS(ON) directly, we employed an innovative tri-complex inhibitor (TCI) modality. Formation of a complex with an intracellular chaperone protein CypA, an inhibitor, and a target protein RAS blocks effector binding, inhibiting downstream RAS signaling and tumor cell proliferation. Herein, we describe the structure-guided SAR journey that led to the discovery of daraxonrasib (RMC-6236), a noncovalent, potent tri-complex inhibitor of multiple RAS mutant and wild-type (WT) variants. This orally bioavailable bRo5 macrocyclic molecule occupies a unique composite binding pocket comprising CypA and SWI/SWII regions of RAS(ON). To achieve broad-spectrum RAS isoform activity, we deployed an SAR campaign that focused on interactions with residues conserved between mutants and WT RAS isoforms. Concurrent optimization of potency and drug-like properties led to the discovery of daraxonrasib (RMC-6236), currently in clinical evaluation in RAS mutant advanced solid tumors (NCT05379985; NCT06040541; NCT06162221; NCT06445062; NCT06128551). 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.,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 J Med Chem. 2025 Mar 8. doi: 10.1021/acs.jmedchem.4c02314. PMID:40056080 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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