10nv

Structure of kRas G12C Bound to Inhibitor 13ba

spinqualitylabelsall models 10nv, resolution 1.52Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 10nv is a 2 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 1.52Å Ligands: A1C60, CA, GDP Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Disease RASK_HUMAN Defects in KRAS are a cause of acute myelogenous leukemia (AML) [MIM:601626. AML is a malignant disease in which hematopoietic precursors are arrested in an early stage of development. Defects in KRAS 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. It is characterized by leukocytosis with tissue infiltration and in vitro hypersensitivity of myeloid progenitors to granulocyte-macrophage colony stimulating factor. Defects in KRAS are the cause of Noonan syndrome type 3 (NS3) [MIM:609942. Noonan syndrome (NS) [MIM:163950 is a disorder characterized by dysmorphic facial features, short stature, hypertelorism, cardiac anomalies, deafness, motor delay, and a bleeding diathesis. It is a genetically heterogeneous and relatively common syndrome, with an estimated incidence of 1 in 1000-2500 live births. Rarely, NS is associated with juvenile myelomonocytic leukemia (JMML). NS3 inheritance is autosomal dominant. Defects in KRAS are a cause of gastric cancer (GASC) [MIM:613659; also called gastric cancer intestinal or stomach cancer. Gastric cancer is a malignant disease which starts in the stomach, can spread to the esophagus or the small intestine, and can extend through the stomach wall to nearby lymph nodes and organs. It also can metastasize to other parts of the body. The term gastric cancer or gastric carcinoma refers to adenocarcinoma of the stomach that accounts for most of all gastric malignant tumors. Two main histologic types are recognized, diffuse type and intestinal type carcinomas. Diffuse tumors are poorly differentiated infiltrating lesions, resulting in thickening of the stomach. In contrast, intestinal tumors are usually exophytic, often ulcerating, and associated with intestinal metaplasia of the stomach, most often observed in sporadic disease. Note=Defects in KRAS are a cause of pylocytic astrocytoma (PA). Pylocytic astrocytomas are neoplasms of the brain and spinal cord derived from glial cells which vary from histologically benign forms to highly anaplastic and malignant tumors. Defects in KRAS are a cause of cardiofaciocutaneous syndrome (CFC syndrome) [MIM:115150; also known as cardio-facio-cutaneous syndrome. CFC syndrome is characterized by a distinctive facial appearance, heart defects and mental retardation. Heart defects include pulmonic stenosis, atrial septal defects and hypertrophic cardiomyopathy. Some affected individuals present with ectodermal abnormalities such as sparse, friable hair, hyperkeratotic skin lesions and a generalized ichthyosis-like condition. Typical facial features are similar to Noonan syndrome. They include high forehead with bitemporal constriction, hypoplastic supraorbital ridges, downslanting palpebral fissures, a depressed nasal bridge, and posteriorly angulated ears with prominent helices. The inheritance of CFC syndrome is autosomal dominant. Note=KRAS mutations are involved in cancer development. Function RASK_HUMAN Ras proteins bind GDP/GTP and possess intrinsic GTPase activity. Publication Abstract from PubMed The KRASG12C mutation is a critical therapeutic target in the management of solid tumors, owing to its role in oncogenic signaling. Recent advances in covalent inhibitors that target mutant KRAS cysteine-12 have demonstrated the potential to halt aberrant signaling associated with this historically "undruggable" target. Here, we report the identification of 6-cyanoquinazoline covalent irreversible KRASG12C inhibitors. Lead optimization used structure-based design to identify novel switch-II pocket-binding motifs and in silico models to forecast in vitro metabolic stability and permeability. Human dose was improved by maximizing the rate of covalent modification (kobs/[I]) of KRASG12C-GDP, along with optimizing ADME parameters, to identify potent, orally bioavailable lead molecule 13de which demonstrated significant antitumor efficacy in the NCI-H1373 human lung adenocarcinoma xenograft model. Studies evaluating KRASG12C-GDP covalent target engagement, pharmacokinetics, and tumor growth inhibition estimated the efficacious human dose of 13de to be 192 mg administered once daily (QD), using allometric scaling. Optimization of Covalent 6-Cyanoquinazoline KRAS(G12C) Inhibitors for the Treatment of Solid Tumors.,Waldo JP, Krawczuk PJ, Kelly CB, Callas CG, Cisar JS, Eccles W, Guerrero CA, Hack MD, Jones WM, Keohane CE, Li LS, Meegalla S, Padilla-Salinas R, Rosano RJ, Shimkin KW, Simonnet YRF, Sitkoff D, Sookezian A, Winters MP, Bush TL, Cheung ST, Del Rosario AM, Hansen R, Janes MR, Janjua H, Kazmi F, Kirkpatrick R, La D, Lenhart R, Lorenzi MV, Liu Y, Mesens N, Milligan CM, Murrey H, Peters U, Ren P, Richter M, Rizzolio M, Rao S, Shaffer P, Stratton CF, Szewczuk LM, Wen J, Wong V, Yanovich C, Laquerre S, Edwards JP, Leonard KA J Med Chem. 2026 Apr 1. doi: 10.1021/acs.jmedchem.5c03610. PMID:41921095 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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