9baj
Crystal structure of GDP-bound human K-RAS in a covalent complex with aryl sulfonyl fluoride compounds.
Structural highlights
DiseaseRASK_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.[1] 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.[2] [3] [4] [5] [6] [7] 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.[8] [9] [10] 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.[11] 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. FunctionRASK_HUMAN Ras proteins bind GDP/GTP and possess intrinsic GTPase activity. Publication Abstract from PubMedThe development of the KRAS G12C inhibitor sotorasib was a major advance towards drugging KRAS. However, the G12C mutation is only found in about 10% of tumors with a KRAS mutation. KRAS tyrosine amino acids could provide alternative sites for covalent drug development. Here, we screen a library of aryl sulfonyl fluorides to explore whether tyrosines on KRAS are accessible for covalent bond formation. We identify compound 1 (SOF-436), which inhibits KRAS nucleotide exchange by guanine exchange factor SOS1 and the binding of KRAS to effector protein RAF. Tyr-64 was the major reaction site of 1 (SOF-436), although minor reaction at Tyr-71 was also observed. The fragment engages the Switch II pocket of KRAS based on mass spectrometry, nucleotide exchange, effector protein binding, nuclear magnetic resonance (NMR), and molecular dynamics simulations. Co-crystal structures of smaller fragments covalently bound to KRAS at Tyr-71 provide a strategy for the development of Switch I/II KRAS covalent inhibitors. A NanoBRET assay revealed that the compound and its analogs inhibit KRAS binding to RAF in mammalian cells. Although not yet suitable as chemical probes, these fragments provide starting points for small molecules to investigate tyrosine as a nucleophile for covalent inhibition of KRAS in tumors. Small-Molecule KRAS Inhibitors by Tyrosine Covalent Bond Formation.,Landgraf A, Brenner R, Ghozayel M, Bum-Erdene K, Gonzalez-Gutierrez G, Meroueh S ChemMedChem. 2025 Mar 18:e202400624. doi: 10.1002/cmdc.202400624. PMID:40099978[12] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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