8cx5
Crystal Structure of small molecule alpha,beta-ketoamide 4 covalently bound to K-Ras(G12R)
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 PubMedKRAS mutations are one of the most common oncogenic drivers in human cancer. While small molecule inhibitors for the G12C mutant have been successfully developed, allele-specific inhibition for other KRAS hotspot mutants remains challenging. Here we report the discovery of covalent chemical ligands for the common oncogenic mutant K-Ras(G12R). These ligands bind in the Switch II pocket and irreversibly react with the mutant arginine residue. An X-ray crystal structure reveals an imidazolium condensation product formed between the alpha,beta-diketoamide ligand and the epsilon- and eta-nitrogens of arginine 12. Our results show that arginine residues can be selectively targeted with small molecule electrophiles despite their weak nucleophilicity and provide the basis for the development of mutant-specific therapies for K-Ras(G12R)-driven cancer. Chemoselective Covalent Modification of K-Ras(G12R) with a Small Molecule Electrophile.,Zhang Z, Morstein J, Ecker AK, Guiley KZ, Shokat KM J Am Chem Soc. 2022 Sep 7;144(35):15916-15921. doi: 10.1021/jacs.2c05377. Epub , 2022 Aug 24. PMID:36001446[12] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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