5kyk | pdb_00005kyk
Covalent GTP-competitive inhibitors of KRAS G12C: Guanosine bisphosphonate Analogs
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 PubMedRas proteins are members of a large family of GTPase enzymes that are commonly mutated in cancer where they act as dominant oncogenes. We previously developed an irreversible guanosine-derived inhibitor, SML-8-73-1, of mutant G12C RAS that forms a covalent bond with cysteine 12. Here we report exploration of the structure-activity relationships (SAR) of hydrolytically stable analogues of SML-8-73-1 as covalent G12C KRAS inhibitors. We report the discovery of difluoromethylene bisphosphonate analogues such as compound 11, which, despite exhibiting reduced efficiency as covalent G12C KRAS inhibitors, remove the liability of the hydrolytic instability of the diphosphate moiety present in SML-8-73-1 and provide the foundation for development of prodrugs to facilitate cellular uptake. The SAR and crystallographic results reaffirm the exquisite molecular recognition that exists in the diphosphate region of RAS for guanosine nucleotides which must be considered in the design of nucleotide-competitive inhibitors. Covalent Guanosine Mimetic Inhibitors of G12C KRAS.,Xiong Y, Lu J, Hunter J, Li L, Scott D, Choi HG, Lim SM, Manandhar A, Gondi S, Sim T, Westover KD, Gray NS ACS Med Chem Lett. 2016 Nov 30;8(1):61-66. doi: 10.1021/acsmedchemlett.6b00373., eCollection 2017 Jan 12. PMID:28105276[12] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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