9pzy
Structure of KRAS G12C bound to Divarasib (GDC6036)
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 G12C is one of the most prevalent oncogenic mutations in nonsmall cell lung cancer. Herein we describe the discovery and optimization of divarasib (GDC-6036), an orally available, highly potent, and selective covalent KRAS G12C inhibitor. We demonstrate a significant noncovalent binding component of divarasib that contributes to its potency and rapid kinetics. Divarasib has greater potency and kinetics of alkylation compared with other KRAS G12C inhibitors in vitro and shows robust tumor growth inhibition in multiple KRAS G12C-positive cell lines. Discovery and Characterization of Divarasib (GDC-6036), a Potent Covalent Inhibitor of KRAS G12C.,Endres NF, Do S, Mroue R, Terrett JA, Saabye M, Oh A, Hunsaker T, Chan E, Tran JC, Nguyen LK, Lian Q, Ma TP, Garner T, Gerosa L, Beresini M, Boudreau A, Bronner SM, Cyr P, Ishisoko N, Izrayelit Y, Jiang F, Kellar T, La H, Labadie S, Lardy M, Liu L, Liu W, Miller S, Rudolph J, Plise E, Sellers BD, Shao C, Wang W, Wang Y, Wei W, Wong S, Yu C, Yu K, Yuen PW, Zang R, Zhang C, Zhou Y, Zhu X, Quinn JG, Ye X, Kiefer JR, Mao J, Evangelista M, Merchant M, Landry ML, Malhotra S, Purkey HE J Med Chem. 2026 Mar 2. doi: 10.1021/acs.jmedchem.5c02272. PMID:41766690[12] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
| ||||||||||||||||||||
