8t8q

Identification of GDC-1971 (RLY-1971), a SHP2 inhibitor designed for the treatment of solid tumors

spinqualitylabelsall models 8t8q, resolution 2.27Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 8t8q 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 2.27Å Ligands: ZJX Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Disease PTN11_HUMAN Defects in PTPN11 are the cause of LEOPARD syndrome type 1 (LEOPARD1) [MIM:151100. It is an autosomal dominant disorder allelic with Noonan syndrome. The acronym LEOPARD stands for lentigines, electrocardiographic conduction abnormalities, ocular hypertelorism, pulmonic stenosis, abnormalities of genitalia, retardation of growth, and deafness. Defects in PTPN11 are the cause of Noonan syndrome type 1 (NS1) [MIM:163950. Noonan syndrome (NS) is a disorder characterized by dysmorphic facial features, short stature, hypertelorism, cardiac anomalies, deafness, motor delay, and a bleeding diathesis. Some patients with Noonan syndrome type 1 develop multiple giant cell lesions of the jaw or other bony or soft tissues, which are classified as pigmented villomoduolar synovitis (PVNS) when occurring in the jaw or joints. Note=Mutations in PTPN11 account for more than 50% of the cases. Rarely, NS is associated with juvenile myelomonocytic leukemia (JMML). NS1 inheritance is autosomal dominant. Defects in PTPN11 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 PTPN11 are a cause of metachondromatosis (MC) [MIM:156250. It is a skeletal disorder with radiologic fetarures of both multiple exostoses and Ollier disease, characterized by the presence of multiple enchondromas and osteochondroma-like lesions. Function PTN11_HUMAN Acts downstream of various receptor and cytoplasmic protein tyrosine kinases to participate in the signal transduction from the cell surface to the nucleus. Dephosphorylates ROCK2 at Tyr-722 resulting in stimulatation of its RhoA binding activity. Publication Abstract from PubMed Protein tyrosine phosphatase SHP2 mediates RAS-driven MAPK signaling and has emerged in recent years as a target of interest in oncology, both for treating with a single agent and in combination with a KRAS inhibitor. We were drawn to the pharmacological potential of SHP2 inhibition, especially following the initial observation that drug-like compounds could bind an allosteric site and enforce a closed, inactive state of the enzyme. Here, we describe the identification and characterization of GDC-1971 (formerly RLY-1971), a SHP2 inhibitor currently in clinical trials in combination with KRAS G12C inhibitor divarasib (GDC-6036) for the treatment of solid tumors driven by a KRAS G12C mutation. Identification of GDC-1971 (RLY-1971), a SHP2 Inhibitor Designed for the Treatment of Solid Tumors.,Taylor AM, Williams BR, Giordanetto F, Kelley EH, Lescarbeau A, Shortsleeves K, Tang Y, Walters WP, Arrazate A, Bowman C, Brophy E, Chan EW, Deshmukh G, Greisman JB, Hunsaker TL, Kipp DR, Saenz Lopez-Larrocha P, Maddalo D, Martin IJ, Maragakis P, Merchant M, Murcko M, Nisonoff H, Nguyen V, Nguyen V, Orozco O, Owen C, Pierce L, Schmidt M, Shaw DE, Smith S, Therrien E, Tran JC, Watters J, Waters NJ, Wilbur J, Willmore L J Med Chem. 2023 Sep 29. doi: 10.1021/acs.jmedchem.3c00483. PMID:37774359 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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