8u7x

Crystal structure of non-receptor protein tyrosine phosphatase SHP2 in complex with inhibitor compound 24

spinqualitylabelsall models 8u7x, resolution 2.06Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 8u7x 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 2.06Å Ligands: WAB 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 SHP2 has emerged as an important target for oncology small-molecule drug discovery. As a nonreceptor tyrosine phosphatase within the MAPK pathway, it has been shown to control cell growth, differentiation, and oncogenic transformation. We used structure-based design to find a novel class of potent and orally bioavailable SHP2 inhibitors. Our efforts led to the discovery of the 5-azaquinoxaline as a new core for developing this class of compounds. Optimization of the potency and properties of this scaffold generated compound 30, that exhibited potent in vitro SHP2 inhibition and showed excellent in vivo efficacy and pharmacokinetic profile. Discovery of 5-Azaquinoxaline Derivatives as Potent and Orally Bioavailable Allosteric SHP2 Inhibitors.,Elsayed MSA, Blake JF, Boys ML, Brown E, Chapsal BD, Chicarelli MJ, Cook AW, Fell JB, Fischer JP, Hanson L, Lemieux C, Martinson MC, McCown J, McNulty OT, Mejia MJ, Neitzel NA, Otten JN, Rodriguez ME, Wilcox D, Wong CE, Zhou Y, Hinklin RJ ACS Med Chem Lett. 2023 Nov 15;14(12):1673-1681. doi: , 10.1021/acsmedchemlett.3c00310. eCollection 2023 Dec 14. PMID:38116446 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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