8er7 | pdb_00008er7

FKBP12-FRB in Complex with Compound 12

spinqualitylabelsall models 8er7, resolution 3.07Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 8er7 is a 6 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 3.07Å Ligands: CL, XZ3 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function B1AKP8_HUMAN Publication Abstract from PubMed Hyperactivation of mTOR kinase by mutations in the PI3K/mTOR pathway or by crosstalk with other mutant cancer drivers, such as RAS, is a feature of many tumors. Multiple allosteric inhibitors of mTORC1 and orthosteric dual inhibitors of mTORC1 and mTORC2 have been developed as anticancer drugs, but their clinical utility has been limited. To address these limitations, we have developed a novel class of "bi-steric inhibitors" that interact with both the orthosteric and the allosteric binding sites in order to deepen the inhibition of mTORC1 while also preserving selectivity for mTORC1 over mTORC2. In this report, we describe the discovery and preclinical profile of the development candidate RMC-5552 and the in vivo preclinical tool compound RMC-6272. We also present evidence that selective inhibition of mTORC1 in combination with covalent inhibition of KRAS(G12C) shows increased antitumor activity in a preclinical model of KRAS(G12C) mutant NSCLC that exhibits resistance to KRAS(G12C) inhibitor monotherapy. Discovery of RMC-5552, a Selective Bi-Steric Inhibitor of mTORC1, for the Treatment of mTORC1-Activated Tumors.,Burnett GL, Yang YC, Aggen JB, Pitzen J, Gliedt MK, Semko CM, Marquez A, Evans JW, Wang G, Won WS, Tomlinson ACA, Kiss G, Tzitzilonis C, Thottumkara AP, Cregg J, Mellem KT, Choi JS, Lee JC, Zhao Y, Lee BJ, Meyerowitz JG, Knox JE, Jiang J, Wang Z, Wildes D, Wang Z, Singh M, Smith JAM, Gill AL J Med Chem. 2022 Dec 19. doi: 10.1021/acs.jmedchem.2c01658. PMID:36533617 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also FKBP 3D structures

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