9fkr

KAT6A IN COMPLEX WITH SMALL MOLECULE INHIBITOR BAY-184

spinqualitylabelsall models 9fkr, resolution 2.69Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 9fkr 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 2.69Å Ligands: A1IDR, ALY, EPE, ZN Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Disease KAT6A_HUMAN Note=Chromosomal aberrations involving KAT6A may be a cause of acute myeloid leukemias. Translocation t(8;16)(p11;p13) with CREBBP; translocation t(8;22)(p11;q13) with EP300. KAT6A-CREBBP may induce leukemia by inhibiting RUNX1-mediated transcription. Inversion inv(8)(p11;q13) generates the KAT6A-NCOA2 oncogene, which consists of the N-terminal part of KAT6A and the C-terminal part of NCOA2/TIF2. KAT6A-NCOA2 binds to CREBBP and disrupts its function in transcription activation. Note=A chromosomal aberration involving KAT6A is a cause of therapy-related myelodysplastic syndrome. Translocation t(2;8)(p23;p11.2) with ASXL2 generates a KAT6A-ASXL2 fusion protein. Function KAT6A_HUMAN Histone acetyltransferase that acetylates lysine residues in histone H3 and histone H4 (in vitro). Component of the MOZ/MORF complex which has a histone H3 acetyltransferase activity. May act as a transcriptional coactivator for RUNX1 and RUNX2. Publication Abstract from PubMed KAT6A and KAT6B genes are two closely related lysine acetyltransferases that transfer an acetyl group from acetyl coenzyme A (AcCoA) to lysine residues of target histone substrates, hence playing a key role in chromatin regulation. KAT6A and KAT6B genes are frequently amplified in various cancer types. In breast cancer, the 8p11-p12 amplicon occurs in 12-15% of cases, resulting in elevated copy numbers and expression levels of chromatin modifiers like KAT6A. Here, we report the discovery of a new acylsulfonamide-benzofuran series as a novel structural class for KAT6A/B inhibition. These compounds were identified through high-throughput screening and subsequently optimized using molecular modeling and cocrystal structure determination. The final tool compound, BAY-184 (29), was successfully validated in an in vivo proof-of-concept study. Discovery and Characterization of BAY-184: A New Potent and Selective Acylsulfonamide-Benzofuran In Vivo-Active KAT6AB Inhibitor.,Ter Laak A, Hillig RC, Ferrara SJ, Korr D, Barak N, Lienau P, Herbert S, Fernandez-Montalvan AE, Neuhaus R, Gorjanacz M, Puetter V, Badock V, Bone W, Strathdee C, Siegel F, Schatz C, Nowak-Reppel K, Doehr O, Gradl S, Hartung IV, Meyerson M, Bouche L J Med Chem. 2024 Oct 25. doi: 10.1021/acs.jmedchem.4c01709. PMID:39450890 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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