7ajs | pdb_00007ajs

Structure of DYRK1A in complex with compound 33

Loading... Status: waiting for Mol* initialization Structural highlights Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 2.15Å Ligands: DMS, GOL, PTR, RKH, SEP Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Publication Abstract from PubMed The kinase DYRK1A is an attractive target for drug discovery programs due to its implication in multiple diseases. Through a fragment screen, we identified a simple biaryl compound that is bound to the DYRK1A ATP site with very high efficiency, although with limited selectivity. Structure-guided optimization cycles enabled us to convert this fragment hit into potent and selective DYRK1A inhibitors. Exploiting the structural differences in DYRK1A and its close homologue DYRK2, we were able to fine-tune the selectivity of our inhibitors. Our best compounds potently inhibited DYRK1A in the cell culture and in vivo and demonstrated drug-like properties. The inhibition of DYRK1A in vivo translated into dose-dependent tumor growth inhibition in a model of ovarian carcinoma. Structure-Guided Discovery of Potent and Selective DYRK1A Inhibitors.,Weber C, Sipos M, Paczal A, Balint B, Kun V, Foloppe N, Dokurno P, Massey AJ, Walmsley DL, Hubbard RE, Murray J, Benwell K, Edmonds T, Demarles D, Bruno A, Burbridge M, Cruzalegui F, Kotschy A J Med Chem. 2021 May 12. doi: 10.1021/acs.jmedchem.1c00023. PMID:33975430 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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