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8G6Z

JAK2 crystal structure in complex with Compound 13

Summary for 8G6Z
Entry DOI10.2210/pdb8g6z/pdb
DescriptorTyrosine-protein kinase JAK2, (3R)-3-cyclopentyl-3-[(4M)-4-{5-methyl-2-[(1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-1H-pyrazol-1-yl]propanenitrile, 1,2-ETHANEDIOL, ... (4 entities in total)
Functional Keywordsinhibitor, complex, kinase inhibitor, transferase, transferase-inhibitor complex, transferase/inhibitor
Biological sourceHomo sapiens (human)
Total number of polymer chains2
Total formula weight75600.15
Authors
Miller, S.T.,Ellis, D.A. (deposition date: 2023-02-16, release date: 2023-06-21, Last modification date: 2024-10-16)
Primary citationGordhan, H.M.,Miller, S.T.,Clancy, D.C.,Ina, M.,McDougal, A.V.,Cutno, D.K.,Brown, R.V.,Lichorowic, C.L.,Sturdivant, J.M.,Vick, K.A.,Williams, S.S.,deLong, M.A.,White, J.C.,Kopczynski, C.C.,Ellis, D.A.
Eyes on Topical Ocular Disposition: The Considered Design of a Lead Janus Kinase (JAK) Inhibitor That Utilizes a Unique Azetidin-3-Amino Bridging Scaffold to Attenuate Off-Target Kinase Activity, While Driving Potency and Aqueous Solubility.
J.Med.Chem., 66:8929-8950, 2023
Cited by
PubMed Abstract: An unmet medical need remains for patients suffering from dry eye disease (DED). A fast-acting, better-tolerated noncorticosteroid anti-inflammatory eye drop could improve patient outcomes and quality of life. Herein, we describe a small-molecule drug discovery effort to identify novel, potent, and water-soluble JAK inhibitors as immunomodulating agents for topical ocular disposition. A focused library of known 3-(4-(2-(arylamino)pyrimidin-4-yl)-1-pyrazol-1-yl)propanenitriles was evaluated as a molecular starting point. Structure-activity relationships (SARs) revealed a ligand-efficient (LE) JAK inhibitor series, amenable to aqueous solubility. Subsequent analysis indicated the potential for off-target toxicity. A KINOME selectivity profile of substantiated the likelihood of widespread series affinity across the human kinome. An sp-to-sp drug design strategy was undertaken to attenuate off-target kinase activity while driving JAK-STAT potency and aqueous solubility. Tactics to reduce aromatic character, increase fraction sp (Fsp), and bolster molecular complexity led to the azetidin-3-amino bridging scaffold in .
PubMed: 37314941
DOI: 10.1021/acs.jmedchem.3c00519
PDB entries with the same primary citation
Experimental method
X-RAY DIFFRACTION (2.45 Å)
Structure validation

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