8G6Z
JAK2 crystal structure in complex with Compound 13
Summary for 8G6Z
Entry DOI | 10.2210/pdb8g6z/pdb |
Descriptor | Tyrosine-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 Keywords | inhibitor, complex, kinase inhibitor, transferase, transferase-inhibitor complex, transferase/inhibitor |
Biological source | Homo sapiens (human) |
Total number of polymer chains | 2 |
Total formula weight | 75600.15 |
Authors | Miller, S.T.,Ellis, D.A. (deposition date: 2023-02-16, release date: 2023-06-21, Last modification date: 2024-10-16) |
Primary citation | Gordhan, 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: 37314941DOI: 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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