8DEG
Crystal structure of DLK in complex with inhibitor DN0011197
Summary for 8DEG
| Entry DOI | 10.2210/pdb8deg/pdb |
| Descriptor | Mitogen-activated protein kinase kinase kinase 12, methyl (1S,4S)-5-{(4P)-4-[5-amino-6-(difluoromethoxy)pyrazin-2-yl]-6-[(1R,4R)-2-azabicyclo[2.1.1]hexan-2-yl]pyridin-2-yl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (3 entities in total) |
| Functional Keywords | dlk, kinase, inhibitor, signaling protein, transferase-inhibitor complex, transferase/inhibitor |
| Biological source | Homo sapiens (human) |
| Total number of polymer chains | 1 |
| Total formula weight | 36883.27 |
| Authors | Srivastava, A.,Lexa, K.,de Vicente, J. (deposition date: 2022-06-20, release date: 2022-12-14, Last modification date: 2024-04-03) |
| Primary citation | Craig 2nd, R.A.,Fox, B.M.,Hu, C.,Lexa, K.W.,Osipov, M.,Thottumkara, A.P.,Larhammar, M.,Miyamoto, T.,Rana, A.,Kane, L.A.,Yulyaningsih, E.,Solanoy, H.,Nguyen, H.,Chau, R.,Earr, T.,Kajiwara, Y.,Fleck, D.,Lucas, A.,Haddick, P.C.G.,Takahashi, R.H.,Tong, V.,Wang, J.,Canet, M.J.,Poda, S.B.,Scearce-Levie, K.,Srivastava, A.,Sweeney, Z.K.,Xu, M.,Zhang, R.,He, J.,Lei, Y.,Zhuo, Z.,de Vicente, J. Discovery of Potent and Selective Dual Leucine Zipper Kinase/Leucine Zipper-Bearing Kinase Inhibitors with Neuroprotective Properties in In Vitro and In Vivo Models of Amyotrophic Lateral Sclerosis. J.Med.Chem., 65:16290-16312, 2022 Cited by PubMed Abstract: Dual leucine zipper kinase (DLK) and leucine zipper-bearing kinase (LZK) are regulators of neuronal degeneration and axon growth. Therefore, there is a considerable interest in developing DLK/LZK inhibitors for neurodegenerative diseases. Herein, we use ligand- and structure-based drug design approaches for identifying novel amino-pyrazine inhibitors of DLK/LZK. DN-1289 (), a potent and selective dual DLK/LZK inhibitor, demonstrated excellent in vivo plasma half-life across species and is anticipated to freely penetrate the central nervous system with no brain impairment based on in vivo rodent pharmacokinetic studies and human in vitro transporter data. Proximal target engagement and disease relevant pathway biomarkers were also favorably regulated in an in vivo model of amyotrophic lateral sclerosis. PubMed: 36469401DOI: 10.1021/acs.jmedchem.2c01056 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.79 Å) |
Structure validation
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