7OLX
MerTK kinase domain with type 1.5 inhibitor containing a tri-methyl pyrazole group
Summary for 7OLX
| Entry DOI | 10.2210/pdb7olx/pdb |
| Descriptor | Tyrosine-protein kinase Mer, ~{N}-[[3-[4-[(dimethylamino)methyl]phenyl]imidazo[1,2-a]pyridin-6-yl]methyl]-~{N}-methyl-5-[3-methyl-5-(1,3,5-trimethylpyrazol-4-yl)pyridin-2-yl]-1,3,4-oxadiazol-2-amine, CHLORIDE ION, ... (4 entities in total) |
| Functional Keywords | tyrosine kinase inhibitor, structure-based drug design, type 1.5 inhibitor, transferase |
| Biological source | Homo sapiens (Human) |
| Total number of polymer chains | 1 |
| Total formula weight | 35085.25 |
| Authors | Pflug, A.,Schimpl, M.,McCoull, W.,Nissink, J.W.M.,Winter-Holt, J. (deposition date: 2021-05-20, release date: 2021-09-15, Last modification date: 2024-01-31) |
| Primary citation | McCoull, W.,Boyd, S.,Brown, M.R.,Coen, M.,Collingwood, O.,Davies, N.L.,Doherty, A.,Fairley, G.,Goldberg, K.,Hardaker, E.,He, G.,Hennessy, E.J.,Hopcroft, P.,Hodgson, G.,Jackson, A.,Jiang, X.,Karmokar, A.,Laine, A.L.,Lindsay, N.,Mao, Y.,Markandu, R.,McMurray, L.,McLean, N.,Mooney, L.,Musgrove, H.,Nissink, J.W.M.,Pflug, A.,Reddy, V.P.,Rawlins, P.B.,Rivers, E.,Schimpl, M.,Smith, G.F.,Tentarelli, S.,Travers, J.,Troup, R.I.,Walton, J.,Wang, C.,Wilkinson, S.,Williamson, B.,Winter-Holt, J.,Yang, D.,Zheng, Y.,Zhu, Q.,Smith, P.D. Optimization of an Imidazo[1,2- a ]pyridine Series to Afford Highly Selective Type I1/2 Dual Mer/Axl Kinase Inhibitors with In Vivo Efficacy. J.Med.Chem., 64:13524-13539, 2021 Cited by PubMed Abstract: Inhibition of Mer and Axl kinases has been implicated as a potential way to improve the efficacy of current immuno-oncology therapeutics by restoring the innate immune response in the tumor microenvironment. Highly selective dual Mer/Axl kinase inhibitors are required to validate this hypothesis. Starting from hits from a DNA-encoded library screen, we optimized an imidazo[1,2-]pyridine series using structure-based compound design to improve potency and reduce lipophilicity, resulting in a highly selective probe compound . We demonstrated dose-dependent efficacy and target engagement in Mer- and Axl-dependent efficacy models using two structurally differentiated and selective dual Mer/Axl inhibitors. Additionally, efficacy was observed in a preclinical MC38 immuno-oncology model in combination with anti-PD1 antibodies and ionizing radiation. PubMed: 34478292DOI: 10.1021/acs.jmedchem.1c00920 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.98 Å) |
Structure validation
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