7OLX

MerTK kinase domain with type 1.5 inhibitor containing a tri-methyl pyrazole group

7OLX の概要

• エントリーDOI: 10.2210/pdb7olx/pdb
• 分子名称: 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)
• 機能のキーワード: tyrosine kinase inhibitor, structure-based drug design, type 1.5 inhibitor, transferase
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 35085.25

構造登録者

Pflug, A.,Schimpl, M.,McCoull, W.,Nissink, J.W.M.,Winter-Holt, J. (登録日: 2021-05-20, 公開日: 2021-09-15, 最終更新日: 2024-01-31)

主引用文献

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

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: 34478292
DOI: 10.1021/acs.jmedchem.1c00920

実験手法

X-RAY DIFFRACTION (1.98 Å)