7AW4

MerTK kinase domain with type 3 inhibitor from a DNA-encoded library

Summary for 7AW4

• Entry DOI: 10.2210/pdb7aw4/pdb
• Descriptor: Tyrosine-protein kinase Mer, 3-methyl-5-(4-methyl-1,2,3-thiadiazol-5-yl)-N-((R)-1-(((R)-3-(methylamino)-3-oxo-1-(4-(trifluoromethyl)phenyl)propyl)amino)-1-oxo-4-phenylbutan-2-yl)isoxazole-4-carboxamide, CHLORIDE ION, ... (5 entities in total)
• Functional Keywords: tyrosine kinase, inhibitor, type3 kinase inhibitor, structure-based drug design, oncology, signaling protein
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 2
• Total formula weight: 73486.91

Authors

Pflug, A.,Nissink, J.W.M.,Blackett, C.,Goldberg, K.,Hennessy, E.J.,Hardaker, E.,McCoull, W.,McMurray, L.,Collingwood, O.,Overman, R.,Preston, M.,Rawlins, P.,Rivers, E.,Schimpl, M.,Smith, P.,Underwood, E.,Truman, C.,Warwicker, J.,Winter, J.,Woodcock, S. (deposition date: 2020-11-06, release date: 2021-03-03, Last modification date: 2024-05-01)

Primary citation

Nissink, J.W.M.,Bazzaz, S.,Blackett, C.,Clark, M.A.,Collingwood, O.,Disch, J.S.,Gikunju, D.,Goldberg, K.,Guilinger, J.P.,Hardaker, E.,Hennessy, E.J.,Jetson, R.,Keefe, A.D.,McCoull, W.,McMurray, L.,Olszewski, A.,Overman, R.,Pflug, A.,Preston, M.,Rawlins, P.B.,Rivers, E.,Schimpl, M.,Smith, P.,Truman, C.,Underwood, E.,Warwicker, J.,Winter-Holt, J.,Woodcock, S.,Zhang, Y.
Generating Selective Leads for Mer Kinase Inhibitors-Example of a Comprehensive Lead-Generation Strategy.
J.Med.Chem., 64:3165-3184, 2021

PubMed Abstract: Mer is a member of the TAM (Tyro3, Axl, Mer) kinase family that has been associated with cancer progression, metastasis, and drug resistance. Their essential function in immune homeostasis has prompted an interest in their role as modulators of antitumor immune response in the tumor microenvironment. Here we illustrate the outcomes of an extensive lead-generation campaign for identification of Mer inhibitors, focusing on the results from concurrent, orthogonal high-throughput screening approaches. Data mining, HT (high-throughput), and DECL (DNA-encoded chemical library) screens offered means to evaluate large numbers of compounds. We discuss campaign strategy and screening outcomes, and exemplify series resulting from prioritization of hits that were identified. Concurrent execution of HT and DECL screening successfully yielded a large number of potent, selective, and novel starting points, covering a range of selectivity profiles across the TAM family members and modes of kinase binding, and offered excellent start points for lead development.

PubMed: 33683117
DOI: 10.1021/acs.jmedchem.0c01904

Experimental method

X-RAY DIFFRACTION (1.98 Å)