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Generating Selective Leads for Mer Kinase Inhibitors-Example of a Comprehensive Lead-Generation Strategy.

Nissink JWM, Bazzaz S, Blackett C, Clark MA, Collingwood O, Disch JS, Gikunju D, Goldberg K, Guilinger JP, Hardaker E, Hennessy EJ, Jetson R, Keefe AD, McCoull W, McMurray L, Olszewski A, Overman R, Pflug A, Preston M, Rawlins PB, Rivers E, Schimpl M, Smith P, Truman C, Underwood E, Warwicker J, Winter-Holt J, Woodcock S, Zhang Y
J Med Chem 64 3165-3184 (2021)
Related entries: 7avy, 7avz, 7aw0, 7aw1, 7aw2, 7aw3, 7aw4

Cited: 5 times
EuropePMC logo PMID: 33683117

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.

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Reviews citing this publication (2)

  1. Small-molecule discovery through DNA-encoded libraries. Peterson AA, Liu DR. Nat Rev Drug Discov 22 699-722 (2023)
  2. Screening Ultra-Large Encoded Compound Libraries Leads to Novel Protein-Ligand Interactions and High Selectivity. Collie GW, Clark MA, Keefe AD, Madin A, Read JA, Rivers EL, Zhang Y. J Med Chem 67 864-884 (2024)

Articles citing this publication (2)

  1. Discovery of Highly Potent and BMPR2-Selective Kinase Inhibitors Using DNA-Encoded Chemical Library Screening. Modukuri RK, Monsivais D, Li F, Palaniappan M, Bohren KM, Tan Z, Ku AF, Wang Y, Madasu C, Li JY, Tang S, Miklossy G, Palmer SS, Young DW, Matzuk MM. J Med Chem 66 2143-2160 (2023)
  2. Pharmacological inhibition of MERTK induces in vivo retinal degeneration: a multimodal imaging ocular safety assessment. Hamm G, Maglennon G, Williamson B, Macdonald R, Doherty A, Jones S, Harris J, Blades J, Harmer AR, Barton P, Rawlins PB, Smith P, Winter-Holt J, McMurray L, Johansson J, Fitzpatrick P, McCoull W, Coen M. Arch Toxicol 96 613-624 (2022)


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