5TD2

Structure-based optimization of 1H-imidazole-2-carboxamides as Axl kinase inhibitors utilizing a Mer mutant surrogate

Summary for 5TD2

• Entry DOI: 10.2210/pdb5td2/pdb
• Descriptor: Tyrosine-protein kinase Mer, N-[2-{4-[(2S)-4-(methylsulfonyl)morpholin-2-yl]-1,3-thiazol-2-yl}-4-(morpholin-4-yl)phenyl]-1H-imidazole-2-carboxamide (3 entities in total)
• Functional Keywords: kinase, inhibitor, surrogate, oncology, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Homo sapiens (Human)
• Cellular location: Membrane ; Single-pass type I membrane protein : Q12866
• Total number of polymer chains: 2
• Total formula weight: 66158.89

Authors

Hoffman, I.D.,Lawson, J.D. (deposition date: 2016-09-16, release date: 2017-01-25, Last modification date: 2024-03-06)

Primary citation

Keung, W.,Boloor, A.,Brown, J.,Kiryanov, A.,Gangloff, A.,Lawson, J.D.,Skene, R.,Hoffman, I.,Atienza, J.,Kahana, J.,De Jong, R.,Farrell, P.,Balakrishna, D.,Halkowycz, P.
Structure-based optimization of 1H-imidazole-2-carboxamides as Axl kinase inhibitors utilizing a Mer mutant surrogate.
Bioorg. Med. Chem. Lett., 27:1099-1104, 2017

PubMed Abstract: Axl has been a target of interest in the oncology field for several years based on its role in various oncogenic processes. To date, no wild-type Axl crystal structure has been reported. Herein, we describe the structure-based optimization of a novel chemotype of Axl inhibitors, 1H-imidazole-2-carboxamide, using a mutated kinase homolog, Mer(I650M), as a crystallographic surrogate. Iterative optimization of the initial lead compound (1) led to compound (21), a selective and potent inhibitor of wild-type Axl. Compound (21) will serve as a useful compound for further in vivo studies.

PubMed: 28082036
DOI: 10.1016/j.bmcl.2016.12.024

Experimental method

X-RAY DIFFRACTION (2.68 Å)