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. 2017 Feb 15;27(4):1099-1104.
doi: 10.1016/j.bmcl.2016.12.024. Epub 2016 Dec 20.

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

Walter Keung  1 , Amogh Boloor  2 , Jason Brown  2 , Andre Kiryanov  2 , Anthony Gangloff  2 , J David Lawson  3 , Robert Skene  3 , Isaac Hoffman  3 , Josephine Atienza  4 , Jason Kahana  4 , Ron De Jong  4 , Pamela Farrell  4 , Deepika Balakrishna  4 , Petro Halkowycz  4
Affiliations

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

Walter Keung et al. Bioorg Med Chem Lett. .

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.

Keywords: Axl; Crystallography; Mer; Modeling; Oncology design; SBDD; Structure design.

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