title: Structure-based optimization of 1H-imidazole-2-carboxamides as Axl kinase inhibitors utilizing a Mer mutant surrogate.
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.
authors.affiliation: Medicinal Chemistry, Takeda California, 10410 Science Center Drive, San Diego, CA 92121, United States. Electronic address: walter.keung@takeda.com.
authors.forename: Walter
authors.initials: W
authors.lastname: Keung
authors.affiliation: Medicinal Chemistry, Takeda California, 10410 Science Center Drive, San Diego, CA 92121, United States.
authors.forename: Amogh
authors.initials: A
authors.lastname: Boloor
authors.affiliation: Medicinal Chemistry, Takeda California, 10410 Science Center Drive, San Diego, CA 92121, United States.
authors.forename: Jason
authors.initials: J
authors.lastname: Brown
authors.affiliation: Medicinal Chemistry, Takeda California, 10410 Science Center Drive, San Diego, CA 92121, United States.
authors.forename: Andre
authors.initials: A
authors.lastname: Kiryanov
authors.affiliation: Medicinal Chemistry, Takeda California, 10410 Science Center Drive, San Diego, CA 92121, United States.
authors.forename: Anthony
authors.initials: A
authors.lastname: Gangloff
authors.affiliation: Computational Sciences and Crystallography, Takeda California, 10410 Science Center Drive, San Diego, CA 92121, United States.
authors.forename: J David
authors.initials: JD
authors.lastname: Lawson
authors.affiliation: Computational Sciences and Crystallography, Takeda California, 10410 Science Center Drive, San Diego, CA 92121, United States.
authors.forename: Robert
authors.initials: R
authors.lastname: Skene
authors.affiliation: Computational Sciences and Crystallography, Takeda California, 10410 Science Center Drive, San Diego, CA 92121, United States.
authors.forename: Isaac
authors.initials: I
authors.lastname: Hoffman
authors.affiliation: Discovery Biology, Takeda California, 10410 Science Center Drive, San Diego, CA 92121, United States.
authors.forename: Josephine
authors.initials: J
authors.lastname: Atienza
authors.affiliation: Discovery Biology, Takeda California, 10410 Science Center Drive, San Diego, CA 92121, United States.
authors.forename: Jason
authors.initials: J
authors.lastname: Kahana
authors.affiliation: Discovery Biology, Takeda California, 10410 Science Center Drive, San Diego, CA 92121, United States.
authors.forename: Ron
authors.initials: R
authors.lastname: De Jong
authors.affiliation: Discovery Biology, Takeda California, 10410 Science Center Drive, San Diego, CA 92121, United States.
authors.forename: Pamela
authors.initials: P
authors.lastname: Farrell
authors.affiliation: Discovery Biology, Takeda California, 10410 Science Center Drive, San Diego, CA 92121, United States.
authors.forename: Deepika
authors.initials: D
authors.lastname: Balakrishna
authors.affiliation: Discovery Biology, Takeda California, 10410 Science Center Drive, San Diego, CA 92121, United States.
authors.forename: Petro
authors.initials: P
authors.lastname: Halkowycz
mesh_terms: D018360:Crystallography, X-Ray; D007093:Imidazoles / Q000737:chemistry* / Q000494:pharmacology*; D015394:Molecular Structure; D009154:Mutation; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics*; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics*; D000076202:c-Mer Tyrosine Kinase; D000094963:Axl Receptor Tyrosine Kinase
chemical_list: D007093:Imidazoles; D047428:Protein Kinase Inhibitors; D011518:Proto-Oncogene Proteins; C097072:MERTK protein, human; D020794:Receptor Protein-Tyrosine Kinases; D000076202:c-Mer Tyrosine Kinase; D000094963:Axl Receptor Tyrosine Kinase
keywords: Axl; Crystallography; Mer; Modeling; Oncology design; SBDD; Structure design