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

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• 作者：Walter Keung^a ; ^{walter.keung@takeda.com} ; Amogh Boloor^a ; Jason Brown^a ; Andre Kiryanov^a ; Anthony Gangloff^a ; J. David Lawson^b ; Robert Skene^b ; Isaac Hoffman^b ; Josephine Atienza^c ; Jason Kahana^c ; Ron De Jong^c ; Pamela Farrell^c ; Deepika Balakrishna^c ; Petro Halkowycz^c
• 关键词：Axl ; Mer ; Structure design ; Oncology design ; Modeling ; Crystallography ; SBDD
• 刊名：Bioorganic & Medicinal Chemistry Letters
• 出版年：2017
• 出版时间：15 February 2017
• 年：2017
• 卷：27
• 期：4
• 页码：1099-1104
• 全文大小：2763 K
• 卷排序：27

文摘

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.