Axl and Mer are members of the TAM (Tyro3, Axl, Mer) receptor tyrosine kinase family. Axl and Mer play an important role in regulating cell proliferation, survival, migration and cytokine production. Axl/Mer are known to be over-expressed in various types of haematological and solid tumour cancers and have been reported as poor prognostic factors. Recent studies indicate that Axl also appears to play a key role in epithelial-to-mesenchymal transitions (EMTs), which is involved in metastases and drug resistance in solid tumour such as NSCLC and breast cancer, and TAM receptor signaling increases innate immune regulation. Hit series of pyrrolopyrimidine derivatives were obtained through high throughput screening, and then modifying of them resulted in the identification of a highly potent and selective Axl/Mer dual inhibitor, N-[4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl]-5-cyclopropyl-2-oxo-1-phenyl-1,2-dihydro-3-pyridinecarboxamide (ONO-6990554, Axl IC50: 1.8 nM, Mer IC50: 1.2 nM, KDR IC50: 1300 nM, IGF1R IC50: 1200 nM, BaF3 Axl IC50: 6.5 nM). This presentation will describe the drug design which includes initial SAR exploration and efforts for improvement of selectivity, pharmacokinetic properties and in vivo efficacy. In addition, we will present the discovery of covalent inhibitor targeting specific cysteine residue at allosteric pocket by analysis of X-ray crystal structure and modeling.

Discovery of potent and selective Axl/Mer dual inhibitors

254th National Meeting (2017)

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