Point mutations within the BRC-ABL tyrosine kinase domain give rise to imatinib-resistant mutants. Designing next generation ligands to counteract TK inhibitor resistance remains a challenging problem. Scaffold replacement is applied to the imatinib framework where the 2-amino-pyrimidine fragment is exchanged through a scaffold screen to produce a number of related congeneric series. 3D ligand optimization is subsequently performed on one of the hits yielding a structurally related isomer of ponatinib, a known selective high affinity tyrosine kinase inhibitor.

Scaffold replacement and 3D ligand optimization applied to the discovery of tyrosine kinase inhibitors

2019 Spring National Meeting

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