Structure-based design of oxygen-linked macrocyclic kinase inhibitors: discovery of SB1518 and SB1578, potent inhibitors of Janus kinase 2 (JAK2) and Fms-like tyrosine kinase-3 (FLT3)

@article{Poulsen2012StructurebasedDO,
  title={Structure-based design of oxygen-linked macrocyclic kinase inhibitors: discovery of SB1518 and SB1578, potent inhibitors of Janus kinase 2 (JAK2) and Fms-like tyrosine kinase-3 (FLT3)},
  author={Anders Poulsen and Anthony William and St{\'e}phanie Blanchard and Angeline Lee and Harish Nagaraj and Haishan Wang and Eeling Teo and Evelyn S Tan and Kee Chuan Goh and Brian W Dymock},
  journal={Journal of computer-aided molecular design},
  year={2012},
  volume={26 4},
  pages={437-50}
}
Macrocycles from our Aurora project were screened in a kinase panel and were found to be active on other kinase targets, mainly JAKs, FLT3 and CDKs. Subsequently these compounds became leads in our JAK2 project. Macrocycles with a basic nitrogen in the linker form a salt bridge with Asp86 in CDK2 and Asp698 in FLT3. This residue is conserved in most CDKs resulting in potent pan CDK inhibition. One of the main project objectives was to achieve JAK2 potency with 100-fold selectivity against CDKs… CONTINUE READING