Conformational adaptation drives potent, selective and durable inhibition of the human protein methyltransferase DOT1L.

@article{Basavapathruni2012ConformationalAD,
  title={Conformational adaptation drives potent, selective and durable inhibition of the human protein methyltransferase DOT1L.},
  author={Aravind Basavapathruni and Lei Jin and Scott R. Daigle and Christina R A Majer and Carly A Therkelsen and Tim J. Wigle and Kevin W. Kuntz and Richard Chesworth and Roy M. Pollock and Margaret Porter Scott and Mikel P. Moyer and Victoria M. Richon and Robert A Copeland and Edward J. Olhava},
  journal={Chemical biology & drug design},
  year={2012},
  volume={80 6},
  pages={971-80}
}
DOT1L is the human protein methyltransferase responsible for catalyzing the methylation of histone H3 on lysine 79 (H3K79). The ectopic activity of DOT1L, associated with the chromosomal translocation that is a universal hallmark of MLL-rearranged leukemia, is a required driver of leukemogenesis in this malignancy. Here, we present studies on the structure-activity relationship of aminonucleoside-based DOT1L inhibitors. Within this series, we find that improvements in target enzyme affinity and… CONTINUE READING
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