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J Med Chem. 2012 Sep 27;55(18):8066-74. Epub 2012 Sep 6.

Synthesis and structure-activity relationship investigation of adenosine-containing inhibitors of histone methyltransferase DOT1L.

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Department of Pharmacology, Baylor College of Medicine, 1 Baylor Plaza, Houston, Texas 77030, USA.


Histone3-lysine79 (H3K79) methyltransferase DOT1L has been found to be a drug target for acute leukemia with MLL (mixed lineage leukemia) gene translocations. A total of 55 adenosine-containing compounds were designed and synthesized, among which several potent DOT1L inhibitors were identified with K(i) values as low as 0.5 nM. These compounds also show high selectivity (>4500-fold) over three other histone methyltransferases. Structure-activity relationships (SAR) of these compounds for their inhibitory activities against DOT1L are discussed. Potent DOT1L inhibitors exhibit selective activity against the proliferation of MLL-translocated leukemia cell lines MV4;11 and THP1 with EC(50) values of 4-11 μM. Isothermal titration calorimetry studies showed that two representative inhibitors bind with a high affinity to the DOT1L:nucleosome complex and only compete with the enzyme cofactor SAM (S-adenosyl-L-methionine) but not the substrate nucleosome.

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