4HRA

Crystal Structure of DOT1L in Complex with EPZ-5676

Summary for 4HRA

• Entry DOI: 10.2210/pdb4hra/pdb
• Related: 3QOW 3QOX 4EK9 4EKG 4EKI
• Descriptor: Histone-lysine N-methyltransferase, H3 lysine-79 specific, 5'-[{cis-3-[2-(5-tert-butyl-1H-benzimidazol-2-yl)ethyl]cyclobutyl}(propan-2-yl)amino]-5'-deoxyadenosine, SULFATE ION (3 entities in total)
• Functional Keywords: histone lysine methyltransferase, transferase, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Homo sapiens (human)
• Cellular location: Nucleus: Q8TEK3
• Total number of polymer chains: 1
• Total formula weight: 49321.07

Authors

Jin, L. (deposition date: 2012-10-26, release date: 2013-07-31, Last modification date: 2023-09-20)

Primary citation

Daigle, S.R.,Olhava, E.J.,Therkelsen, C.A.,Basavapathruni, A.,Jin, L.,Boriack-Sjodin, P.A.,Allain, C.J.,Klaus, C.R.,Raimondi, A.,Scott, M.P.,Waters, N.J.,Chesworth, R.,Moyer, M.P.,Copeland, R.A.,Richon, V.M.,Pollock, R.M.
Potent inhibition of DOT1L as treatment of MLL-fusion leukemia.
Blood, 122:1017-1025, 2013

PubMed Abstract: Rearrangements of the MLL gene define a genetically distinct subset of acute leukemias with poor prognosis. Current treatment options are of limited effectiveness; thus, there is a pressing need for new therapies for this disease. Genetic and small molecule inhibitor studies have demonstrated that the histone methyltransferase DOT1L is required for the development and maintenance of MLL-rearranged leukemia in model systems. Here we describe the characterization of EPZ-5676, a potent and selective aminonucleoside inhibitor of DOT1L histone methyltransferase activity. The compound has an inhibition constant value of 80 pM, and demonstrates 37 000-fold selectivity over all other methyltransferases tested. In cellular studies, EPZ-5676 inhibited H3K79 methylation and MLL-fusion target gene expression and demonstrated potent cell killing that was selective for acute leukemia lines bearing MLL translocations. Continuous IV infusion of EPZ-5676 in a rat xenograft model of MLL-rearranged leukemia caused complete tumor regressions that were sustained well beyond the compound infusion period with no significant weight loss or signs of toxicity. EPZ-5676 is therefore a potential treatment of MLL-rearranged leukemia and is under clinical investigation.

PubMed: 23801631
DOI: 10.1182/blood-2013-04-497644

Experimental method

X-RAY DIFFRACTION (3.15 Å)