5DRT

Crystal structure of Dot1L in complex with inhibitor CPD2 [2-(2-(5-((2-chlorophenoxy)methyl)-1H-tetrazol-1-yl)acetyl)-N-(4-chlorophenyl)hydrazinecarboxamide]

Summary for 5DRT

• Entry DOI: 10.2210/pdb5drt/pdb
• Descriptor: Histone-lysine N-methyltransferase, H3 lysine-79 specific, 2-({5-[(2-chlorophenoxy)methyl]-1H-tetrazol-1-yl}acetyl)-N-(4-chlorophenyl)hydrazinecarboxamide, POTASSIUM ION, ... (4 entities in total)
• Functional Keywords: inhibitor, complex, methyltransferase, transferase
• Biological source: Homo sapiens (Human)
• Cellular location: Nucleus : Q8TEK3
• Total number of polymer chains: 2
• Total formula weight: 77824.79

Authors

Scheufler, C.,Gaul, C.,Be, C.,Moebitz, H. (deposition date: 2015-09-16, release date: 2016-06-15, Last modification date: 2024-01-10)

Primary citation

Chen, C.,Zhu, H.,Stauffer, F.,Caravatti, G.,Vollmer, S.,Machauer, R.,Holzer, P.,Mobitz, H.,Scheufler, C.,Klumpp, M.,Tiedt, R.,Beyer, K.S.,Calkins, K.,Guthy, D.,Kiffe, M.,Zhang, J.,Gaul, C.
Discovery of Novel Dot1L Inhibitors through a Structure-Based Fragmentation Approach.
Acs Med.Chem.Lett., 7:735-740, 2016

PubMed Abstract: Oncogenic MLL fusion proteins aberrantly recruit Dot1L, a histone methyltransferase, to ectopic loci, leading to local hypermethylation of H3K79 and misexpression of HoxA genes driving MLL-rearranged leukemias. Inhibition of the methyltransferase activity of Dot1L in this setting is predicted to reverse aberrant H3K79 methylation, leading to repression of leukemogenic genes and tumor growth inhibition. In the context of our Dot1L drug discovery program, high-throughput screening led to the identification of 2, a weak Dot1L inhibitor with an unprecedented, induced pocket binding mode. A medicinal chemistry campaign, strongly guided by structure-based consideration and ligand-based morphing, enabled the discovery of 12 and 13, potent, selective, and structurally completely novel Dot1L inhibitors.

PubMed: 27563395
DOI: 10.1021/acsmedchemlett.6b00167

Experimental method

X-RAY DIFFRACTION (2.69 Å)