Crystal structures of two inhibitors in complex with histone lysine demethylase 4D (KDM4D) provide new insights for rational drug design

Histone lysine demethylase 4D (KDM4D), also known as JMJD2D, plays an important role in cell proliferation and survival and has been associated with several tumor types. KDM4D has emerged as a potential target for the treatment of human cancer. Here, we reported crystal complex structures for two KDM4D inhibitors, OWS [2-(1H-pyrazol-3-yl)isonicotinic acid] and 10r (5-hydroxy-2-methylpyrazolo [1,5-a]pyrido[3,2-e]pyrimidine-3-carbonitrile), which were both determined to 2.0 angstrom. OWS is a newly discovered KDM4D inhibitor (IC50 = 4.28 mu M) and the critical pharmacophores of this compound are confirmed by the complex structure. Compound 10r is a KDM4D inhibitor reported by us previously. To clarify the binding mode in more detail, the crystal structure was determined and the comparison analysis revealed unique interactions that had never been observed before. Overall, our data provide new structural insights for rational design and offer an opportunity for optimization of KDM4D inhibitors. (C) 2021 Published by Elsevier Inc.

Automated summary

Crystal complex structures of two KDM4D inhibitors, OWS and 10r, have been determined, offering new insights for rational design and optimization of KDM4D inhibitors.