The crystal structure of MPK38 in complex with OTSSP167, an orally administrative MELK selective inhibitor

Area of Science:

• Biochemistry
• Molecular Biology
• Structural Biology

Background:

• Murine protein serine/threonine kinase 38 (MPK38), also known as maternal embryonic leucine zipper kinase (MELK), is implicated in human cancers and cancer stem cell development.
• Selective inhibition of MELK is a potential therapeutic strategy for cancer treatment.

Purpose of the Study:

• To determine the crystal structure of the active MPK38 (T167E) mutant in complex with the MELK inhibitor OTSSP167.
• To elucidate the detailed protein-inhibitor interactions for structure-based drug design.

Main Methods:

• X-ray crystallography was employed to obtain the structure of MPK38 (T167E) bound to OTSSP167.
• Analysis of protein-inhibitor interactions within the active site.

Main Results:

• The crystal structure reveals how OTSSP167 effectively binds to the active site of MPK38.
• OTSSP167 demonstrates potent in vitro (IC50 = 0.41nM) and in vivo activity against human cancer xenografts.
• Detailed interactions between OTSSP167 and MPK38 were characterized.

Conclusions:

• The determined structure provides a molecular basis for the high affinity of OTSSP167 to MELK.
• This structural information can guide the rational design and optimization of novel MELK inhibitors for cancer therapy.