5-Keto-3-cyano-2,4-diaminothiophenes as selective maternal embryonic leucine zipper kinase inhibitors

Bioorg Med Chem Lett. 2019 Feb 15;29(4):607-613. doi: 10.1016/j.bmcl.2018.12.051. Epub 2018 Dec 24.


Maternal embryonic leucine zipper kinase (MELK) is involved in several key cellular processes and displays increased levels of expression in numerous cancer classes (colon, breast, brain, ovary, prostate and lung). Although no selective MELK inhibitors have yet been approved, increasing evidence suggest that inhibition of MELK would constitute a promising approach for cancer therapy. A weak high-throughput screening hit (17, IC50 ≈ 5 μM) with lead-like properties was optimized for MELK inhibition. The early identification of a plausible binding mode by molecular modeling offered guidance in the choice of modifications towards compound 52 which displayed a 98 nM IC50. A good selectivity profile was achieved for a representative member of the series (29) in a 486 protein kinase panel. Future elaboration of 52 has the potential to deliver compounds for further development with chemotherapeutic aims.

Keywords: 5-Keto-3-cyano-2,4-diaminothiophene; Cancer; Kinase; MELK inhibitor; Maternal embryonic leucine zipper kinase (MELK).

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis / drug effects
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Drug Screening Assays, Antitumor
  • Female
  • High-Throughput Screening Assays
  • Humans
  • Inhibitory Concentration 50
  • Protein Serine-Threonine Kinases / antagonists & inhibitors*
  • Thiophenes / pharmacology*


  • Thiophenes
  • MELK protein, human
  • Protein Serine-Threonine Kinases