5-Keto-3-cyano-2,4-diaminothiophenes as selective maternal embryonic leucine zipper kinase inhibitors.
Bioorg Med Chem Lett
; 29(4): 607-613, 2019 02 15.
Article
in En
| MEDLINE
| ID: mdl-30626559
ABSTRACT
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, IC50â¯≈â¯5⯵M) 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 98â¯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.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Thiophenes
/
Protein Serine-Threonine Kinases
Type of study:
Guideline
Limits:
Female
/
Humans
Language:
En
Journal:
Bioorg Med Chem Lett
Journal subject:
BIOQUIMICA
/
QUIMICA
Year:
2019
Document type:
Article
Affiliation country:
Poland