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

Autor: Boutard N; Selvita S.A, Bobrzyńskiego, 14, 30-338 Kraków, Poland., Sabiniarz A; Selvita S.A, Bobrzyńskiego, 14, 30-338 Kraków, Poland., Czerwińska K; Selvita S.A, Bobrzyńskiego, 14, 30-338 Kraków, Poland., Jarosz M; Selvita S.A, Bobrzyńskiego, 14, 30-338 Kraków, Poland., Cierpich A; Selvita S.A, Bobrzyńskiego, 14, 30-338 Kraków, Poland., Kolasińska E; Selvita S.A, Bobrzyńskiego, 14, 30-338 Kraków, Poland., Wiklik K; Selvita S.A, Bobrzyńskiego, 14, 30-338 Kraków, Poland., Gluza K; Selvita S.A, Bobrzyńskiego, 14, 30-338 Kraków, Poland., Commandeur C; Selvita S.A, Bobrzyńskiego, 14, 30-338 Kraków, Poland., Buda A; Selvita S.A, Bobrzyńskiego, 14, 30-338 Kraków, Poland., Stasiowska A; Selvita S.A, Bobrzyńskiego, 14, 30-338 Kraków, Poland., Bobowska A; Selvita S.A, Bobrzyńskiego, 14, 30-338 Kraków, Poland., Galek M; Selvita S.A, Bobrzyńskiego, 14, 30-338 Kraków, Poland., Fabritius CH; Selvita S.A, Bobrzyńskiego, 14, 30-338 Kraków, Poland., Bugaj M; Selvita S.A, Bobrzyńskiego, 14, 30-338 Kraków, Poland., Palacz E; Selvita S.A, Bobrzyńskiego, 14, 30-338 Kraków, Poland., Mazan A; Selvita S.A, Bobrzyńskiego, 14, 30-338 Kraków, Poland., Zarębski A; Selvita S.A, Bobrzyńskiego, 14, 30-338 Kraków, Poland., Krawczyńska K; Selvita S.A, Bobrzyńskiego, 14, 30-338 Kraków, Poland., Żurawska M; Selvita S.A, Bobrzyńskiego, 14, 30-338 Kraków, Poland., Zawadzki P; Selvita S.A, Bobrzyńskiego, 14, 30-338 Kraków, Poland., Milik M; Selvita S.A, Bobrzyńskiego, 14, 30-338 Kraków, Poland., Węgrzyn P; Selvita S.A, Bobrzyńskiego, 14, 30-338 Kraków, Poland., Dobrzańska M; Selvita S.A, Bobrzyńskiego, 14, 30-338 Kraków, Poland., Brzózka K; Selvita S.A, Bobrzyńskiego, 14, 30-338 Kraków, Poland., Kowalczyk P; Selvita S.A, Bobrzyńskiego, 14, 30-338 Kraków, Poland. Electronic address: piotr.kowalczyk@selvita.com.
Jazyk: angličtina
Zdroj: Bioorganic & medicinal chemistry letters [Bioorg Med Chem Lett] 2019 Feb 15; Vol. 29 (4), pp. 607-613. Date of Electronic Publication: 2018 Dec 24.
DOI: 10.1016/j.bmcl.2018.12.051
Abstrakt: 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, IC 50  ≈ 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 IC 50 . 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.
(Copyright © 2018. Published by Elsevier Ltd.)
Databáze: MEDLINE
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