Journal
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
Volume 227, Issue -, Pages -Publisher
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.ejmech.2021.113904
Keywords
Bisindole; Tousled-like kinases; Anti-cancer agents; DNA replication; Genome instability
Categories
Funding
- Ministry of Science and Technology, Taiwan [MOST 108-2311-B-038-001, MOST109-2311-B-038-001]
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This study introduces novel bisindole molecules as anti-cancer agents that effectively inhibit TLKs activity and demonstrated their anti-cancer effects in vitro. Through structure optimization, six derivatives with potent TLK inhibitory activity were identified, with potential applications in the treatment of various cancers.
This study presents the design, synthesis, and characterization of bisindole molecules as anti-cancer agents against Tousled-like kinases (TLKs). We show that compound 2 composed of an indirubin-3'-oxime group linked with a (N-methylpiperidin-2-yl)ethyl moiety possessed inhibitory activity toward both TLK1 and TLK2 in vitro and diminished the phosphorylation level of the downstream substrate anti-silencing function 1 (ASF1) in replicating cells. The treatment of compound 2 impaired DNA replication, slowed S-phase progression, and triggered DNA damage response in replicating cells. Structure optimization further discovered six derivatives exhibiting potent TLK inhibitory activity and revealed the importance of the tertiary amine-containing moiety of the side chain. Moreover, the derivatives 6, 17, 19, and 20 strongly suppressed the growth of triple-negative breast cancer MDA-MB-231 cells, non-small cell lung cancer A549 cells, and colorectal cancer HCT-116 cells, while normal lung fibroblast MRC5 and IMR90 cells showed a lower response to these compounds. Taken together, this study identifies tertiary amine-linked indirubin-30-oximes as potent anticancer agents that inhibit TLK activity. (C) 2021 Elsevier Masson SAS. All rights reserved.
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