MyJournals Home  

RSS FeedsMolecules, Vol. 28, Pages 1269: Design, Synthesis, and Antiproliferative Activity of New 5-Chloro-Indole-2-Carboxylate and Pyrrolo[3,4-b]indol-3-One Derivatives as Potent Inhibitors of EGFRT790M/BRAFV600E Pathways (Molecules)

 
 

28 january 2023 08:07:34

 
Molecules, Vol. 28, Pages 1269: Design, Synthesis, and Antiproliferative Activity of New 5-Chloro-Indole-2-Carboxylate and Pyrrolo[3,4-b]indol-3-One Derivatives as Potent Inhibitors of EGFRT790M/BRAFV600E Pathways (Molecules)
 


Mutant EGFR/BRAF pathways are thought to be crucial targets for the development of anticancer drugs since they are over-activated in several malignancies. We present here the development of a novel series of 5-chloro-indole-2-carboxylate 3a–e, 4a–c and pyrrolo[3,4-b]indol-3-ones 5a–c derivatives as potent inhibitors of mutant EGFR/BRAF pathways with antiproliferative activity. The cell viability assay results of 3a–e, 4a–c, and 5a–c revealed that none of the compounds tested were cytotoxic, and that the majority of those tested at 50 µM had cell viability levels greater than 87%. Compounds 3a–e, 4a–c, and 5a–c had significant antiproliferative activity with GI50 values ranging from 29 nM to 78 nM, with 3a–e outperforming 4a–c and 5a–c in their inhibitory actions against the tested cancer cell lines. Compounds 3a–e were tested for EGFR inhibition, with IC50 values ranging from 68 nM to 89 nM. The most potent derivative was found to be the m-piperidinyl derivative 3e (R = m-piperidin-1-yl), with an IC50 value of 68 nM, which was 1.2-fold more potent than erlotinib (IC50 = 80 nM). Interestingly, all the tested compounds 3a–e had higher anti-BRAFV600E activity than the reference erlotinib but were less potent than vemurafenib, with compound 3e having the most potent activity. Moreover, compounds 3b and 3e showed an 8-fold selectivity index toward EGFRT790M protein over wild-type. Additionally, molecular docking of 3a and 3b against BRAFV600E and EGFRT790M enzymes revealed high binding affinity and active site interactions compared to the co-crystalized ligands. The pharmacokinetics properties (ADME) of 3a–e revealed safety and good pharmacokinetic profile.


 
92 viewsCategory: Biochemistry, Chemistry, Molecular Biology
 
Molecules, Vol. 28, Pages 1268: Role of Fungi in Biodegradation of Imidazolium Ionic Liquids by Activated Sewage Sludge (Molecules)
Molecules, Vol. 28, Pages 1272: Synthesis of Iron on Carbon Foam for Use in the Removal of Phenol from Aqueous Solutions (Molecules)
 
 
blog comments powered by Disqus


MyJournals.org
The latest issues of all your favorite science journals on one page

Username:
Password:

Register | Retrieve

Search:

Molecular Biology


Copyright © 2008 - 2024 Indigonet Services B.V.. Contact: Tim Hulsen. Read here our privacy notice.
Other websites of Indigonet Services B.V.: Nieuws Vacatures News Tweets Nachrichten