Novel, selective acrylamide linked quinazolines for the treatment of double mutant EGFR-L858R/T790M Non-Small-Cell lung cancer (NSCLC)

Copyright © 2021 Elsevier Inc. All rights reserved..

T790M mutation is the most common mechanism of acquired resistance to first-generation epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs). To overcome this resistance, 4-anilinoquinazoline-based irreversible inhibitors afatinib, dacomitinib has been developed. However, the clinical application of these irreversible inhibitors is limited due to its narrow selectivity against L858R/T790M mutant EGFR. In an attempt to develop potent and selective EGFR T790M inhibitors, we have designed and synthesized two series of novel acrylamide linked quinazolines. Among them, compounds 2i (IC50 0.171 µM) and 11h (IC50 0.159 µM) were identified as potent compounds, which displayed selective and potent anti-proliferative activity on gefitinib-resistant cell line NCI-H1975 as compared to the gefitinib and WZ4002 in cellular assay. Furthermore, a molecular dynamic simulation of 11h was carried out to assess the stability to form a complex with the L858R/T790M EGFR Kinase domain, which demonstrated that complex was stable for the 100 ns and form strong crucial covalent binding contacts with the thiol group of Cys797 residue. Finally, satisfactory in silico pharmacokinetics properties of 2i, 11h and 11i compounds were predicted. The synthesized compounds were also evaluated for in vitro cytotoxic activity/hepatotoxicity against HepG2 cell line through MTT assay. The results revealed that compounds exhibited lower cytotoxicity to HepG2 cells.

Medienart:

E-Artikel

Erscheinungsjahr:

2021

Erschienen:

2021

Enthalten in:

Zur Gesamtaufnahme - volume:115

Enthalten in:

Bioorganic chemistry - 115(2021) vom: 16. Okt., Seite 105234

Sprache:

Englisch

Beteiligte Personen:

Pawara, Rahul [VerfasserIn]
Ahmad, Iqrar [VerfasserIn]
Nayak, Deepika [VerfasserIn]
Wagh, Shivani [VerfasserIn]
Wadkar, Avinash [VerfasserIn]
Ansari, Azim [VerfasserIn]
Belamkar, Sateesh [VerfasserIn]
Surana, Sanjay [VerfasserIn]
Nath Kundu, Chanakya [VerfasserIn]
Patil, Chandragauda [VerfasserIn]
Patel, Harun [VerfasserIn]

Links:

Volltext

Themen:

20R035KLCI
Acrylamide
Acrylamide linked Quinazolines
Antineoplastic Agents
EC 2.7.10.1
EGFR L858R/T790M
EGFR protein, human
ErbB Receptors
Journal Article
MD simulation
Non Small-Cell Lung Cancer (NSCLC)
Protein Kinase Inhibitors
Quinazolines
Research Support, Non-U.S. Gov't

Anmerkungen:

Date Completed 30.12.2021

Date Revised 30.12.2021

published: Print-Electronic

Citation Status MEDLINE

doi:

10.1016/j.bioorg.2021.105234

funding:

Förderinstitution / Projekttitel:

PPN (Katalog-ID):

NLM329429612