Discovery of novel 2,4-diarylaminopyrimidine analogues as ALK and ROS1 dual inhibitors to overcome crizotinib-resistant mutants including G1202R

Discovery of novel 2,4-diarylaminopyrimidine analogues as ALK and ROS1 dual inhibitors to... Aiming to explore novel anaplastic lymphoma kinase (ALK) and proto-oncogene tyrosine-protein kinase ROS (ROS1) dual inhibitors to overcome crizotinib-resistant mutants, two series of 2,4-diarylaminopyrimidine (DAAP) analogues bearing thiazole or 1,2,3-triazole moieties were designed and synthesized based upon the cocrystal structure of ceritinib with ALKWT (PDB 4MKC) as well as the binding model of ceritinib with ALKG1202R. The cellular and enzymatic assays validated 34c (WY-135) as a promising ALK (IC50 = 1.4 nM) and ROS1 (IC50 = 1.1 nM) dual inhibitor superior to crizotinib and ceritinib. 34c showed significantly inhibitory activities on ALK-dependent cell lines KARPAS299 (IC50 = 21 nM) and H2228 (IC50 = 95 nM) as well as ROS1-positive cell line HCC78 (IC50 = 40 nM). In particular, 34c was potent against a variety of frequently observed crizotinib-resistant mutants, particularly the L1196M mutant (IC50 = 3.1 nM) identified as the “gatekeeper” mutation and the G1202R mutant (IC50 = 8.7 nM) which conferred resistance to all clinical stage ALK inhibitors. Furthermore, 34c was capable of inducing cell apoptosis and strongly inhibiting cellular ALK and ROS1 activity. In addition, the binding models of 34c with ALKWT, ALKL1196M and ALKG1202R provided structural bases for SARs observations. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png European Journal of Medicinal Chemistry Elsevier

Discovery of novel 2,4-diarylaminopyrimidine analogues as ALK and ROS1 dual inhibitors to overcome crizotinib-resistant mutants including G1202R

Loading next page...
 
/lp/elsevier/discovery-of-novel-2-4-diarylaminopyrimidine-analogues-as-alk-and-ros1-76jlB06Vhb
Publisher
Elsevier
Copyright
Copyright © 2017 Elsevier Masson SAS
ISSN
0223-5234
eISSN
1768-3254
D.O.I.
10.1016/j.ejmech.2017.11.008
Publisher site
See Article on Publisher Site

Abstract

Aiming to explore novel anaplastic lymphoma kinase (ALK) and proto-oncogene tyrosine-protein kinase ROS (ROS1) dual inhibitors to overcome crizotinib-resistant mutants, two series of 2,4-diarylaminopyrimidine (DAAP) analogues bearing thiazole or 1,2,3-triazole moieties were designed and synthesized based upon the cocrystal structure of ceritinib with ALKWT (PDB 4MKC) as well as the binding model of ceritinib with ALKG1202R. The cellular and enzymatic assays validated 34c (WY-135) as a promising ALK (IC50 = 1.4 nM) and ROS1 (IC50 = 1.1 nM) dual inhibitor superior to crizotinib and ceritinib. 34c showed significantly inhibitory activities on ALK-dependent cell lines KARPAS299 (IC50 = 21 nM) and H2228 (IC50 = 95 nM) as well as ROS1-positive cell line HCC78 (IC50 = 40 nM). In particular, 34c was potent against a variety of frequently observed crizotinib-resistant mutants, particularly the L1196M mutant (IC50 = 3.1 nM) identified as the “gatekeeper” mutation and the G1202R mutant (IC50 = 8.7 nM) which conferred resistance to all clinical stage ALK inhibitors. Furthermore, 34c was capable of inducing cell apoptosis and strongly inhibiting cellular ALK and ROS1 activity. In addition, the binding models of 34c with ALKWT, ALKL1196M and ALKG1202R provided structural bases for SARs observations.

Journal

European Journal of Medicinal ChemistryElsevier

Published: Jan 1, 2018

References

You’re reading a free preview. Subscribe to read the entire article.


DeepDyve is your
personal research library

It’s your single place to instantly
discover and read the research
that matters to you.

Enjoy affordable access to
over 18 million articles from more than
15,000 peer-reviewed journals.

All for just $49/month

Explore the DeepDyve Library

Search

Query the DeepDyve database, plus search all of PubMed and Google Scholar seamlessly

Organize

Save any article or search result from DeepDyve, PubMed, and Google Scholar... all in one place.

Access

Get unlimited, online access to over 18 million full-text articles from more than 15,000 scientific journals.

Your journals are on DeepDyve

Read from thousands of the leading scholarly journals from SpringerNature, Elsevier, Wiley-Blackwell, Oxford University Press and more.

All the latest content is available, no embargo periods.

See the journals in your area

DeepDyve

Freelancer

DeepDyve

Pro

Price

FREE

$49/month
$360/year

Save searches from
Google Scholar,
PubMed

Create lists to
organize your research

Export lists, citations

Read DeepDyve articles

Abstract access only

Unlimited access to over
18 million full-text articles

Print

20 pages / month

PDF Discount

20% off