Identification of 4-Phenoxyquinoline Based Inhibitors for L1196M Mutant of Anaplastic Lymphoma Kinase by Structure-Based Design

Cited 0 time in webofscience Cited 0 time in scopus
64 Viewed 7 Downloaded
Title
Identification of 4-Phenoxyquinoline Based Inhibitors for L1196M Mutant of Anaplastic Lymphoma Kinase by Structure-Based Design
Author(s)
Shinmee Mah; Jung Hee Park; Hoi-Yun Jung; Kukcheol Ahn; Soyeon Choi; Hyun Seop Tae; Kyung Hee Jung; Jin Kyung Rho; Jae Cheol Lee; Soon-Sun Hong; Sungwoo Hong
Publication Date
2017-11
Journal
JOURNAL OF MEDICINAL CHEMISTRY, v.60, no.22, pp.9205 - 9221
Publisher
AMER CHEMICAL SOC
Abstract
Dysregulation of anaplastic lymphoma kinase (ALK) has been detected in nonsmall cell lung cancer (NSCLC) in the form of EML4-ALK fusion. Secondary mutations opposing activity of the first generation ALK inhibitor crizotinib came into existence, requiring mutation-targeting drug discovery for the powerful second-line treatment. In this study, we report 4-phenoxyquinoline-based inhibitors that overcome crizotinib resistance to ALK L1196M, discovered by the fragment-growing strategy. The protonation of 4-aminoquinoline core could interrupt the ability the N atom of quinoline to act as a hydrogen bond acceptor; therefore, the pK(a) and calculated ionization pH values of relevant pyridine-based core moieties were carefully analyzed. The replacement of amine linkage with ether resulted in single-digit nanomolar range inhibitors. The inhibitors exhibited significant antiproliferative effects on H2228 CR crizotinib-resistant cells by decreasing PI3K/AKT and MAPK signaling. This work constitutes the first of ionization pH on activity in this system © 2017 American Chemical Society
URI
https://pr.ibs.re.kr/handle/8788114/4775
ISSN
0022-2623
Appears in Collections:
Center for Catalytic Hydrocarbon Functionalizations(분자활성 촉매반응 연구단) > Journal Papers (저널논문)
Files in This Item:
hong_2017_identification.pdfDownload

qrcode

  • facebook

    twitter

  • Items in DSpace are protected by copyright, with all rights reserved, unless otherwise indicated.
해당 아이템을 이메일로 공유하기 원하시면 인증을 거치시기 바랍니다.

Items in DSpace are protected by copyright, with all rights reserved, unless otherwise indicated.

Browse