Designing Dual Inhibitors of Anaplastic Lymphoma Kinase (ALK) and Bromodomain-4 (BRD4) by Tuning Kinase Selectivity.

Journal of Medicinal Chemistry
Ellen WattsSwen Hoelder

Abstract

Concomitant inhibition of anaplastic lymphoma kinase (ALK) and bromodomain-4 (BRD4) is a potential therapeutic strategy for targeting two key oncogenic drivers that co-segregate in a significant fraction of high-risk neuroblastoma patients, mutation of ALK and amplification of MYCN. Starting from known dual polo-like kinase (PLK)-1-BRD4 inhibitor BI-2536, we employed structure-based design to redesign this series toward compounds with a dual ALK-BRD4 profile. These efforts led to compound ( R)-2-((2-ethoxy-4-(1-methylpiperidin-4-yl)phenyl)amino)-7-ethyl-5-methyl-8-((4-methylthiophen-2-yl)methyl)-7,8-dihydropteridin-6(5 H)-one (16k) demonstrating improved ALK activity and significantly reduced PLK-1 activity, while maintaining BRD4 activity and overall kinome selectivity. We demonstrate the compounds' on-target engagement with ALK and BRD4 in cells as well as favorable broad kinase and bromodomain selectivity.

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Citations

Jul 1, 2020·International Journal of Cancer. Journal International Du Cancer·Xin ZhangJens T Siveke
Jul 23, 2020·Scientific Reports·Kendra R VannTatiana G Kutateladze
Nov 11, 2020·Biochimica Et Biophysica Acta. Reviews on Cancer·Christopher A RaabKlaus Strebhardt
Mar 26, 2021·European Journal of Medicinal Chemistry·Zheng ZhangTingting Liu
Apr 4, 2021·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Jan Chasák, Lucie Brulíková
Jun 10, 2021·Organic & Biomolecular Chemistry·Ellen E GuestJonathan D Hirst
Nov 19, 2020·ACS Infectious Diseases·Corentine M C LaurinStuart J Conway
Sep 19, 2019·ACS Medicinal Chemistry Letters·Angela S CarlsonJoseph J Topczewski
Aug 28, 2021·European Journal of Medicinal Chemistry·Osama M SoltanMohamed Abdel-Aziz
Oct 29, 2021·Journal of Medicinal Chemistry·Rezaul Md KarimErnst Schönbrunn

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Methods Mentioned

BETA
X-ray
NMR
thermal shift
flow cytometry
column chromatography
Thermal
gel filtration
transfection
BRET
electrophoresis

Software Mentioned

COOT
Schrödinger Suite
BESSY
XDS
CCP4
iMOSFLM
DiscoverX
REFMAC
LigPrep
PHASER

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