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

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

  • J Med Chem. 2019 Mar 14;62(5):2618-2637. doi: 10.1021/acs.jmedchem.8b01947.
Ellen Watts 1,  David Heidenreich 2 3,  Elizabeth Tucker 4,  Monika Raab 5,  Klaus Strebhardt 5,  Louis Chesler 4,  Stefan Knapp 2 3 6,  Benjamin Bellenie 1,  Swen Hoelder 1
Affiliations

Affiliations

  • 1 Cancer Research UK Cancer Therapeutics Unit at The Institute of Cancer Research , London SM2 5NG , U.K.
  • 2 Institute for Pharmaceutical Chemistry , Johann Wolfgang Goethe-University , Max-von-Laue-Strasse 9 , D-60438 Frankfurt am Main , Germany.
  • 3 Structural Genomics Consortium, BMLS , Goethe-University Frankfurt , 60438 Frankfurt , Germany.
  • 4 Paediatric and Solid Tumour Biology and Therapeutics Group , The Institute of Cancer Research , 15 Cotswold Road , London SM2 5NG , U.K.
  • 5 Department of Gynecology and Obstetrics , Johann Wolfgang Goethe-University , Theodor-Stern Kai 7 , 60590 Frankfurt am Main , Germany.
  • 6 German Cancer Network (DKTK) , Site Frankfurt/Mainz , D-60438 Frankfurt am Main , Germany.
PMID: 30789735 DOI: 10.1021/acs.jmedchem.8b01947
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.

Figures