Discovery and Optimization of 2-Arylquinazolin-4-ones into a Potent and Selective Tankyrase Inhibitor Modulating Wnt Pathway Activity

Journal of Medicinal Chemistry
Hans-Peter BuchstallerChristina Esdar

Abstract

Tankyrases 1 and 2 (TNKS1/2) are promising pharmacological targets that recently gained interest for anticancer therapy in Wnt pathway dependent tumors. 2-Aryl-quinazolinones were identified and optimized into potent tankyrase inhibitors through SAR exploration around the quinazolinone core and the 4'-position of the phenyl residue. These efforts were supported by analysis of TNKS X-ray and WaterMap structures and resulted in compound 5k, a potent, selective tankyrase inhibitor with favorable pharmacokinetic properties. The X-ray structure of 5k in complex with TNKS1 was solved and confirmed the design hypothesis. Modulation of Wnt pathway activity was demonstrated with this compound in a colorectal xenograft model in vivo.

References

Mar 12, 2003·Journal of Pharmacological and Toxicological Methods·Janice A Brown, Ravi B Marala
Jul 27, 2004·BioEssays : News and Reviews in Molecular, Cellular and Developmental Biology·Jean-Christophe AméGilbert de Murcia
Sep 1, 1994·Acta Crystallographica. Section D, Biological Crystallography·UNKNOWN Collaborative Computational Project, Number 4
Dec 2, 2004·Acta Crystallographica. Section D, Biological Crystallography·Paul Emsley, Kevin Cowtan
Jul 11, 2006·Nature Reviews. Molecular Cell Biology·Valérie SchreiberGilbert de Murcia
Jan 6, 2007·Proceedings of the National Academy of Sciences of the United States of America·Tom YoungRichard A Friesner
Feb 13, 2008·Journal of the American Chemical Society·Robert AbelRichard A Friesner
Sep 18, 2009·Nature·Shih-Min A HuangFeng Cong
Feb 4, 2010·Acta Crystallographica. Section D, Biological Crystallography·Wolfgang Kabsch
Mar 8, 2011·Molecular & Cellular Proteomics : MCP·Katrin LuckertOliver Pötz
Jul 30, 2011·PloS One·Marinella G CallowMike Costa
Feb 22, 2012·Nature Biotechnology·Elisabet WahlbergJohan Weigelt
Mar 23, 2012·PloS One·Hakan GunaydinXin Huang
Jul 20, 2012·Nature·UNKNOWN Cancer Genome Atlas Network
Aug 14, 2012·European Journal of Pharmaceutical Sciences : Official Journal of the European Federation for Pharmaceutical Sciences·Christoph Saal, Anna Christine Petereit
Dec 1, 2012·Nature Reviews. Drug Discovery·Jenna L RiffellAlan Ashworth
May 8, 2013·The FEBS Journal·Lari LehtiöStefan Krauss
Dec 4, 2013·Journal of Medicinal Chemistry·Zihao HuaErin F Dimauro
Jun 6, 2014·Nature Reviews. Cancer·Sejal Vyas, Paul Chang
Jun 6, 2014·ACS Medicinal Chemistry Letters·Amit NathubhaiMichael D Threadgill
Jun 6, 2014·ACS Medicinal Chemistry Letters·Hongbing HuangErin F DiMauro
Jul 1, 2014·Current Pharmaceutical Design·Teemu HaikarainenLari Lehtio
Sep 30, 2014·Current Topics in Medicinal Chemistry·Ahmed KamalAbdul Rahim
May 11, 2016·European Journal of Medicinal Chemistry·Amit NathubhaiMichael D Threadgill
Sep 8, 2016·Acta Crystallographica. Section D, Structural Biology·Arnau CasanasMeitian Wang
Sep 15, 2017·British Journal of Pharmacology·Laura MariottiSebastian Guettler
Nov 7, 2017·European Journal of Medicinal Chemistry·Martina FerriEmidio Camaioni
Jul 30, 2018·Biochemical and Biophysical Research Communications·Chen FanXuewu Zhang
Jan 19, 2019·Scientific Reports·Malini MenonChristopher J Lord

❮ Previous
Next ❯

Citations

Feb 12, 2021·Expert Opinion on Therapeutic Patents·Chirag C Mehta, Hardik G Bhatt
Jun 9, 2020·Journal of Medicinal Chemistry·Jo WaalerStefan Krauss
Sep 3, 2020·European Journal of Medicinal Chemistry·Manoj G DamaleJaiprakash N Sangshetti
Aug 20, 2020·Journal of Chemical Information and Modeling·Christina E M SchindlerDaniel Kuhn

❮ Previous
Next ❯

Related Concepts

Trending Feeds

COVID-19

Coronaviruses encompass a large family of viruses that cause the common cold as well as more serious diseases, such as the ongoing outbreak of coronavirus disease 2019 (COVID-19; formally known as 2019-nCoV). Coronaviruses can spread from animals to humans; symptoms include fever, cough, shortness of breath, and breathing difficulties; in more severe cases, infection can lead to death. This feed covers recent research on COVID-19.

Blastomycosis

Blastomycosis fungal infections spread through inhaling Blastomyces dermatitidis spores. Discover the latest research on blastomycosis fungal infections here.

Nuclear Pore Complex in ALS/FTD

Alterations in nucleocytoplasmic transport, controlled by the nuclear pore complex, may be involved in the pathomechanism underlying multiple neurodegenerative diseases including Amyotrophic Lateral Sclerosis and Frontotemporal Dementia. Here is the latest research on the nuclear pore complex in ALS and FTD.

Applications of Molecular Barcoding

The concept of molecular barcoding is that each original DNA or RNA molecule is attached to a unique sequence barcode. Sequence reads having different barcodes represent different original molecules, while sequence reads having the same barcode are results of PCR duplication from one original molecule. Discover the latest research on molecular barcoding here.

Chronic Fatigue Syndrome

Chronic fatigue syndrome is a disease characterized by unexplained disabling fatigue; the pathology of which is incompletely understood. Discover the latest research on chronic fatigue syndrome here.

Evolution of Pluripotency

Pluripotency refers to the ability of a cell to develop into three primary germ cell layers of the embryo. This feed focuses on the mechanisms that underlie the evolution of pluripotency. Here is the latest research.

Position Effect Variegation

Position Effect Variagation occurs when a gene is inactivated due to its positioning near heterochromatic regions within a chromosome. Discover the latest research on Position Effect Variagation here.

STING Receptor Agonists

Stimulator of IFN genes (STING) are a group of transmembrane proteins that are involved in the induction of type I interferon that is important in the innate immune response. The stimulation of STING has been an active area of research in the treatment of cancer and infectious diseases. Here is the latest research on STING receptor agonists.

Microbicide

Microbicides are products that can be applied to vaginal or rectal mucosal surfaces with the goal of preventing, or at least significantly reducing, the transmission of sexually transmitted infections. Here is the latest research on microbicides.