10-iodo-11H-indolo[3,2-c]quinoline-6-carboxylic acids are selective inhibitors of DYRK1A

Journal of Medicinal Chemistry
Hannes FalkeConrad Kunick

Abstract

The protein kinase DYRK1A has been suggested to act as one of the intracellular regulators contributing to neurological alterations found in individuals with Down syndrome. For an assessment of the role of DYRK1A, selective synthetic inhibitors are valuable pharmacological tools. However, the DYRK1A inhibitors described in the literature so far either are not sufficiently selective or have not been tested against closely related kinases from the DYRK and the CLK protein kinase families. The aim of this study was the identification of DYRK1A inhibitors exhibiting selectivity versus the structurally and functionally closely related DYRK and CLK isoforms. Structure modification of the screening hit 11H-indolo[3,2-c]quinoline-6-carboxylic acid revealed structure-activity relationships for kinase inhibition and enabled the design of 10-iodo-substituted derivatives as very potent DYRK1A inhibitors with considerable selectivity against CLKs. X-ray structure determination of three 11H-indolo[3,2-c]quinoline-6-carboxylic acids cocrystallized with DYRK1A confirmed the predicted binding mode within the ATP binding site.

References

Aug 1, 1989·Proceedings of the National Academy of Sciences of the United States of America·Z RahmaniA Aurias
Jan 1, 1997·Archives of Biochemistry and Biophysics·H KimR R Ramsay
Apr 4, 1997·Journal of Molecular Biology·G JonesR Taylor
Mar 31, 2000·Bioorganic & Medicinal Chemistry Letters·C KunickL Meijer
Nov 23, 2000·Protein Expression and Purification·A PrimotL Meijer
Sep 11, 2002·Archiv der Pharmazie·Karen WiekingConrad Kunick
Jan 22, 2003·The Biochemical Journal·Jenny BainPhilip Cohen
Dec 30, 2003·Journal of Medicinal Chemistry·Conrad KunickThomas Lemcke
Dec 31, 2003·Bioorganic & Medicinal Chemistry Letters·Conrad KunickThomas Lemcke
Sep 1, 1994·Acta Crystallographica. Section D, Biological Crystallography·UNKNOWN Collaborative Computational Project, Number 4
May 1, 1997·Acta Crystallographica. Section D, Biological Crystallography·G N MurshudovE J Dodson
Sep 14, 2004·Archiv der Pharmazie·Tanja PiesConrad Kunicke
Feb 8, 2005·Chembiochem : a European Journal of Chemical Biology·Conrad KunickThomas Lemcke
Mar 23, 2006·Acta Crystallographica. Section D, Biological Crystallography·Jay Painter, Ethan A Merritt
Apr 17, 2007·Protein Expression and Purification·Jens ReinhardtLaurent Meijer
Apr 25, 2007·Nucleic Acids Research·Ian W DavisDavid C Richardson
Aug 19, 2007·Current Topics in Medicinal Chemistry·Andrea Regier Voth, P Shing Ho
Oct 2, 2007·The Journal of Biological Chemistry·Soo-Ryoon RyooWoo-Joo Song
Oct 16, 2007·European Journal of Paediatric Neurology : EJPN : Official Journal of the European Paediatric Neurology Society·Mohammed Rachidi, Carmela Lopes
Jan 10, 2008·Nature Biotechnology·Mazen W KaramanPatrick P Zarrinkar
Aug 1, 2007·Journal of Applied Crystallography·Airlie J McCoyRandy J Read
Aug 18, 2009·Cellular and Molecular Life Sciences : CMLS·Joongkyu ParkKwang Chul Chung
Feb 4, 2010·Acta Crystallographica. Section D, Biological Crystallography·Wolfgang Kabsch
Apr 13, 2010·Acta Crystallographica. Section D, Biological Crystallography·P EmsleyK Cowtan
Oct 29, 2010·Nature Communications·Yasushi OgawaMasatoshi Hagiwara
Dec 4, 2010·The FEBS Journal·Walter Becker, Wolfgang Sippl
Dec 16, 2010·The FEBS Journal·Francisco J Tejedor, Barbara Hämmerle
Dec 16, 2010·The FEBS Journal·Jerzy WegielYu-Wen Hwang
Feb 1, 2011·Chemistry & Biology·Oleg FedorovStefan Knapp
Apr 5, 2011·Acta Crystallographica. Section D, Biological Crystallography·T Geoff G BattyeAndrew G W Leslie
Apr 26, 2011·Current Topics in Medicinal Chemistry·Nadine Tolle, Conrad Kunick

❮ Previous
Next ❯

Citations

Apr 14, 2016·Future Medicinal Chemistry·Silvia StotaniFederico Medda
Feb 21, 2016·European Journal of Medicinal Chemistry·Marica MarianoMatthias Engel
Jan 6, 2017·Human Molecular Genetics·Jochem M G EversCaroline F Wright
Jan 28, 2017·Journal of Molecular Graphics & Modelling·Tomoko KoyamaShuichi Hirono
Jan 25, 2018·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Rosanna MeineConrad Kunick
Aug 30, 2017·Organic & Biomolecular Chemistry·Benyapa KaewmeeJuthanat Kaeobamrung
Dec 31, 2016·Pharmacological Reviews·David O BatesLucy F Donaldson
Apr 29, 2020·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Kunal KumarRobert J DeVita
Nov 27, 2019·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Christian LechnerConrad Kunick
Sep 23, 2020·International Journal of Molecular Sciences·Hye Ree YoonNam Sook Kang
Dec 31, 2020·The Journal of Biological Chemistry·Vasudha TandonSourav Banerjee
Dec 6, 2020·European Journal of Medicinal Chemistry·Fatemeh SalehianMehdi Khoobi
Aug 20, 2019·Bioorganic & Medicinal Chemistry Letters·Surendar ChittiKondapalli Venkata Gowri Chandra Sekhar
Oct 1, 2018·Pharmacology & Therapeutics·Maria L ArbonesJean M Delabar
May 13, 2021·Journal of Medicinal Chemistry·Csaba WeberAndras Kotschy
Jun 7, 2021·The Journal of Biological Chemistry·Astrid BuchbergerReinhard W Köster
Jun 19, 2021·Journal of Medicinal Chemistry·David Lee WalmsleyRoderick E Hubbard
Jul 3, 2021·International Journal of Molecular Sciences·Mattias F Lindberg, Laurent Meijer
Aug 23, 2019·Journal of Medicinal Chemistry·Jan S KramerEwgenij Proschak
Jan 9, 2020·Journal of Medicinal Chemistry·Daniel A ErlansonPaul N Mortenson
Jul 10, 2018·Journal of Medicinal Chemistry·Dnyandev B JarhadLak Shin Jeong
Aug 28, 2021·International Journal of Molecular Sciences·Barbara PucelikAnna Czarna
Sep 15, 2021·Journal of Medicinal Chemistry·Zhen QinJinlei Bian

❮ Previous
Next ❯

Methods Mentioned

BETA
X-ray
column chromatography

Software Mentioned

MOE
Phaser
Refmac
COOT
GraphPad
97
EZ Chrom Elite Client /
GOLD
Linux
CCP4

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.