Converting a weaker ATP-binding site inhibitor into a potent hetero-bivalent ligand by tethering to a unique peptide sequence derived from the same kinase

Organic & Biomolecular Chemistry
Samanth Reddy Kedika, D Gomika Udugamasooriya

Abstract

Attaching an additional binding site directed moiety or a ligand to an ATP-binding site inhibitor has been used as a strategy to increase kinase binding affinity and specificity. The moieties typically used here as the second binding partner are varied from simple organic groups to ligands such as peptides derived from substrate binding site sequences. So far these hetero-bivalent ligands were developed targeting additional binding sites closer to the ATP-binding pocket. Here we report a unique expansion of this hetero-bivalent idea by: (I) targeting a new binding site much farther away from ATP-binding site, (II) using a peptide uniquely derived from a portion of the same kinase sequence that has been reported to turn and bind to the above distance binding pocket (used as the second binding ligand), and (III) optimizing a much longer and flexible linker (to connect ATP-binding site inhibitor and above mentioned second peptide sequence) with multistep, yet complete on-bead synthesis approach. We converted a very weak EphA3-kinase ATP-binding site inhibitor-PP2 into a potent hetero-bivalent ligand by tethering to a unique 5-mer peptide sequence that derived from the linker region of EphA3 that connects kinase and sterile alpha m...Continue Reading

References

Jan 1, 1991·Journal of Medicinal Chemistry·A RicouartC Sergheraert
Jan 3, 2001·Nature Structural Biology·K ParangP A Cole
Aug 23, 2002·Pharmacology & Therapeutics·Keykavous Parang, Philip A Cole
Nov 9, 2002·Organic Letters·Hernando J OlivosThomas Kodadek
Dec 25, 2003·Journal of the American Chemical Society·Kui Shen, Philip A Cole
May 6, 2004·Bioorganic & Medicinal Chemistry Letters·Aliya C Hines, Philip A Cole
Apr 23, 2005·Organic Letters·Tanya L SchneiderAlanna Schepartz
Mar 7, 2006·Biochemical and Biophysical Research Communications·Brian P FoxRaj P Kandpal
Jun 1, 2007·Journal of the American Chemical Society·Hyun-Suk LimThomas Kodadek
Oct 20, 2007·Journal of the American Chemical Society·Scott C MeyerIndraneel Ghosh
Jan 10, 2008·Nature Biotechnology·Mazen W KaramanPatrick P Zarrinkar
Nov 6, 2008·The Journal of Biological Chemistry·Neal K WilliamsJamie Rossjohn
Aug 20, 2011·European Journal of Cancer : Official Journal for European Organization for Research and Treatment of Cancer (EORTC) [and] European Association for Cancer Research (EACR)·Nirmitha I HerathAndrew W Boyd
Dec 20, 2011·Biopolymers·Jared C HooksD Gomika Udugamasooriya
May 11, 2012·Current Pharmaceutical Design·Vandana Lamba, Indraneel Ghosh
May 19, 2012·ACS Chemical Biology·Kristoffer R BrandvoldMatthew B Soellner
Feb 26, 2014·Critical Reviews in Biochemistry and Molecular Biology·Carrie M GowerDustin J Maly
Oct 11, 2012·ACS Medicinal Chemistry Letters·Hongtao ZhaoAmedeo Caflisch
Nov 14, 2014·Growth Factors·Peter W JanesMary E Vail
Jan 16, 2015·ACS Medicinal Chemistry Letters·Jing DongAmedeo Caflisch
Mar 21, 2015·ACS Chemical Biology·Kristoffer R BrandvoldMatthew B Soellner
Jun 9, 2016·Bioconjugate Chemistry·Taylor K Johnson, Matthew B Soellner
Jul 26, 2017·ACS Medicinal Chemistry Letters·Bernhard C LechtenbergElena B Pasquale

❮ Previous
Next ❯

Citations

Mar 18, 2021·European Journal of Medicinal Chemistry·Seungbeom LeeHwayoung Yun
Apr 4, 2021·International Journal of Molecular Sciences·Paweł ŁukasikIzabela Gutowska

❮ Previous
Next ❯

Methods Mentioned

BETA
ELISA

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.