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Targeting STAT3 – a rational structure based approach towards drug discovery

19 August 2014

 

 

Project description
When incorrectly activated the Signal Transducer and Activator of Transcription (STAT3) protein can induces both tumorgenesis and inflammatory diseases.

Stat3

Up-stream regulators of STAT3 work by phosphorylating residues in the SH2 domain, thereby stabilising dimerization and enhancing activation. Importantly STAT3 function can be modulated through use of small molecule inhibitors that are designed to target and prevent dimerization via their SH2 domains.
Constitutive activated STAT3 is an important anti-cancer target as it has been identified in 50%-90% of cancers.

Our focus is to provide a unique molecular understanding of STAT3, focusing on at the factors involved STAT3 SH2 dimerisation, the effects of gain of function mutations and to explore direct STAT3/DNA interactions. So far we have generated crystal forms highlighting new molecular arrangements, and identified unexpected sites of ligand interaction.

Focusing on drug discovery we are building on the high-throughput (HT) screening data derived from a CR-UK programme grant (Prof Thurston) along with newly constructed protein variants to structurally validate many of the small molecule hits. With our collaborators we are currently integrating new biophysical and structural data to advance some of these compounds to lead molecules.

People involved
Principal Investigator: Dr Gary Parkinson
Co-applicant: Dr Andrew Wilderspin, UCL
Senior postdoc for structural biology: Dr Charlie Nichols, UCL
Collaborators: Senior postdoc for medicinal chemistry, Dr Daniela Massciocchi. Prof Daniela Barlocco, Scienze Farmaceutiche, Milan. Prof David Thurston, King’s College.

Funding
Two your Project Grant to advance our investigations awarded by the Association for International Cancer Research

Publications
Observation of unphosphorylated STAT3 core protein binding to target dsDNA by PEMSA and X-ray crystallography. Nkansah E, Shah R, Collie GW, Parkinson GN, Palmer J, Rahman KM, Bui TT, Drake AF, Husby J, Neidle S, Zinzalla G, Thurston DE, Wilderspin AF. FEBS Lett. 2013, 587: 833-839.

Crystal structure

These images show the crystals grown of STAT3βtc/DNA complex and the resulting crystallographic structure drawn as a ribbon diagram representation showing the interactions between the DNA and STAT3 dimer (drawn by Charlie Nichols).

Crystallographic structure showing the interactions between the DNA and STAT3 dimer (drawn by Charlie Nichols).

This image shows the consequence of the introduction of an unphosphorylated tyrosine and the resulting tyrosine displacement away from the phosphate binding pocket and formation of a new ion–solvent interaction. The phos-STAT3βtc structure (1BG1) (purple) is shown overlaying the unphos-STAT3β (gold) structure (RMSD = 0.56 Cα). Electron density 2ІFoІ-ІFcІ, is drawn at the 1σ level.

Further information

Dr Gary Parkinson
http://www.pcrf.org.uk/

Contact: gary.parkinson@ucl.ac.uk