Principal Investigator

Principal Investigator

Giovanna Zinzalla

Affiliated to research

Principal Investigator

Department and organisational affiliation:

About me

Principal Investigator

E-mail: giovanna.zinzalla@ki.se

Phone: +46 (0)70 4893 455 

AREAS OF EXPERTISE

Organic and Medicinal Chemistry, Biochemistry, Structural Biology, Biochemical and Biophysical Assays, Protein-Protein Interactions, Transcription Factors, Drug Discovery

LATEST PUBLICATIONS: 

For the up-to-date publication list (i.e., including Early View/Just Accepted articles) click on the ResearchGate link in the Links section, or paste into your internet browser: https://www.researchgate.net/profile/Giovanna_Zinzalla

"The structure of INI1/hSNF5 RPT1 and its interactions with the c-MYC:MAX heterodimer provide insights into the interplay between MYC and the SWI/SNF chromatin remodeling complex." The FEBS Journal, 2018 (DOI: 10.3410/f.734028197.793551162), has been recommended in F1000Prime as being of special significance in its field by F1000 Faculty Member Wolfgang Jahnke (Novartis Institutes for Biomedical Research, Basel, Switzerland).

BIOGRAPHY

Dr. Zinzalla obtained her first class honours Laurea in Chemistry (equivalent to MChem) from the University of Milan and carried out her PhD studies with Prof. Stefano Maiorana and Dr Clara Baldoli also at the University of Milan. Her research focused on developing new metal complex conjugates of Peptide Nucleic Acids (PNAs) as biosensors, and she investigated novel trace-less linkers for solid-phase synthesis of drug-like small molecules in collaboration with GlaxoSmithKline.

In 2004 she was awarded a Marie Curie EIF Individual Research Fellowship and appointed as Postdoctoral Research Assistant at the University of Cambridge with Professor Steven Ley, where she initiated a project focused on exploring the role of molecular diversity for drug discovery, with the design of natural product-like compounds as novel therapeutic agents.

In June 2006 she joined the School of Pharmacy, University College London (UCL) (London, UK) as a Senior Research Fellow funded by Cancer Research UK (CR UK), within the CR UK Protein-Protein Interactions Drug Discovery Research Group (unit director: Prof. David E. Thurston). As a co-PI of a CR UK Small Molecule Drug Discovery Initiative program she led the research aimed at discovering protein-protein inhibitors of transcriptional factors such as Hypoxia Inducible Factor 1 (HIF-1) and Signal Transducer and Activator of Transcription 3 (STAT3 ).

In January 2012 she took up the position at the Karolinska Institutet as Assistant Professor in Chemical Biology and a PI (junior Group Leader) within the Center for Advanced Cancer Therapies (ACT), MTC Department.

Research description

HOW TRANSCRIPTION FACTOR INTERACTION NETWORKS CONTROL GENE EXPRESSION PROGRAMS

My research focuses on dissecting and manipulating the networks of protein-protein interactions that transcription factors use to regulate cell growth and differentiation, metabolism, and tissue renewal. My work encompasses structural biology, biophysics, biochemistry, and chemistry. The ultimate goal is to develop therapeutic agents to treat human diseases, and new approaches for regenerative medicine.

I am currently working on two key molecular machineries that control the activation and repression of genes required for the differentiation, proliferation and survival of normal and malignant cells: (1) the c-MYC family of transcription factors and (2) SWI/SNF (BAF) chromatin remodelling complexes.

Our work on c-MYC is focused on determining: how transcription factor cooperation leads to gene repression; and how the extended network of MYC-like bHLHLZ transcription factors regulate metabolism.

Projects on the SWI/SNF complexes are currently directed to understand: how these chromatin remodelling complexes control MYC gene expression; and how the BAF60 subunit mediates interactions with diverse transcription factors with roles in cellular processes, such as cardiac development, regeneration and metabolism. We are also exploring ways to target the SWI/SNF complexes for the development of new therapies.

RESEARCH COLLABORATIONS

Prof. Don Ayer, Huntsman Cancer Institute, University of Utah, USA; Dr Mark Bycroft, University of Cambridge, Cambridge, UK; Prof. Gerard Evan, University of Cambridge, UK; Prof. Sophia Yaliraki, Imperial College London, UK; Prof. Lars-Gunnar Larsson, Karolinska Institute, Sweden.

SELECTED PUBLICATIONS

Structure of the BRK domain of the SWI/SNF chromatin remodeling complex subunit BRG1 reveals a potential role in protein-protein interactions. Allen MD, Bycroft M, Zinzalla G Protein Sci. 2020 Jan;():

Crystal Structures and Nuclear Magnetic Resonance Studies of the Apo Form of the c-MYC:MAX bHLHZip Complex Reveal a Helical Basic Region in the Absence of DNA. Sammak S, Hamdani N, Gorrec F, Allen MD, Freund SMV, Bycroft M, et al Biochemistry 2019 Jul;():

The structure of INI1/hSNF5 RPT1 and its interactions with the c-MYC:MAX heterodimer provide insights into the interplay between MYC and the SWI/SNF chromatin remodeling complex. Sammak S, Allen MD, Hamdani N, Bycroft M, Zinzalla G FEBS J. 2018 11;285(22):4165-4180

A selective high affinity MYC-binding compound inhibits MYC:MAX interaction and MYC-dependent tumor cell proliferation. Castell A, Yan Q, Fawkner K, Hydbring P, Zhang F, Verschut V, et al Sci Rep 2018 Jul;8(1):10064

Targeting MYC: is it getting any easier? Zinzalla G Future Med Chem 2016 Oct;8(16):1899-1902 A New Way Forward in Cancer Drug Discovery: Inhibiting the SWI/SNF Chromatin Remodelling Complex. Zinzalla G Chembiochem 2016 Apr;17(8):677-82

Paving the way to targeting HECT ubiquitin ligases. Zinzalla G Future Med Chem 2015 ;7(16):2107-11

Targeting protein-protein interactions (PPIs) of transcription factors: Challenges of intrinsically disordered proteins (IDPs) and regions (IDRs). Sammak S, Zinzalla G Prog. Biophys. Mol. Biol. 2015 Oct;119(1):41-6

The SWI/SNF Subunit INI1 Contains an N-Terminal Winged Helix DNA Binding Domain that Is a Target for Mutations in Schwannomatosis. Allen MD, Freund SM, Zinzalla G, Bycroft M Structure 2015 Jul;23(7):1344-9

Tetracycline analogues with a selective inhibitory effect on HIF-1alpha Bendiabdellah Y, Rahman, KM, Uranchimeg B, Nahar KS, Antonow D, Shoemaker R.H., Melillo G, Zinzalla G, Thurston, DE Med. Chem. Commun., 2014,5, 923-926.

Understanding and Exploiting ProteinProtein Interactions as Drug Targets Zinzalla, Giovanna October 2013, Future Medicine book series, Publisher: Future Science Group

Investigation of the protein alkylation sites of the STAT3:STAT3 inhibitor Stattic by mass spectrometry. Heidelberger S, Zinzalla G, Antonow D, Essex S, Basu BP, Palmer J, et al Bioorg. Med. Chem. Lett. 2013 Aug;23(16):4719-22

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, et al FEBS Lett. 2013 Apr;587(7):833-9

Small-molecule inhibition of c-MYC:MAX leucine zipper formation is revealed by ion mobility mass spectrometry. Harvey SR, Porrini M, Stachl C, MacMillan D, Zinzalla G, Barran PE J. Am. Chem. Soc. 2012 Nov;134(47):19384-92

Molecular dynamics studies of the STAT3 homodimer:DNA complex: relationships between STAT3 mutations and protein-DNA recognition. Husby J, Todd AK, Haider SM, Zinzalla G, Thurston DE, Neidle S J Chem Inf Model 2012 May;52(5):1179-92

A novel small-molecule inhibitor of IL-6 signalling. Zinzalla G, Haque MR, Basu BP, Anderson J, Kaye SL, Haider S, et al Bioorg. Med. Chem. Lett. 2010 Dec;20(23):7029-32

Facile nucleophilic substitution at the C3a tertiary carbon of the 3a-bromohexahydropyrrolo[2,3-b]indole scaffold. Villanueva-Margalef I, Thurston DE, Zinzalla G Org. Biomol. Chem. 2010 Dec;8(23):5294-303

Facile oxidation of electron-poor benzo[b]thiophenes to the corresponding sulfones with an aqueous solution of H2O2 and P2O5. Antonow D, Marrafa T, Dawood I, Ahmed T, Haque MR, Thurston DE, et al Chem. Commun. (Camb.) 2010 Apr;46(13):2289-91

Targeting protein-protein interactions for therapeutic intervention: a challenge for the future. Zinzalla G, Thurston DE Future Med Chem 2009 Apr;1(1):65-93

Natural-product-like spiroketals and fused bicyclic acetals as potential therapeutic agents for B-cell chronic lymphocytic leukaemia. Milroy LG, Zinzalla G, Loiseau F, Qian Z, Prencipe G, Pepper C, et al ChemMedChem 2008 Dec;3(12):1922-35

Chemical variation of natural-product-like scaffolds: design, synthesis, and biological activity of fused bicyclic acetal derivatives. Milroy LG, Zinzalla G, Prencipe G, Michel P, Ley SV, Gunaratnam M, et al Angew. Chem. Int. Ed. Engl. 2007 ;46(14):2493-6

Chemical variation of natural product-like scaffolds: design and synthesis of spiroketal derivatives. Zinzalla G, Milroy LG, Ley SV Org. Biomol. Chem. 2006 May;4(10):1977-2002

Polymer-supported haloarene chromium dicarbonyl isonitrile complexes: a study of their synthesis and reactivity. Baldoli C, Maiorana S, Licandro E, Casiraghi L, Zinzalla G, Seneci P, et al J Comb Chem ;5(6):809-13

Synthesis of chiral chromium tricarbonyl labeled thymine PNA monomers via the Ugi reaction. Baldoli C, Maiorana S, Licandro E, Zinzalla G, Perdicchia D Org. Lett. 2002 Nov;4(24):4341-4

Bendiabdellah, Y.; Margalef-Villanueva, I.; Misale, A.; Nahar, K.; Haque, M.R.; Thurston, D.E.; Zinzalla, G. One-pot synthesis of fused tetracyclic scaffolds via a Lewis acid promoted domino reaction of naphthoquinones Synthesis 2011, 14, 2321 View the Abstract Online

Baldoli, C.; Giannini, C.; Licandro, E.; Maiorana, S.; Zinzalla, G., A Thymine-PNA monomer as new isocyanide component in the Ugi reaction: a direct entry to PNA dimers Synlett, 2004, 6, 1044 View the Abstract Online

 

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