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From encoded libraries to clinical-stage targeted therapeutics

CMCB Green Seminar

Datum:13.12.2018, 16:00 - 17:00
Sprecher: Dario Neri, ETH Zurich, Institute of Pharmaceutical Sciences, Department of Chemistry and Applied Biosciences
Ort: CRTD, auditorium left
Gastgeber: Yixin Zhang

Outline of the talk
Virtually all drugs are molecular (be them large or small) capable of binding to one or more target proteins of biomedical interest. Thus, the isolation of binders to protein targets is a central step in the drug discovery process. Two methodologies, which rely on the preparation of very large encoded combinatorial libraries, have revolutionized the way protein ligands are discovered. On one hand, antibody phage display libraries (pioneered by Sir Gregory Winter, Nobel Prize Chemistry 2018) allow the construction and screening of very large collections, comprising billions of different antibodies. On the other hand, DNA-encoded chemical libraries allow the construction and screening of large collections of small molecules, individually coupled to DNA tags, serving as amplifiable indentification barcodes. In this lecture, I will show how antibody phage libraries and DNA-encoded chemical libraries have been used in my laboratory (in collaboration with the Philogen group), in order to generate products, which are currently investigated in clinical trials.

Recent Publications of the Neri Group

Enhanced Therapeutic Activity of Non-Internalizing Small-Molecule-Drug Conjugates Targeting Carbonic Anhydrase IX in Combination with Targeted Interleukin-2. Cazzamalli S, Ziffels B, Widmayer F, Murer P, Pellegrini G, Pretto F, Wulhfard S, Neri D. Clin Cancer Res. 2018 Aug 1;24(15):3656-3667.

Versatile protein recognition by the encoded display of multiple chemical elements on a constant macrocyclic scaffold. Li Y, De Luca R, Cazzamalli S, Pretto F, Bajic D, Scheuermann J, Neri D. Nat Chem. 2018 Apr;10(4):441-448.

Chemically Defined Antibody- and Small Molecule-Drug Conjugates for in Vivo Tumor Targeting Applications: A Comparative Analysis. Cazzamalli S, Dal Corso A, Widmayer F, Neri D. J Am Chem Soc. 2018 Feb 7;140(5):1617-1621.

DNA-Encoded Chemical Libraries: A Selection System Based on Endowing Organic Compounds with Amplifiable Information. Neri D, Lerner RA. Annu Rev Biochem. 2018 Jun 20;87:479-502.

Sarcoma Eradication by Doxorubicin and Targeted TNF Relies upon CD8+ T-cell Recognition of a Retroviral Antigen. Probst P, Kopp J, Oxenius A, Colombo MP, Ritz D, Fugmann T, Neri D. Cancer Res. 2017 Jul 1;77(13):3644-3654.

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