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Engineering the Targeted Drugs of the Future: A General Approach

English title Engineering the Targeted Drugs of the Future: A General Approach
Applicant Neri Dario
Number 160699
Funding scheme Sinergia
Research institution Institut für Pharmazeutische Wissenschaften ETH Zürich
Institution of higher education ETH Zurich - ETHZ
Main discipline Organic Chemistry
Start/End 01.08.2015 - 31.07.2018
Approved amount 1'320'976.00
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All Disciplines (2)

Discipline
Organic Chemistry
Pharmacology, Pharmacy

Keywords (6)

DNA-encoded chemical libraries; Tumor targeting; Pharmacodelivery; Drug release; Macrocycles; Smart drugs

Lay Summary (Italian)

Lead
Molti farmaci, comunemente usati per la terapia dei tumori e altre patologie gravi, non si localizzano nelle aree malate, causando tossicita’ nei tessuti normali e impedendo il raggiungimento di dosi terapeutiche. Farmaci capaci di localizzarsi e agire selettivamente nei siti di malattia dovrebbero consentire un notevole aumento dell’efficacia terapeutica, riducendo gli effetti collaterali indesiderati.
Lay summary

Il progetto mira allo sviluppo di una piattaforma generale e ampiamente applicabile per lo sviluppo di farmaci mirati. Al fine di consentire l’isolamento di molecole leganti, specifiche per marcatori tumorali o di altre patologie, svilupperemo librerie chimiche estremamente ampie (i.e., contenenti milioni di molecole), usando una metodologia avanzata di “codifica” dei composti chimici. Cosi’ come in un supermercato i codici a barre facilitano l’identificazione dei prodotti, in perfetta analogia la coniugazione di fragmenti di DNA a singole molecule organiche consente la produzione di librerie chimiche codificate (“DNA-encoded chemical libraries”), in cui ogni composto chimico puo’ essere identificato mediante la sequenza di DNA a cui esso e’ legato. In particolare, costruiremo librerie di molecole organiche a base di “macrocicli”, in quanto tali strutture sono particolarmente adatte per mediare un’interazione ad alta affinita’ con proteine bersaglio.

I leganti molecolari, isolati dalle librerie chimiche codificate mediante DNA, fungeranno da “veicolo” selettivo, per portare farmaci nelle zone malate. Quali agenti terapeutici, ci concentreremo principalmente su farmaci citotossici e su una nuova classe di peptidi altamente bioattivi, capaci di interferire con l’integrita’ della membrana delle cellule malate. In aggiunta, lavoreremo sull’ottimizzazione di linkers tra la molecola “veicolo” e l’agente terapeutico, in modo da favorire una scissione selettiva nelle zone malate e il rilascio del principio attivo.

Complessivamente, ci aspettiamo che la collaborazione tra gruppi attivi nella costruzione di librerie chimiche (Neri all’ETH Zurigo e Gillingham all’Universita’ di Basilea), con l’aiuto di tecniche di modellizzazione molecolare (Gisbert all’ETH Zurigo) possa facilitare lo sviluppo di una nuova generazione di farmaci mirati, che possano essere studiati in modelli preclinici, gia’ disponibile nei nostri laboratori del Politecnico di Zurigo.

 

Direct link to Lay Summary Last update: 13.07.2015

Responsible applicant and co-applicants

Employees

Publications

Publication
A DNA-encoded chemical library incorporating elements of natural macrocycles
Stress Cedric, Sauter Basilius, Schneider Lukas, Sharpe Timothy, Gillingham Dennis (2019), A DNA-encoded chemical library incorporating elements of natural macrocycles, in Angewandte Chemie International Edition, 1.
Enhanced Therapeutic Activity of Non-Internalizing Small-Molecule-Drug Conjugates Targeting Carbonic Anhydrase IX in Combination with Targeted Interleukin-2
Cazzamalli Samuele, Ziffels Barbara, Widmayer Fontaine, Murer Patrizia, Pellegrini Giovanni, Pretto Francesca, Wulhfard Sarah, Neri Dario (2018), Enhanced Therapeutic Activity of Non-Internalizing Small-Molecule-Drug Conjugates Targeting Carbonic Anhydrase IX in Combination with Targeted Interleukin-2, in Clinical Cancer Research, 24(15), 3656-3667.
A DNA-Encoded Library of Chemical Compounds Based on Common Scaffolding Structures Reveals the Impact of Ligand Geometry on Protein Recognition
Favalli Nicholas, Biendl Stefan, Hartmann Marco, Piazzi Jacopo, Sladojevich Filippo, Gräslund Susanne, Brown Peter J., Näreoja Katja, Schüler Herwig, Scheuermann Jörg, Franzini Raphael, Neri Dario (2018), A DNA-Encoded Library of Chemical Compounds Based on Common Scaffolding Structures Reveals the Impact of Ligand Geometry on Protein Recognition, in ChemMedChem, 13(13), 1303-1307.
Designing Anticancer Peptides by Constructive Machine Learning
Grisoni Francesca, Neuhaus Claudia S., Gabernet Gisela, Müller Alex T., Hiss Jan A., Schneider Gisbert (2018), Designing Anticancer Peptides by Constructive Machine Learning, in ChemMedChem, 13(13), 1300-1302.
DNA-Encoded Chemical Libraries: A Selection System Based on Endowing Organic Compounds with Amplifiable Information
Neri Dario, Lerner Richard A. (2018), DNA-Encoded Chemical Libraries: A Selection System Based on Endowing Organic Compounds with Amplifiable Information, in Annual Review of Biochemistry, 87(1), 479-502.
DNA-encoded chemical libraries - achievements and remaining challenges
Favalli Nicholas, Bassi Gabriele, Scheuermann Jörg, Neri Dario (2018), DNA-encoded chemical libraries - achievements and remaining challenges, in FEBS Letters, 592(12), 2168-2180.
Versatile protein recognition by the encoded display of multiple chemical elements on a constant macrocyclic scaffold
Li Yizhou, De Luca Roberto, Cazzamalli Samuele, Pretto Francesca, Bajic Davor, Scheuermann Jörg, Neri Dario (2018), Versatile protein recognition by the encoded display of multiple chemical elements on a constant macrocyclic scaffold, in Nature Chemistry, 10(4), 441-448.
Chemically Defined Antibody– and Small Molecule–Drug Conjugates for in Vivo Tumor Targeting Applications: A Comparative Analysis
Cazzamalli Samuele, Dal Corso Alberto, Widmayer Fontaine, Neri Dario (2018), Chemically Defined Antibody– and Small Molecule–Drug Conjugates for in Vivo Tumor Targeting Applications: A Comparative Analysis, in Journal of the American Chemical Society, 140(5), 1617-1621.
Rational Design of Membrane-Pore-Forming Peptides
Pillong Max, Hiss Jan A., Schneider Petra, Lin Yen-Chu, Posselt Gernot, Pfeiffer Bernhard, Blatter Markus, Müller Alex T., Bachler Simon, Neuhaus Claudia S., Dittrich Petra S., Altmann Karl-Heinz, Wessler Silja, Schneider Gisbert (2017), Rational Design of Membrane-Pore-Forming Peptides, in Small, 13(40), 1701316-1701316.
A non-internalizing antibody-drug conjugate based on an anthracycline payload displays potent therapeutic activity in vivo
Dal Corso Alberto, Gébleux Rémy, Murer Patrizia, Soltermann Alex, Neri Dario (2017), A non-internalizing antibody-drug conjugate based on an anthracycline payload displays potent therapeutic activity in vivo, in Journal of Controlled Release, 264, 211-218.
Protease-Cleavable Linkers Modulate the Anticancer Activity of Noninternalizing Antibody–Drug Conjugates
Dal Corso Alberto, Cazzamalli Samuele, Gébleux Rémy, Mattarella Martin, Neri Dario (2017), Protease-Cleavable Linkers Modulate the Anticancer Activity of Noninternalizing Antibody–Drug Conjugates, in Bioconjugate Chemistry, 1826-1833.
A Specific and Covalent JNK-1 Ligand Selected from an Encoded Self-Assembling Chemical Library
Zimmermann Gunther, Rieder Ulrike, Bajic Davor, Vanetti Sara, Chaikuad Apirat, Knapp Stefan, Scheuermann Jorg, Mattarella Martin, Neri Dario (2017), A Specific and Covalent JNK-1 Ligand Selected from an Encoded Self-Assembling Chemical Library, in CHEMISTRY-A EUROPEAN JOURNAL, (34), 8152-8155.
modlAMP: Python for antimicrobial peptides
Müller Alex T., Gabernet Gisela, Hiss Jan A., Schneider Gisbert (2017), modlAMP: Python for antimicrobial peptides, in Bioinformatics, 1-3.
Hit-Validation Methodologies for Ligands Isolated from DNA-Encoded Chemical Libraries
Zimmermann Gunther, Li Yizhou, Rieder Ulrike, Mattarella Martin, Neri Dario, Scheuermann Jorg (2017), Hit-Validation Methodologies for Ligands Isolated from DNA-Encoded Chemical Libraries, in CHEMBIOCHEM, (9), 853-857.
Quantitative PCR is a Valuable Tool to Monitor the Performance of DNA-Encoded Chemical Library Selections
Li Yizhou, Zimmermann Gunther, Scheuermann Joerg, Neri Dario (2017), Quantitative PCR is a Valuable Tool to Monitor the Performance of DNA-Encoded Chemical Library Selections, in CHEMBIOCHEM, (9), 848-852.
Non-internalizing antibody-drug conjugates display potent anti-cancer activity upon proteolytic release of monomethyl auristatin E in the subendothelial extracellular matrixNon-internalizing antibody-drug conjugates and their anti-cancer activity
Gébleux Rémy, Stringhini Marco, Casanova Ruben, Soltermann Alex, Neri Dario (2017), Non-internalizing antibody-drug conjugates display potent anti-cancer activity upon proteolytic release of monomethyl auristatin E in the subendothelial extracellular matrixNon-internalizing antibody-drug conjugates and their anti-cancer activity, in International Journal of Cancer, 140(7), 1670-1679.
Hybrid Network Model for “Deep Learning” of Chemical Data: Application to Antimicrobial Peptides
Schneider Petra, Müller Alex T., Gabernet Gisela, Button Alexander L., Posselt Gernot, Wessler Silja, Hiss Jan A., Schneider Gisbert (2017), Hybrid Network Model for “Deep Learning” of Chemical Data: Application to Antimicrobial Peptides, in Molecular Informatics, 36(1-2), 1600011-1600011.
Characterisation of anticancer peptides at the single-cell level
Armbrecht Lucas, Gabernet Gisela, Kurth Felix, Hiss Jan A, Schneider Gisbert, Dittrich Petra S (2017), Characterisation of anticancer peptides at the single-cell level, in Lab Chip, 2933-2940.
Linker stability influences the anti-tumor activity of acetazolamide-drug conjugates for the therapy of renal cell carcinoma
Cazzamalli Samuele, Corso Alberto Dal, Neri Dario (2017), Linker stability influences the anti-tumor activity of acetazolamide-drug conjugates for the therapy of renal cell carcinoma, in Journal of Controlled Release, 39-45.
Automated screening for small organic ligands using DNA-encoded chemical libraries
Decurtins Willy, Wichert Moreno, Franzini Raphael M, Buller Fabian, Stravs Michael A, Zhang Yixin, Neri Dario, Scheuermann Jörg (2016), Automated screening for small organic ligands using DNA-encoded chemical libraries, in Nature Protocols, 11(4), 764-780.
Acetazolamide Serves as Selective Delivery Vehicle for Dipeptide-Linked Drugs to Renal Cell Carcinoma
Cazzamalli S., Dal Corso A., Neri D. (2016), Acetazolamide Serves as Selective Delivery Vehicle for Dipeptide-Linked Drugs to Renal Cell Carcinoma, in Molecular Cancer Therapeutics, (12), 2926-2935.
Optimized Reaction Conditions for Amide Bond Formation in DNA-Encoded Combinatorial Libraries.
Li Yizhou, Gabriele Elena, Samain Florent, Favalli Nicholas, Sladojevich Filippo, Scheuermann Jörg, Neri Dario (2016), Optimized Reaction Conditions for Amide Bond Formation in DNA-Encoded Combinatorial Libraries., in ACS combinatorial science, 438-443.
Antibody Format and Drug Release Rate Determine the Therapeutic Activity of Noninternalizing Antibody-Drug Conjugates.
Gébleux Rémy, Wulhfard Sarah, Casi Giulio, Neri Dario (2015), Antibody Format and Drug Release Rate Determine the Therapeutic Activity of Noninternalizing Antibody-Drug Conjugates., in Molecular cancer therapeutics, (11), 2606-12.

Collaboration

Group / person Country
Types of collaboration
Philochem AG, Otelfingen Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
Swiss Chemical Society Fall Meeting Talk given at a conference Synthesis of a DNA-encoded macrocycle library 07.09.2018 Bern, Switzerland Stress Cedric;
Protein & Peptides Poster "SPR or MST? What is Best for Drug-like Compound Screening? 23.07.2018 Geneva, Switzerland Brunner Cyrill;
Protein & Peptides Poster "Anticancer Peptide Maturation Towards Greater Cytotoxicity by Simulated Molecular Evolution” 23.07.2018 Geneva, Switzerland Neuhaus Claudia;
FEBS 2018 Congress Talk given at a conference From encoded libraries to clinical-stage targeted therapeutics 11.07.2018 Prague, Czech Republic Neri Dario;
Lecture at the Novartis Institute for Functional Genomics Talk given at a conference From encoded libraries to clinical-stage targeted therapeutics 18.06.2018 La Jolla, United States of America Neri Dario;
Lecture at Nanjing University Individual talk DNA and RNA as a target of chemistry and a material for chemistry 07.06.2018 Nanjing, China Gillingham Dennis;
Lecture at Tianjin University Individual talk DNA and RNA as a target of chemistry and a material for chemistry 05.06.2018 Tianjin, China Gillingham Dennis;
Lecture at Beijing University Individual talk DNA and RNA as a target of chemistry and a material for chemistry 04.06.2018 Beijing, China Gillingham Dennis;
Lecture at the Department of Pharmacy, University of Bologna Talk given at a conference From encoded combinatorial libraries to targeted therapeutics 02.03.2018 Bologna, Italy Neri Dario;
Fall One-Day Thematic Symposium of the SCT (Conjugates and Drug Discovery Chemistry: new challenges for targeted therapies), Talk given at a conference Antibody-Drug Conjugates and Small Molecule-Drug Conjugates: a comparative evaluation 07.12.2017 Paris, France Neri Dario;
DTU Immunology Seminars Series, Technical University of Denmark, Copehagen Talk given at a conference From encoded combinatorial libraries to targeted therapeutics 24.11.2017 Copenhagen, Denmark Neri Dario;
Lecture at AstraZeneca Talk given at a conference From encoded combinatorial libraries to targeted therapeutics 02.10.2017 Mölndal, Sweden Neri Dario;
Annual BMWZ Symposium, Centre of Biomolecular Drug Research Talk given at a conference From encoded combinatorial libraries to targeted therapeutics 14.09.2017 Hannover, Germany Neri Dario;
Workshop “Life Science Community" Talk given at a conference Biologics: from academic idea to the clinic 12.09.2017 Stockholm, Sweden Neri Dario;
SciForLife, Seminar Series, University Uppsala Talk given at a conference From encoded combinatorial libraries to targeted therapeutics 11.09.2017 Uppsala, Sweden Neri Dario;
Swiss Pharma Day Poster "Anticancer Peptide Maturation Towards Greater Cytotoxicity” 22.08.2017 Bern, Switzerland Neuhaus Claudia;


Abstract

We will build a general and broadly-applicable platform technology for the targeted delivery of drugs. In contrast to current approaches our targeting motifs will derive from libraries of modular small molecule macrocyclic scaffolds, opening the door to a variety of previously inaccessible targets. Our guided drugs will be designed to be released at the target through the development of smart linkers that respond to a disease microenvironment or cell receptor. The drugs themselves will derive from known compounds complemented by designs created in the Schneider group. Many pharmaceutical agents are unselective, causing toxicity to normal organs and preventing dose escalation to therapeutically active regimens. Selectively delivering and activating drugs at the site of disease holds great promise for dramatically increasing the therapeutic index of bioactive molecules, thus providing substantial benefits to patients. A successful general platform that exploits small ligands for pharmacodelivery applications would represent a transformative innovation for both academia and industry.Current strategies for targeted drug delivery rely mainly on antibodies as “vehicles”, but recent disappointments in Phase III clinical trials (>5 high-profile clinical failures) with antibody-drug conjugates call into question their real value. Moreover, because of their large size and unacceptably high cost, antibodies can only be used for delivering ultra-potent drugs, hindering development opportunities with conventional pharmaceutical agents and in areas outside oncology. A handful of naturally-occurring small organic ligands for common receptors (folate receptor, carbonic anhydrase IX) have been proposed as an alternative to antibodies for pharmacodelivery strategies, but a general approach that avoids large biomolecules has not been described due to limitations in ligand discovery and to the lack of suitable strategies for drug release at the site of disease. The ability to create “smart drugs” will emerge from advances made in each of the subgroups: Specifically, we will construct encoded chemical libraries of unprecedented size and quality (dozens of millions of compounds) and screen these libraries for ligands against at least ten validated accessible markers of cancer and chronic inflammation. In addition, we will develop and implement innovative technologies for the smart release and activation of bioactive payloads at the site of disease. The linker/release triggers for therapeutic payloads will be tailored to respond to the disease microenvironment and to selectively act on the target cells of choice. In addition to employing well-known cytotoxic agents like tubulin inhibitors (DM1, MMAE) as payloads, we will primarily explore the use of membrane-disruptive peptides. These designed cytotoxic peptides have the unique advantage of (i) directly addressing the plasma membrane of cancer cells as target without the involvement of proteins, which minimizes the risk of cancer cell escape by mutation or development of resistances; (ii) cancer cell-selective membrane targeting as a result of our molecular design aiming at custom-tailored highly potent cytotoxic peptide payloads; and (iii) rapid plasma clearance so that the peptides, once released from the carrier, will act only locally at the site of release, thereby minimizing unwanted off-target and side-effects.The proposal is bold, requiring expertise in chemical, biochemical, and computational technology - a combination beyond the reach of any one research group. The synergy created through the participation of three complementary teams is essential. Prof. Neri (ETH Zürich) will be responsible for the production of target proteins, for the construction and screening of DNA-encoded libraries of chemically-modified cyclic peptides, for the development of small molecule-drug conjugates and for in vivo testing of the most promising compounds in mouse models of cancer and of rheumatoid arthritis. Prof. Gillingham (University of Basel) will be responsible for creating macrocycle libraries, importing them into the DNA encoded format, as well as developing new redox-responsive cleavable linkers. Prof. Schneider (ETH Zürich) will be responsible for the computational design, chemical synthesis, biochemical testing and engineering of novel peptide cytotoxins that kill target cells from the outside by direct cancer cell disruption.
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