Project

Discipline

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

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

Active participation

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.