Solute carrier proteins and the uptake of cytotoxic approved drugs

Informacje na temat projektu

DrugsUP

Identyfikator umowy o grant: 661491

DOI

10.3030/661491

Projekt został zamknięty

Data podpisania przez KE 28 Kwietnia 2015

Data rozpoczęcia 1 Maja 2015

Data zakończenia 30 Kwietnia 2017

Finansowanie w ramach

• EXCELLENT SCIENCE - Marie Skłodowska-Curie Actions

Koszt całkowity

€ 178 156,80

Wkład UE

€ 178 156,80

Koordynowany przez

CEMM - FORSCHUNGSZENTRUM FUER MOLEKULARE MEDIZIN GMBH
Austria

Periodic Reporting for period 1 - DrugsUP (Solute carrier proteins and the uptake of cytotoxic approved drugs)

Okres sprawozdawczy: 2015-05-01 do 2017-04-30

Podsumowanie kontekstu i ogólnych celów projektu

The transport of nutrients and metabolites across lipid membranes is a critical and essential biological process in both normal and pathological conditions. Specialized integral membrane proteins known as transporters are responsible for the movement of virtually any known class of biologically active molecules across membranes. Perhaps not surprisingly, there is increasing evidence that many drugs in clinical use also use carried-mediated transport as the predominant entry method into the cell. Understanding the molecular and physiological basis of transporter-mediated drug uptake is therefore a key step toward the development of improved pharmacokinetics and models of toxicity for current and future therapeutically active compounds. We hypothesized that most approved drugs may require specific members of the solute carrier (SLC) family to cross the cell membrane, a phenomenon that would directly affect the compound activity, and that this process is basically underestimated in its importance. To test this hypothesis, the studies performed aimed at identifying SLC transporters involved in the uptake of a well-characterized set of commercialized drugs by a functional genetics screening approach. By screening a large panel of drugs in the HAP1 human cell line with a focused, custom-made CRISPR/Cas9 library, we identify a large number of SLC-drug associations that encompass both known and novel interactions.

Prace wykonane od początku projektu do końca okresu sprawozdawczego oraz najważniejsze dotychczasowe rezultaty

Within the project we generated a set of tools to study systematically the largely uncharacterized family of solute carrier (SLCs), comprising most of the human membrane transporters. In particular, we generated a library of CRISPR/Cas9 constructs able to selectively inactivate SLCs genes in human cells, allowing us to screen for genes that are involved in determining the potency of cytotoxic approved drugs (such as for example antitumour drugs). A large set of such compounds (>50) was identified and tested with the library, yielding a number of SLC-drug associations that are now undergoing validation to confirm and understand further their role and mechanism of action. By using different concentration of the compounds, we were able to find correlation between the strength of the hit SLCs and the selective pressure applied, providing an additional layer of validation. Importantly, we identify many known SLC-drug associations (such for example the role of folate transporters in anti-folate drugs uptake or the role of nucleoside transporters in decitabine/cytarabine uptake) therefore confirming the robustness of our approach. The results generated will be disseminated by both presentation at international conferences and by scientific publications, currently in preparation.

Innowacyjność oraz oczekiwany potencjalny wpływ (w tym dotychczasowe znaczenie społeczno-gospodarcze i szersze implikacje społeczne projektu)

The identification of a set of novel drug interactions is an exciting progress in a highly understudied field with the potential to improve the distribution and potency of drugs and improve our understanding of side effects and interaction with other compounds. By knowing how drugs enter cells and how metabolism influences the potency of a drug, it would be possibly to design compounds with improved efficacy (improved metabolism, increased uptake), a better distribution profile (higher uptake, less excretion) and limited side effects (by for example targeting only specific organs based on the pattern of transporters expressed). As these are some of the factors that critically affect the rate at which new compounds are approved for clinical use, we expect that these findings will have large and significant societal and economic implications.

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