Biopharmaceutics characterization of PROTACs using computer models

Terrmin

HT24

Beskrivning

Background
PROTACs, or degraders, are a new and very promising type of drug that binds to and degrades specific intracellular signaling proteins by activating the body's own selective degradation system 1. The technology allows new target proteins to be reached with high specificity while avoiding the development of resistance in cancer treatment. In the pharmaceutical industry, there is currently a strong interest in developing this therapeutic strategy for a number of indications. However, the molecular properties of PROTACs and in vitro cell permeability data often suggest that they will have low oral absorption and bioavailability, which is not always reflected in vivo, with reports showing that absorption and disposition are more extensive 2. In order to enable effective research and development of this group of substances, it is therefore of utmost importance to understand the relationship between absorption and disposition in vitro versus in vivo.
Aim
The aim is to characterize and describe intestinal absorption of PROTACs using physiologically based pharmacokinetic (PBPK) modelling.
Methods
The experimental work that will be carried may include the following
(i) Learn the basic principle of computer simulations using PBPK modelling
(ii) Describe the disposition of PROTACs after oral and intravenous administration in rat
(iii) Identify experimental parameters necessary for predictions of oral PROTAC absorption
Expect 8 h work days at BMC.
Contact
Please contact me if you have any questions: david.dahlgren@uu.se, 0735834900
References
1. Békés M, Langley DR, Crews CM. PROTAC targeted protein degraders: the past is prologue. Nat Rev Drug Discov. 2022:1-20.
2. Pike A, Williamson B, Harlfinger S, Martin S, McGinnity DF. Optimising proteolysis-targeting chimeras (PROTACs) for oral drug delivery: a drug metabolism and pharmacokinetics perspective. Drug Discovery Today. 2020;25(10):1793-1800.

Huvudområde

Farmaceutisk vetenskap

Ämne

Biofarmaci

Typ

Laborativ studie

Företag

Uppsala Universitet

Ort/Plats

Uppsala

Handledarens namn

David Dahlgren

Handledarens e-post

david.dahlgren@uu.se

Institution

Institutionen för farmaceutisk biovetenskap

Program

Apotekarprogrammet

Kurs

Fördjupningsprojekt i biofarmaci 30 hp - 3FG008

Omfattning/hp

15hp

Hur många studenter kan antagas för detta projekt?

1

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