Assessing synthetized molecules as potential inhibitors to PARP14 - Prospects of new chemosensitizers
(2023) KEMK10 20231Department of Chemistry
- Abstract
- Poly (ADP-Ribose) Polymerase 14 (PARP14) is an ADP-ribosyltransferase, an enzyme whose catalytic activity is to transfer ADP ribose (ADPr) to a target molecule, utilizing its substrate NAD+. PARP14 has been discovered to partake in the development of different kinds of cancers such as multiple myeloma, B-cell lymphoma and sarcoma, which has led to the interest of using PARP14 as a drug target for cancer treatment by inhibiting its activity. The challenge is to find an inhibitor that not only inhibits the enzyme at low concentrations, but also is selective to PARP14. The aim with this study is to evaluate new synthetized compounds that potentially could inhibit PARP14, and to determine their IC50 values. The methods used for this are... (More)
- Poly (ADP-Ribose) Polymerase 14 (PARP14) is an ADP-ribosyltransferase, an enzyme whose catalytic activity is to transfer ADP ribose (ADPr) to a target molecule, utilizing its substrate NAD+. PARP14 has been discovered to partake in the development of different kinds of cancers such as multiple myeloma, B-cell lymphoma and sarcoma, which has led to the interest of using PARP14 as a drug target for cancer treatment by inhibiting its activity. The challenge is to find an inhibitor that not only inhibits the enzyme at low concentrations, but also is selective to PARP14. The aim with this study is to evaluate new synthetized compounds that potentially could inhibit PARP14, and to determine their IC50 values. The methods used for this are different adaptations of the MacroGreen assay, which make use of a fluorescent tag that binds to ADPr and thus enables to quantify the amount of modified protein over time as well as how the activity decreases when a compound is introduced. The results show that the compound with the highest inhibition efficiency has an IC50 value of 0.68 µM, which is, compared to the literature, a very potent inhibitor, but not as potent as one already existing (0.16 µM). The conclusions that can be made from this are that the compounds whose IC50 values are determined, are highly efficient inhibiting PARP14, but they are yet to be tested for their selectivity. (Less)
- Popular Abstract
- In our everyday life we make use of some kind of communication to interact with each other. Think of it as the indicator of a car, letting you know if the driver is intending to turn right or left. Or when someone wants your attention from a distance and they wave their arms and shout your name. Signaling is all around us, present in different kinds of way and always with a purpose – letting us know something. If we scale this down from the big world around us, and instead look at a cellular level, signaling is present in all organisms. Indeed, without signals, nothing in our bodies would work.
Our bodies are made up of many different types of cells. New cells arise from cell division, where a mother cell is divided into two new... (More) - In our everyday life we make use of some kind of communication to interact with each other. Think of it as the indicator of a car, letting you know if the driver is intending to turn right or left. Or when someone wants your attention from a distance and they wave their arms and shout your name. Signaling is all around us, present in different kinds of way and always with a purpose – letting us know something. If we scale this down from the big world around us, and instead look at a cellular level, signaling is present in all organisms. Indeed, without signals, nothing in our bodies would work.
Our bodies are made up of many different types of cells. New cells arise from cell division, where a mother cell is divided into two new daughter cells. The daughter cells then grow and divide again into two new daughter cells, and so on. However, when something is wrong with the cell beyond repair, it is programmed to die – a process called apoptosis. Special types of cells can evade apoptosis, and therefor continue to divide and increase in numbers for longer periods of time. These are the cancer cells. Nonetheless, there are still ways for these cells to die, one of which is cell death following DNA damage that is not repaired.
The enzyme that is studied in this report, Poly ADP-Ribose Polymerase 14 (PARP14), has been found to be part of the development of certain cancer types, for example multiple myeloma. It cleaves a molecule, Nicotinamide Adenine Dinucleotide (NAD+), and transfers a part of it onto a target molecule. This is seen as a signal by other molecules in the cell that something is needed to be done with the targeted molecule. When the target is damaged DNA, the signal perceived is to recruit DNA repairing molecules to the site of damage. However, in cancer cells this is not a desired response, since the consequence of this signaling is that the DNA is repaired and the cancer cell continues to live. Herein lays the interest, as well as the aim of the study, to find a molecule that is able to inhibit the activity of PARP14, which would hinder the DNA repair and thus leading to death of the cancer cell.
This study evaluated synthetized compounds that could be potential inhibitors of PARP14, by assessing how much they decrease the activity of the enzyme. This was done using an enzymatic assay called MacroGreen, which enables comparing between a non-inhibited enzyme to an inhibited enzyme. The results showed that some of the compounds tested are able to inhibit PARP14 at low concentrations, but not as efficiently as some compounds already existing in the literature. (Less)
Please use this url to cite or link to this publication:
http://lup.lub.lu.se/student-papers/record/9118805
- author
- Olsson, Elin LU
- supervisor
- organization
- course
- KEMK10 20231
- year
- 2023
- type
- M2 - Bachelor Degree
- subject
- keywords
- ADP ribosylation, Biochemistry, Cancer, Inhibition, MacroGreen, PARP14
- language
- English
- id
- 9118805
- date added to LUP
- 2023-06-08 12:29:25
- date last changed
- 2023-06-08 12:29:25
@misc{9118805,
abstract = {{Poly (ADP-Ribose) Polymerase 14 (PARP14) is an ADP-ribosyltransferase, an enzyme whose catalytic activity is to transfer ADP ribose (ADPr) to a target molecule, utilizing its substrate NAD+. PARP14 has been discovered to partake in the development of different kinds of cancers such as multiple myeloma, B-cell lymphoma and sarcoma, which has led to the interest of using PARP14 as a drug target for cancer treatment by inhibiting its activity. The challenge is to find an inhibitor that not only inhibits the enzyme at low concentrations, but also is selective to PARP14. The aim with this study is to evaluate new synthetized compounds that potentially could inhibit PARP14, and to determine their IC50 values. The methods used for this are different adaptations of the MacroGreen assay, which make use of a fluorescent tag that binds to ADPr and thus enables to quantify the amount of modified protein over time as well as how the activity decreases when a compound is introduced. The results show that the compound with the highest inhibition efficiency has an IC50 value of 0.68 µM, which is, compared to the literature, a very potent inhibitor, but not as potent as one already existing (0.16 µM). The conclusions that can be made from this are that the compounds whose IC50 values are determined, are highly efficient inhibiting PARP14, but they are yet to be tested for their selectivity.}},
author = {{Olsson, Elin}},
language = {{eng}},
note = {{Student Paper}},
title = {{Assessing synthetized molecules as potential inhibitors to PARP14 - Prospects of new chemosensitizers}},
year = {{2023}},
}