Master of Science Marc Boomgaren vil fredag 6. mars klokken 12.15 offentlig forsvare sin avhandling for graden ph.d. i realfag.
Tittel på avhandlingen:
«Two approaches to novel anticancer agents. Small-molecule library synthesis and evaluation»
Populærvitenskapelig sammendrag:
The work presented in this dissertation combines two fully independent approaches for targeting cancer mediating enzymes with small molecule libraries.
Project 1: Development of compounds inhibiting human dUTPase as an amplifier of a thymidylate synthase inhibitor based cancer therapy Uracil in DNA can lead to point mutations and cell death. This principle is used by thymidylate synthase (TS)-inhibitors in anticancer treatment. TS-inhibitors initialize uprising concentrations of the nucleoside triphosphate dUTP, resulting in increased uracil incorporation in DNA. The human dUTPase is a gatekeeper enzyme, protecting DNA from uracil incorporation, and counteracting effects of TS-inhibitors. Some cancer cells express higher amounts of human dUTPase and become resistant to treatment. The inhibition of the enzyme has the potential to amplify or to recover cytotoxic effects and is therefore an interesting target for drug development. In this work, the synthesis and evaluation of new compounds targeting human dUTPase are presented. First biological results show an affinity of the synthesized compounds to the enzyme dUTPase and gave an impression how to continue in the development process to new dUTPase inhibitors.
Project 2: Synthesis of dasatinib analogs enabled to form covalent connections with tyrosine kinases
Dasatinib is a FDA-approved drug for the treatment of chronic myeloid leukemia (CML) and belongs to the group of tyrosine kinase inhibitors. Tyrosine kinases are involved in cell signaling processes related to cell growth, cell division and apoptosis processes among others. Malfunctioning kinases like BCR-ABL, responsible for CML, can lead to increased cell signaling with the consequence of uncontrolled cell growth and cancer development. The inhibition of tyrosine kinases lower the signaling process and normalize cell growth.
The potential of tyrosine kinase inhibitors is often lowered by resistance developments. Structural changes in the active site of the kinases can lead to loss of inhibitor affinity. This problem can be reduced by covalent binding inhibitors resulting in a permanent interaction. Therefore, covalent binding became of interest in the recent years and led to approved inhibitors. Many tyrosine kinases exhibit cysteines in their active sites which can be addressed by Michael acceptors. Often, noncovalent binding inhibitors are modified with these structure element to generate new covalent inhibitors with modified affinities and selectivity patterns.
The aim of the project 2 was to turn the noncovalent binding inhibitor dasatinib into a platform for new covalent dasatinib compounds with modified kinase selectivity and affinity profiles to its known targets. The work presents the synthesis and the evaluation of the achieved compounds.
Cell assays with different cancer cell lines showed that three compounds significantly decreased cell survival relative to their reference compounds and dasatinib. These results indicate that covalent binding effects for some inhibitors may be present.
Veiledere:
Bedømmelseskomité:
Leder av disputasen: Instituttleder Annette Bayer, Institutt for kjemi, Fakultet for naturvitenskap og teknologi, UiT
Prøveforelesning:
6. mars klokken 10.15 samme sted. Tittel på prøveforelesningen er:
«Targeting Human Immunodeficiency Virus with Small-molecular Drugs»