Developing Small Molecule Inhibitors of ALK2: A Serine/Threonine Kinase Implicated in Diffuse Intrinsic Pontine Glioma
Year: 2020
Type: dissertation
Abstract: Diffuse intrinsic pontine glioma (DIPG) is an aggressive pediatric cancer for which no effective chemotherapeutic drugs exist. Analysis of the genomic landscape of this disease has led to the identification of the serine/threonine kinase ALK2 as a potential target for therapeutic intervention. In this work, we developed two separate series of potent type I inhibitors of ALK2 based on the previously reported inhibitor LDN-214117. The first structure-activity relationship (SAR) study focuses on improving the selectivity, permeability and pharmacokinetic profile of M4K2149, a benzamide analogue with reduced off-target affinity for the hERG potassium channel. The second part of this thesis highlights the efforts made to develop a conformationally constrained inhibitor that was rigidified into the biologically active configuration of M4K2009, the lead compound of this project. Future studies will assess the permeability of select compounds in a Caco-2 permeability assay and their PK profiles in vivo.
Source: TSpace (University of Toronto)
Author: Deeba Ensan
Language: English
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W3125566657