The Discovery and Synthesis of Novel DYRK1A Inhibitors for Various Oncologic Targets

Abstract

This dissertation describes the research of small molecule kinase inhibitors focused on in silico design, targeted synthesis, and their biological evaluation for the interest in translational medicinal chemistry projects with an emphasis in oncology. The first project (Chapter 1) is the identification and synthesis of novel “6,5” heterocycle based dual specificity tyrosine phosphorylation regulated kinase-1A (DYRK1A) as a potential treatment approach for certain DYRK associated pathologies. A series of Groebke–Blackburn–Bienaymé (GBB) based analogs were synthesized and assessed, showing somewhat promising activity. Further profiling of this series has led to a potential in vivo candidate DYR794 (49) and has revealed a new series of urea-based linkers which provide an opportunity for further exploration of other kinases and Poly-pharmacology approaches. The second project (Chapter 2) is focused on the development of Glial Blastoma Multiforme (GBM) based “6,6 Aryl-Pip” quinazoline based analogs. These compounds serendipitously inhibit key GBM relevant kinases as a novel approach to treat this specific cancer. A series of molecules were made and analyzed in revealing potential IND candidates and in vivo candidates that are orally bioavailable. The intent of the third project (Chapter 3) is the synthesis of low nanomolar WNT-pathway inhibitors for the treatment of Colorectal Cancer (CRC). These “6,6 Pip-Aryl” quinazoline based inhibitors showcased promising activity in both CRC and GBM cell lines with a clear direction for in vivo candidacy. This series binds to higher order cyclin dependent kinases (CDKs) which help regulate DNA transcription.