Exploration of Novel Chemotypes that Ameliorate Cellular Senescence

Abstract

Dementia is an umbrella term which refers to a variety of neurodegenerative diseases with fatal prognoses. Current treatment options are limited as aetiologies and mechanisms of disease progression are unclear. As the global population and human lifespans continuing to increase, it is expected that more people will be diagnosed with some form of neurodegenerative disease. This will place increase the burden on economies, so the need for better therapeutics for these diseases is more pressing than ever. A hypothesis for the onset of neurodegeneration is the accumulation of senescent cells (SCs). SCs have undergone a growth arrest and secrete a cocktail of inflammatory factors, known as the senescence-associated secretory phenotype (SASP). They have been implicated in many disease states correlated with inflammation. Molecules capable of clearing SCs, termed ‘senolytics’, exploit differences to healthy cells to induce apoptosis. The focus of this work has therefore been to explore novel senolytic chemotypes. The breast cancer lymphoma family of proteins is one such group involved in the prevention of apoptosis. Animal models have demonstrated that the inhibition of BCL family members reduces the burden of senescent cells while also maintaining healthy cells. Indeed, several inhibitors of these proteins are reported in literature, and thus have become useful starting points for the investigations detailed in this work. A major focus of this work has been the application of medicinal chemistry techniques to generate new and potentially senolytic chemotypes. Methods such as iterative reconstruction, scaffold hopping and probing of structure-activity relationships are discussed, following which chemical synthesis is detailed. The biological evaluation of these compounds, while still ongoing, may provide valuable information to advance the current understanding of senolytics and treatments for neurodegenerative disease.