Structure-based drug development targeting cancer

Cancer 

is an enormous challenge to treat and the 

progression

 of the disease

results in significant limitations to quality of life, and even death [1]. Although cancer is associated with 

increasing 

age, it affects all age groups. For example, an analysis of global cancer statistics from 1990 to 2019 shows a slight overall increase in cancer among younger age groups [2]. 

While there has been a

 decrease in 

cancer-associated

 mortality 

due to the development of

 more advanced diagnostics and treatment options

, the disease is still a major global public health problem and

 the development of

therapeutic approaches is still a life-saving necessity.

A promising therapeutic approach

 for treating cancer

 is to 

target

 proteins 

involved in

 nucleotide metabolism [3]. 

C

ancer cells 

grow at a faster rate than healthy cells, which they 

achieve through 

upregulating their

 primary metabolism. The excessive use of the respiratory chain 

then 

leads to increased formation of reactive oxygen species, which in turn

 damages DNA

 base

s, ultimately leading to

mutations

. In order to avoid and 

remove

 the

se

 base lesions, metabolic nucleotide pathways

 are upregulated and therefore become essential for cancer cells. I

nhibition of 

key proteins involved in nucleotide metabolism 

leads to the interruption of the respective 

pathway

, and 

as a result 

cancer cells die

due to increased mutations

 [4, 5].

Effective inhibitor development from a starter molecule requires a combination of X-ray crystallography and enzyme activity studies. The focus of my PhD is on structure-based drug design to find and improve inhibitors targeting enzymes of nucleotide metabolism. To find potential inhibitors, I perform a comprehensive screening of fragment compound libraries. This is done by crystallographic fragment screening at synchrotron facilities. By obtaining protein­–inhibitor complex structures from a screening, the binding of potential inhibitors can be analysed. The inhibitors are then optimised within an interdisciplinary project in order to improve their inhibitory effect. As soon as a potent inhibitor is created, it can be tested in clinical trials for final drug authorisation.