Discovery, synthesis, and optimization of small molecules identified via multiple screening techniques for targeting cancer-related proteins

With the advent of genomic sequencing, our understanding of cancer has drastically improved, revealing unique molecular characteristics in each tumor that require tailored therapeutic approaches. Modern drug discovery methodologies such as Fragment-Based Drug Discovery (FBDD), DNA-Encoded Libraries (DEL), and virtual screening are revolutionizing precision oncology. This thesis first investigates Structure Activity Relationship (SAR) studies on compound 8, identified via 19F-NMR screening, which inhibits the RAD51-BRCA2 interaction—a key process in DNA repair—at micromolar potency. SAR analysis revealed that compound 8’s core structure is critical for activity, with derivatives showing significantly reduced potency. These findings provide a foundation for further optimization and structural analysis. The second part of this thesis explores work conducted during my research stay at Philochem AG on the application and development of DEL technology for diverse important oncology targets. Following Prof. Cavalli’s research focus, the RAD51-BRCA2 interaction was studied, yielding new binding hits and valuable insights into the rare application of DEL technology to DNA-binding proteins. DEL screenings also identified high-affinity, selective ligands for tumor-associated antigens, PSMA and CAIX, with compound 39 surpassing the gold standard acetazolamide in CAIX selectivity and biodistribution, and compound 59 outperforming the approved drug Pluvicto in PSMA selectivity. Additionally, a new ligand (compound 73) was validated for the immune target NKG2D, showing nanomolar binding affinity in vitro. To enhance DEL chemical diversity, this thesis also details work on optimizing DNA-compatible reactions, such as urea, thiourea, and sulfonamide formations, thereby expanding the chemical space accessible for ligand discovery. Finally, virtual screening was integrated with laboratory chemistry to discover novel TRAP1 inhibitors, a mitochondrial HSP90 chaperone linked to cancer metabolism. This effort led to the identification of a new class of allosteric inhibitors selective for TRAP1 over other HSP90 isoforms, currently undergoing biophysical and cellular evaluation.