Cell-based assays are crucial for identifying lead molecules suitable for clinical advancement by providing a more physiologically relevant model. However, the field faces significant challenges due to the lack of robust screening technologies and efficient compound library generation, resulting in high attrition rates. In this dissertation, I discuss the development of two novel cell-based platforms aimed at enhancing the effectiveness of early-phase drug screening and accelerating the delivery of promising small molecules.Chapter 2 focuses on the development and application of a targeted protein degradation system using an engineered variant of the DNA-repair protein O6-alkylguanine-DNA-alkyltransferase (hAGT) and novel benzylguanine (BG) substrates, demonstrating versatility across proteins in different cellular localizations. Chapter 3 refines this system, enhancing degradation efficiency and exploring practical chemistry without requiring specialized equipment. Chapter 4 introduces a 3D cellular screening platform that integrates DNA-encoded libraries (DELs) with intracellular assays, showcasing its potential to transform early drug discovery through efficient, scalable interrogation of complex intracellular pathways with novel chemical matter. All together, this dissertation explores advancements in cell-based assays through targeted protein degradation and DNA-encoded library technologies, improving our ability to manipulate and understand cellular functions at a molecular level, thus enhancing the scope of targets and tractability of small molecules identified in early drug discovery efforts.