Drug development is time consuming and costly with little certainty of eventually leading to an approved medicine. As new therapies are urgently needed, research is required to scrutinize the status quo to reduce the guesswork for a more efficient process. The overall goal of our program is to evaluate aspects of drug development and offer new methods that expose flaws and opportunities for the accelerated delivery of new therapies. Our projects utilize protein kinases as platforms to inform best practices relevant to virtually all drug development campaigns. Each of our program areas are made capable of filling interrelated gaps in knowledge because of innovative applications of our novel ATP-allosteric bivalent inhibitors (AABIs) that were originally designed to target the epidermal growth factor receptor (EGFR). The first program area is directed to selectively target the inactive state broadly in human kinases. Our AABIs are only able to bind the inactive state enabling the rapid discernment of promising new targets. We will tailor AABIs in cutting-edge target engagement assays as proteolysis targeting chimera (PROTAC) degraders to enable innovative discovery approaches of kinases in their native cellular contexts, which will serve as inspiration for other streamlined discovery approaches in drug discovery. The second program area seeks to use EGFR as a model system for elucidating the molecular and structural factors that influence the activity of linked compounds. Recent progress highlights our ability to develop structural and functional understandings of linker design relevant to fragment-based drug design in addition to fine tuning of properties of PROTAC degraders. Our third program area sets out to acquire deeper appreciation of what causes variabilities in covalent inhibitor activity assays that potentially confuse drug optimization. We have discovered that covalent EGFR inhibitors exhibit large potency differences based on their chemical properties as a result of minor changes in how activity assays are performed. Our structurally diverse covalent EGFR AABIs allow for a maximally comprehensive analysis of these effects as they can be made with a variety of chemical structures. The work in this program will successfully fill gaps in our knowledge related to drug development and pave the way for the accelerated production of new therapies. Our projects are interconnected by their ability to improve drug development enabled by innovative applications of our novel AABI kinase inhibitors. Additionally, these efforts are designed to logically evolve in future directions for upcoming MIRA periods relevant to developing novel kinase inhibitors and applications across diverse pharmacological approaches including covalent inhibitors, PROTAC degraders, fragment-based drug design, and others. The PI is the main driver of this research program with multi-disciplinary expertise and a long-term vision to leverage the molecular and structural insigh...