Kinases regulate normal physiological response to environmental perturbations. When dysregulated, either through aberrant expression or mutation, protein kinases have been implicated in a host of diseases, from developmental disorders to cancer. Accordingly, many of the successful targeted therapeutics for cancer and developmental diseases have been generated against aberrantly activated kinases. Unfortunately, the therapeutic efficacy of most of these agents has been largely disappointing due to the emergence of resistance caused in part by rewiring of the signaling networks and by mutations that interfere with drug binding. In many cases, mutant kinases cannot be efficiently inhibited due to our incomplete understanding of the effect that disease mutations exert on kinase activation state and anticipated response to a drug. Understanding the normal physiological role of protein kinases, the structural plasticity of their drug binding sites, as well as their altered substrates and signaling networks in disease states, will significantly improve our ability to selectively target disease-associated kinases and will enable the development of next-generation targeted combinatorial therapeutics with greatly increased efficacy. There are three specific objectives of the FASEB 2018 Protein Phosphorylation Networks in Health and Disease Conference. The first objective is to describe the state of the art in kinase structure, function, localization, regulation, interactions, and targeting in both normal and pathological cell states. To accomplish this goal we have planned a series of keynote and plenary speakers from many of the leading experts in the field, multiple short talks selected from the poster abstracts, poster sessions, several focused workshops, and informal discussions. Since the challenges in this field are daunting and will require collaborative efforts to solve them, the second goal is to enhance interactions between academia, industry, and clinical science. To this end, we have specifically invited speakers representing each of these topics, and are planning a workshop to discuss career trajectories in different disciplines and navigating productive collaborations. The third objective is to invest intellectually and financially in the future by supporting promising young trainees. The goal is to encourage trainees to be successful and stay in the field by providing intellectual support through discussions with senior scientists, poster sessions, opportunities to speak, awards that recognize their achievements, and by providing financial support with competitive travel awards. The expected outcomes are increased collaborations, retention of young scientists in the field, identification of new developmental processes and diseases linked to tyrosine kinase signaling, and exploration of new state of the art approaches for identifying and developing therapeutic targets and strategies to combat cancer, developmental deficiencies, and other diseases.
This application requests funding to provide partial support of a conference focused on the role of protein phosphorylation and protein kinases in normal biology and cancer. Efficacy of targeted therapeutics has been limited by resistance mechanisms driven by signaling network rewiring and mutations that often exert allosteric effects on drug binding pockets. Participants at this conference will be exposed to the challenges of kinase- based therapeutics and be provided with ideas on how to address them, newest experimental methods to study allosteric transitions in kinases that define specificity of drug binding, and be encouraged to incorporate these ideas, as well as new collaborative interactions, into their future research programs.
