Targeting of oncogenic kinases with small molecule inhibitors is now a well validated paradigm for treatment of cancer types and approximately 25 drugs directed at targets such as ALK, EGFR, BCR-ABL, BTK, C-KIT, b- RAF and PDFGR? are now in routine clinical use. Unfortunately, except for long-term responses to BCR-ABL inhibitors in Chronic Myeloid Leukemia, resistance to other inhibitors typically develops 1-2 years after an initially successful response. In addition, some tumors depend on the scaffolding function of a kinase and not on enzymatic kinase activity, thereby rendering inhibitors ineffective. For example the pseudokinase Her3 is an obligate heterodimerization partner with EGFR and Her2 but its kinase activity is not required. Here we propose to explore a fundamentally new approach to abrogating kinase function using small molecules that can selectively promote the degradation of kinase targets of interest. In particular, we will exploit a recently described approach involving the development of bivalent small molecules that induce ubiquitination and subsequent proteasomal degradation of targets of interest. We will use ligands related to thalidomide, which can recruit the E3 ligase CUL4-RBX1-DDB1-CRBN (CRL4CRBN) that we call `selective degraders' (also known as PROTACs or degronimids). We have developed a powerful mass spectrometry- based proteomics approach that has allowed us to determine which kinases are more susceptible to degradation by this strategy, which has identified two well credentialed targets that are very efficiently degraded: BTK and FLT3. We have developed excellent prototype degraders for FLT3 and BTK which will be further optimized to obtain compounds capable of degrading these targets in vivo. In addition, we have identified a target of therapeutic interest, HER3 that is a pseudokinase (catalytically inactive) but serves as a critical dimerization partner with EGFR and HER2 and therefore represents a unique opportunity for targeting through degradation. The goal of this grant application is to develop optimized small molecule degraders of BTK, FLT3 and HER3 and to understand the biochemical and structural underpinnings of their mechanism of action. Well validated cellular models that exhibit dependencies on these kinases, will be used to investigate how the cellular response differs between kinase inhibition and degradation.!