Chimeric targeting molecules (CTMs) are bi-functional degrader molecules that simultaneously bind to a protein of interest (POI) and an E3 ligase. The process of degrading the POI consists of recruiting an E3 ligase for ubiquitylation, and subsequent degradation by the 26S proteasome. We are focused on discovering drugs that directly inhibit E3 ligases as well those that harnessing ligase ubiquitination activity for degradation of neo-substrates. The concept of disease modification through protein degradation offers several advantages as compared to traditional small molecule inhibition: the compounds behave catalytically and require sub-stoichiometric quantities, they simultaneously address the enzymatic and scaffolding functions of a POI and may put previously ‘undrugabble’ targets within reach. As an emerging field, there remain many fundamental questions about the CTM mechanism of action. The E3 ligase and POI must form a ternary complex facilitated by the CTM. The nature of that newly-enabled interaction and its molecular structure are active areas of research by us and others 1,2,3. A handful of CTM-E3 ligase-POI ternary complex structures are available in the public domain. We use these to develop a protein-protein docking protocol designed to prospectively predict ternary complex structures and guide the optimization of CTM molecules for potency and selectivity. The results of the validation of the method, utility, as well as its challenges will be described for a series of kinase-degrading CTMs synthetized and tested at Nurix Therapeutics.

Development and validation of a computational modeling workflow to characterize the structure of bi-functional degraders-protein-protein ternary complex

2019 Fall National Meeting

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