PROJECT SUMMARY CHEMICAL BIOLOGY CORE The Chemical Biology Core (CBC) offers centralized cutting-edge technologies and expertise that facilitates and accelerates basic and drug discovery research. Established in 2004, the CBC has broad usage by the Programs of the Center, where CBC promotes the identification, synthesis and further development of small molecules and chemical probes specific for cancer targets, to elucidate underlying molecular mechanisms driving cancer and to support drug discovery efforts by providing state-of-the-art equipment and unique services. Specifically, the Scientific Co-Directors and staff of the CBC have broad knowledge and a wealth of expertise in synthetic and medicinal chemistry, chemical biology, biophysics, structural biology and drug discovery that supports the high-impact research of Members, and that expands the repertoire of research capabilities at Moffitt. To support the research efforts of Members, CBC activities are organized into three Specific Aims: Aim 1: To assist Members in study design, the synthesis of focused small molecule libraries, hit-to-lead optimization, and chemical probe syntheses. Aim 2: To provide services and infrastructure to study the structures and functions of proteins involved in cancer. Aim 3: To conduct training and education for Members and staff. CBC is integrally involved in, and has pivotally contributed to, the success of Member research projects. CBC chemistry services include synthesis of: 1) focused libraries for hit-to-lead-optimization; 2) chemical probes; 3) designed tagged small molecules for affinity-based chemical proteomics; and 4) medicinal chemistry and scale-up to provide pre-clinical compounds for efficacy, potency, selectivity and safety studies. CBC structural biology services include: 1) cloning, expression, and large-scale purification of target proteins; 2) protein crystallization; 3) high-resolution structure determination; 4) binding studies of protein-protein and protein- ligand/drug interactions; and 5) assisting with structure-guided design of small molecules. Since 2016, CBC supported 40 Members (a 54% increase from previous review), contributed to 21 new grant awards to Members, and supported 59 peer reviewed publications (7 high impact). In FY20 alone, CBC supported 25 Members (72% peer reviewed) in four of the five Programs (CBE 22%, CE 6%, MM 61%, IO 11%), representing 95% of all CBC usage. CBC will continue to provide exceptional chemical and structural biology services and technologies to Members in the upcoming cycle. Future CBC priorities are to: 1) generate in-house focused compound and fragment libraries for cell-based screening projects; 2) with BBSR and machine learning Members, develop new tools for drug design; 3) synthesize 13C-labeled metabolites that support metabolic flux analyses; 4) provide automated imaging for x-ray crystallization screens; and 5) expand support of cryo-electron microscopy studies.