COMBINATORIAL CHEMISTRY AND CHEMICAL BIOLOGY SHARED RESOURCE (CCCBSR) PROJECT SUMMARY/ABSTRACT The Combinatorial Chemistry and Chemical Biology Shared Resource (CCCBSR) provides outstanding services and expertise on rapid lead discovery through one-bead one-compound (OBOC) and one-bead two- compound (OB2C) combinatorial library platforms for cancer researchers to screen thousands to millions of diverse molecules in a high throughput fashion against a variety of targets such as cancer cells, T cells, cancer-associated proteins, antibodies and exosomes. The OBOC and OB2C libraries provided by the CCCBSR cover various classes of chemical which include peptides containing unnatural amino acids, peptidomimetics, peptoids, peptide nucleic acids (PNAs), macrocycles and small molecules; thereby meeting a variety of scientific needs. These powerful combinatorial library methods not only offer great potential for facilitating the drug discovery process but also provide powerful tools for basic research in various disciplines. These methods enable investigators to generate and screen large numbers of chemical compounds that can be used as valuable sources for the discovery of drug leads, molecular imaging agents, and capturing agents for molecular biomarkers. For basic research, large collections of chemical compounds can be used to probe their effects on specific cellular function. Compounds that elicit or suppress a specific cellular response can then be identified and used as reagents to study cellular pathways involved in these cellular functions. The CCCBSR also provides rapid lead optimization via combination of combinatorial library approach and standard medicinal chemistry techniques to members of the UC Davis Comprehensive Cancer Center (UCDCCC). Oversight and management of the CCCBSR is provided by the Director, Kit Lam, MD, PhD, an expert in clinical, biochemical, and industrial experiences which are highly relevant to clinical translational research; and the co-Director, Ruiwu Liu, PhD, an expert in organic and peptide synthesis, and multi-step synthesis of natural products and derivatives. The CCCBSR will provide hands-on technology training to resource users and offer timely technical support for their projects. The Specific Aims for the CCCBSR are to: 1) Provide pre- made OBOC and OB2C combinatorial libraries. 2) Design, synthesize, and screen custom-made OBOC and OB2C combinatorial libraries. 3) Screen the premade OBOC and OB2C combinatorial libraries synthesized in the CCCBSR. 4) Determine chemical structure of the positive hits containing both natural and unnatural α- amino acids by microsequencing or mass spectroscopy. 5) Re-synthesize compounds (peptides, peptoids and small molecules) in on-bead or soluble form for in vitro and in vivo evaluation. 6) Provide telodendrimer-based nanomicelles for nanoformulation and in vivo delivery of hydrophobic drugs. 7) Provide polyvinyl alcohol (PVA)- based nanoplatform with the capacity for covalent ...