Cancer Chemical and Structural Biology

PROJECT SUMMARY/ABSTRACT The major goals of the Sidney Kimmel Comprehensive Cancer Center (SKCCC) Cancer Chemical and Structural Biology (CCSB) Program are to: 1) discover, validate and characterize novel molecular targets for prospective therapeutic agents against human cancers; 2) identify and optimize new small molecules with anticancer potential; and 3) provide tools for targeting and assessing therapeutic delivery. To achieve these goals, CCSB fosters significant interactivity among its 31 Program Members and other SKCCC Members. The program is composed of 31 Members (28 Full Members and three Associate Members) (Table 1), across twelve departments and four schools. Of the 31 members, 26 have cancer-relevant peer-reviewed funding. The program brings together cross-disciplinary expertise throughout the university, including the School of Medicine, the Whiting School of Engineering, the Bloomberg School of Public Health, and the Krieger School of Arts and Sciences. The total direct cancer-relevant peer-reviewed funding is $8.9 million (Data Table 2A), with $2.1 million from the National Cancer Institute. The success of CCSB is evidenced by a robust pipeline of over 19 novel lead compounds in various stages of preclinical (14) and clinical (five) development. The scholarship, including 355 publications, demonstrates broad interactions of which 46 (13%) were Intra- Programmatic, 162 (45.6%) were Inter-Programmatic and 244 (68.7%) were external collaborations. Activities for the next project period focus on three synergistic aims: Aim 1: To accelerate anticancer target discovery and validation. Aim 2: To develop novel small-molecule screening platforms, and identify and optimize novel compounds against cancer targets. Aim 3: To develop methods for monitoring, predicting and optimizing anticancer drug delivery and immunomodulation. Aim 1 uses discovery-driven approaches to identify and validate targets along with proof-of-principle experiments to assess merit and feasibility for translational approaches. These activities include molecular, structural and cell biology studies, coupled with biological and preclinical therapeutic studies, and pharmacokinetic analyses. Aim 2 is focused on developing new small-molecule libraries and screening both existing and novel chemical libraries against identified cancer targets. Aim 3 centers on developing new methods for small-molecule and nucleic acid delivery (prodrugs, encapsulation methods), and for antibody design and use (immunoengineering). CCSB efforts will provide new preclinical drug candidates, along with the biology of pertinent molecular targets. These will support clinical translation and development by investigators across all SKCCC Programs. CCSB deliverables will have a broad and powerful impact on translational and clinical research, expediting basic science discoveries to promote the development of new cancer therapeutics.