YALE CENTER FOR MOLECULAR DISCOVERY - PROJECT SUMMARY/ABSTRACT Yale Center for Molecular Discovery (YCMD) is a core facility providing high throughput and high content assay development, screening and hit validation services to the scientific community. The Center maintains and makes available for screening a diverse collection of drug-like small molecules and genomic libraries. YCMD also maintains a sophisticated infrastructure, including cutting-edge screening instrumentation and analysis databases, to support high throughput assay design, testing, liquid handling and reformatting needs. YCMD develops biochemical, cell-based, and model organism-based assays with both plate reader and high content microscopy-based readouts. Highly trained and experienced staff offers the Center’s customers unique and deep expertise in assay optimization, screening and validation. YCMD staff works closely with the members of Yale Cancer Center (YCC) and other Yale laboratories to plan their programs, design, develop and miniaturize assays, and execute robust screening experiments. As a YCC shared resource, YCMD offers services that span a range of investigator-driven goals. Established in 2003, the Center currently serves a very diverse and broad user base. During the fiscal year 2022 (July 2021 through June 2022), 34 laboratories have used YCMD. Twenty-five of these users (74%) were YCC members. This Shared Resource was most widely used by Genomics, Genetics, and Epigenetics, but nearly all the YCC Research Programs benefited from this core. YCMD’s technologies and practical experience are applied to help YCC members address fundamental questions in both basic and translational research. In pursuit of translational research, YCMD scientists support siRNA and sgRNA/CRISPR screening to understand basic biological processes and help discover and validate novel therapeutic targets. YCMD scientists also work closely with YCC members to help discover novel small molecule probes that may serve as tool molecules or starting points for new therapeutics. Novel concepts are developed in an efficient and cost-effective manner by mining pathways or identifying small molecule leads, expanding the capabilities and impact of YCC investigators’ research. The Specific Aims of YCMD are to: 1) Facilitate new lines of research for YCC members and other Yale faculty; 2) Make the YCMD suite of technologies, resources and expertise required for assay development and high throughput screening accessible to a wide user base; and 3) Support early-stage development for translational research programs.