Most approved drugs today target proteins. There are approximately 20,000 proteins in the human proteome, of which, ~5,000 play critical roles in human disease. Of these 5,000, roughly 12% have been successfully targeted with small molecules and the remainder remain effectively un-assayable for drug development. Belharra Therapeutics is developing and employing a novel chemo-proteomic drug discovery engine utilizing drug-like photoaffinity probes to uncover functional and actionable ligands for any protein, in any state, in any cell type. Paramount to achieving this vision is enabling a high-throughput chemo-proteomics screening platform which is centered on quantitative mass-spectrometry (MS) based analysis. Historically, MS technology has been underutilized for discovery screening efforts due to limitations with throughput (low multiplexing) and the perception of high costs. As MS instrumentation has advanced, multiplexing capabilities have expanded, and automation in sample preparation has become feasible, the tools are in place to enable high-throughput chemo-proteomics is within reach. The data presented will highlight our efforts to address both throughput and cost challenges associated with MS-based proteomics approaches. We have optimized TMT reagent usage with our platform to appropriately balance over- and under-labeling, while reducing reagent associated costs and hands on time associated with aliquoting reagents. Taken together, these advances have enabled us to screen more than 100 compounds per day per mass spectrometer, realizing a 4X to >10X gain in throughput depending on sample complexity.