Abstract The stunning clinical success of Gleevec (imatinib) two decades ago appeared to usher in a new era for cancer treatment, whereby a molecular defect in a patient’s tumor was known and could be exploited with a selective drug. A suite of such selective drugs were envisioned, 100s of different drugs that could be prescribed to appropriate patients based on tumor profiling of 100s of different potential defects. Unfortunately this vision has not come to pass, and, with only a handful of approved drug-target pairs, the full potential of personalized medicine in oncology has not been realized. While drugs such as imatinib (and vemurafenib, osimertinib, and a few others) have been game-changers for those cancer subtypes (e.g., certain cancer types with Bcr-Abl translocation, BRAFV600E mutation, and EGFRT790M mutation, respectively), there remain 100s of cancer subtypes and hundreds of exploitable molecular defects that are not matched with drugs. The plodding progress of traditional drug discovery in this realm suggests new approaches are needed to fully realize the potential of targeted therapy for oncology. My lab has developed a discovery platform – from compound synthesis, to cell culture, to target identification, to sophisticated animal models, to translation – that has resulted in 4 novel cancer drugs licensed and moving to cancer patients in 15 years. Building off the observation that truly selective drugs that are successful in human cancer patients also show exquisite selectivity in cell culture, we have identified compounds that have wide activity differential for killing sensitive cell lines versus non-sensitive cell lines; through this method we have identified compounds with >100-fold selectivity and that have advanced (or are advancing) to human cancer patients. In work for the OIA we will create an unprecedented collection of complex-and-diverse compounds, with the novel twist that these compounds will be biased for anticancer activity through incorporation of an electrophile. Compounds able to induce selective death in a panel of >100 cancer cell lines and normal cell types will be advanced through medicinal chemistry optimization. Top compounds will then progress through two parallel tracks, 1) discovery of the biological target (basis for the anticancer selectivity), with our experience showing that in most cases this work will reveal novel exploitable defects in cancer, and 2) translational advancement through the pharmacokinetic/toxicology/efficacy studies and assessment of the ability to engage the immune system, experiments needed to move the very best compounds to clinical trials in cancer patients. We have demonstrated the ability to accomplish all parts of this workflow at a high level, enlisting key collaborators as needed. Through this OIA we will increase our output 2-5-fold, meaning the discovery and development of 4-10 novel cancer drug/target pairs during the 7 year OIA. As importantly, this work will provide a b...