MyT Bioscience discovers potent and selective inhibitors for the protein kinase PKMYT1. Cancers that are driven by cyclin E (CCNE) are dependent on PKMYT1 for survival, so our inhibitors are synthetically lethal in these cancers of unmet need. MyT Bioscience inhibitors are orally bioavailable and enhance the efficacy of antibody-drug conjugates (ADCs) carrying a DNA-damaging payload such as a topoisomerase (TOPO) I inhibitor.