In this Article, we present how a genome-scale genetic interaction screen in a cellular model of CCNE1 amplification led to the identification of a vulnerability to PKMYT1 inhibition and report the discovery of RP-6306, a selective inhibitor of the PKMYT1 kinase that inhibits CCNE1-amplified cell and tumour growth. The gene discussed is PKMYT1; the disease is neoplasm.