Significance Cancers with mutant p53 often show increased metastasis, genomic instability, and higher chemoresistance. The development of drugs targeting tumors with mutant p53 background is a current strategy for anticancer therapy. We found that certain activated electrophilic 2-sulfonylpyrimidines are a new class of thiol-reactive anticancer agents. These agents are especially effective in killing cancer cells with mutant or inactivated p53 or impaired reactive oxygen species detoxification and have relatively low cytotoxicity toward normal cells; they are mild electrophiles, some of which will, for example, stabilize mutant p53 by selective targeting of its thiol groups and have little general alkylating reactivity.