The p53 transactivation domain 1 TAD1 plays a critical role in inducing p53 mediated cell-cycle arrest and apoptosis in response to acute DNA damage caused by irradiation. During radiation therapy of cancers, this p53-induced apoptosis triggers various deleterious pathological side effects in normal tissues. Interestingly, recent studies from our laboratory have demonstrated that p53 TAD1 is completely dispensable for tumor suppression in diverse mouse cancer models. We hypothesize that specific inhibition of p53 TAD1 should ameliorate the p53-associated pathologies occurring in response to acute DNA damage, while keeping p53-mediated tumor suppression intact, thus allowing improvement in the therapeutic index of radiation therapy in cancer. Importantly, because the majority of cancers, such as advanced prostate cancers, have inactivated the p53 pathway, such inhibitors should not compromise the efficacy of treating tumors. We propose to perform high-throughput chemical library screens to identify specific inhibitor of p53TAD1 that may be administered as adjuvants of chemotherapy and radiotherapy in the context of prostate cancer.