Significance Dysregulated expression of master transcription factor c-MYC has been shown to promote proliferation and cell survival programs in cancer cells to mediate resistance to anticancer therapies and promote metastasis. Development of pharmacological agents to inhibit c-MYC as an anticancer therapy is a longstanding but elusive goal in the cancer field. Our study provides a potential widely applicable pharmacological strategy for targeting c-MYC–driven oncogenic activity by inhibiting cIAP1 E3 ubiquitin ligase activity as a treatment for cancers. Furthermore, we demonstrate the pharmacological interference in the dynamic interaction of an E3 ubiquitin ligase with its E2s as a strategy for inhibiting ubiquitination reactions.