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• Novel sulfonamide derivatives containing dithiocarbamate moiety were synthesized as potent PKM2 activators. • Compound 8k has good PKM2 activation potency (AC 50 = 56 nM). • Compound 8k has great anti-proliferation activities on 6 tumor cell lines (IC 50 = 0.28 ~ 1.86 µM). • Compound 8k could effectively inhibit the colony formation of MCF7 cells. • Compound 8k could reduce the PKM2 nuclear localization and block the downstream signaling pathways of PKM2. Pyruvate kinase M2 isoform (PKM2) plays a key role in cancer progression through both metabolic and non-metabolic functions, thus it is recognized as a potential target for cancer diagnosis and treatment. In this study, we discovered a sulfonamide-dithiocarbamate compound 8a as a novel PKM2 activator from a random screening of an in-house compound library. Then, a series of lead compound 8a analogs were designed and synthesized for screening as potent PKM2 activators. Among them, compound 8b (AC 50 = 0.136 µM) and 8k (AC 50 = 0.056 µM) showed higher PKM2 activation activities than positive control NZT (AC 50 = 0.228 µM), and they (IC 50 < 1 µM) exhibited more significant anti-proliferative activities against human tumor cell lines than NZT (IC 50 > 10 µM). Especially, compound 8k inhibited the proliferation of multiple cancer cells, but showed little toxicity on normal cells. In addition, we found that compound 8k inhibit the colony formation of MCF7 cells. Western blot analysis demonstrated that 8k could reduce PKM2 nuclear localization and block the downstream signaling pathway of PKM2, resulting in suppression of tumor cell proliferation. Overall, compound 8k may be a promising candidate for further mechanistic investigation of PKM2 and cancer therapy. [ABSTRACT FROM AUTHOR]