SU212

SU212 is a podophyllotoxin-derived ENO1 inhibitor and AMPK activator. SU212 can selectively induce oxidative phosphorylation, reduce glycolysis activity and glucose uptake in tumor cells, and directly bind to ENO1 without affecting these pathways in normal cells. SU212 induces apoptosis and promotes ENO1 degradation via proteasomal and autophagic pathways without inhibiting the catalytic activity. SU212 leads to mitotic arrest and apoptosis in TNBC (triple-negative breast cancer) cells by activating AMPK, demonstrating potent anti-tumor activity in vitro. SU212 inhibits tumor growth and metastasis in syngeneic, xenograft, and diabetic mouse models, exhibiting an excellent safety profile. SU212 can be used in research on t TNBC, diabetes, and fatty liver disease^[1][2].

SU212 (0.01-850 μM, 48 h) demonstrates lower toxicity and higher potency against TNBC cells (MDA-MB-231) than Etoposide with an IC₅₀ of 0.26 μM; inhibits 50% cell viability in human TNBC cells with IC₅₀s values of 0.1, 0.24, and 0.037 μM for MDA-MB-468, SUM159, and BT549 respectively, and in mouse TNBC cell lines with IC₅₀ values of 0.85, 0.18, 0.039, and 0.31 μM for 4T1, EMT6, E0771, and PY8119^[1][2].
SU212 (0.5 μM, 6 h) has a different target than Etoposide in MDA-MB-231 cells and promotes ENO1 degradation through both proteasomal and autophagic pathways; this effect is partially blocked by co-treatment with MG132 or 3MA^[1].
SU212 (0.1-10 μM, 3 min-6 h) increases the thermal stability of both ENO1 and ENO3 and stronger interaction with ENO1 cells and exhibits a dose-dependent in multiple TNBC cell lines (MDA-MB-231, MDA-MB-468, and EMT6^[1].
SU212 (0.25 or 0.5 μM, 1.5 h) inhibits the overall oxygen consumption rate, extracellular acidification rate, and glycolytic rate in MDA-MB-231, MCF12A, and HEK293 cells, without affecting the glycolytic rate or viability of normal cells^[1].
SU212 (0.1-0.5 μM, 6-10 days) inhibits the clonogenic potential, reflecting the suppression of tumor regeneration and recurrence, in TNBC cells^[1].
SU212 (0.1-0.5 μM, 6 or 12 h) induces G2-/M-phase arrest in MDA-MB-468 and MDA-MB-231^[2].
SU212 (0.5 μM, 12 h) decreases the abundances of different forms of tubulin in MCF10A and MCF12A or TNBC MDA-MB-231 and MDA-MB-468 cell lines^[2].
SU212 (0.25 or 0.5 μM, 12-48 h) induces 12-60% apoptotic cell death but not autophagic cell death in MDA-MB-468, MDA-MB-231^[2].
SU212 (0.25 or 0.5 μM, 1 h-6 h) activates AMPK via phosphorylation of AMPKα at Thr172 in MDA-MB-231 cell and induces robust activation of AMPKα in MDA-MB-468, MDA-MB-231^[2].
SU212 (0.25 μM-0.5 μM, 30 min-6 h) inhibits lactate production and decreases the cellular in MDA-MB-468 and MDA-MB-231, not affect the cellular level of D-glucose, glucose-6-phosphate/fructose-6-phosphate, ATP, citrate, OCR and ECAR α-ketoglutarate in MDA-MB-231 cells^[2].
SU212 (0.5 μM, 12 h) significantly increases in the levels of proteins associated with oxidative phosphorylation, decreases the levels of proteins associated with glycolysis and the pentose phosphate pathway in MDA-MB-231 and MDA-MB-468 cell lines but not in normal breast cell lines^[2].
SU212 (0.1-0.5 μM, 6 or 72 h) has cytotoxic effect that dependent on AMPK activation in MDA-MB-468 and MDA-MB-231^[2].
SU212 (0.2-0.6 μM, 48 h) activates AMPK independent of energy stress in TNBC cell lines^[2].

SU212 (30 mg/kg, i.p., once daily for 3 days) reduces cellular glycolytic rate, lowering the overall glucose demand of tumor cells in MDA-MB-231 cells induced- female NSG mice^[1].
SU212 (100-400 mg/kg, i.p., once) has well tolerance in in female C57BL/6 mice and SD rats^[1].
SU212 (30 mg/kg, i.p. 5 days a week for 21 days or 24 days) not induce liver or kidney toxicity in syngeneic orthotopic TNBC models^[1].
SU212 (20 mg/kg, i.p., five days a week) has positive effect on tumor development and progression in hemizygous MMTV-PyMT transgenic female mouse model^[1].
SU212 (30 mg/kg, i.p., 5 days/week for 21 days) leads to altered subcellular localization and impaired moonlighting functions by inducing the degradation of ENO1 in orthotopic EMT6 mouse model of TNBC^[1].
SU212 (10 mg/kg, i.p., 5 days/week for 32 days) restrains tumor growth in hyperglycemic and hyperinsulinemic conditions and may help improve diabetic and fatty liver conditions in Lepr ^db (Db/Db) mouse model^[1].
SU212 (15 or 30 mg/kg, i.p., 21 days) inhibits tumour progression in luciferase-labelled MDA-MB-231 xenograft mouse model^[2].
SU212 (30 mg/kg, i.p., 30 days) inhibits lung metastasis in tail-vein lung-metastasis mouse model^[2].
SU212 (30 mg/kg, i.p., 21 days) demonstrates potent antitumor growth and anti-metastatic activity by activating the AMPK pathway with no significant body weight loss or hepatorenal toxicity, improves lipid metabolism in 4T1 syngeneic mouse xenograft^[2].

References:
[1]. Tailor D, et al., Malhotra SV. Non-orthosteric inhibition of enolase 1 impedes growth of triple-negative breast cancer. Cell Rep Med. 2025 Nov 18;6(11):102451.  
[2]. Tailor D, et al., Novel Aza-podophyllotoxin derivative induces oxidative phosphorylation and cell death via AMPK activation in triple-negative breast cancer. Br J Cancer. 2021 Feb;124(3):604-615.