ACT-PFK-158 is a novel anti-cancer agent that inhibits glucose uptake in cancer cells. The primary objective of the study will be to determine the maximum tolerated dose (MTD) and to describe any dose limiting toxicity. The secondary objectives of the study will be to determine the safety profile of the drug, to determine the pharmacokinetic profile, to identify any anti-tumor activity, and to determine the pharmacodynamic profile of ACT-PFK-158.

Start Date01 Mar 2014

Sponsor / Collaborator

Advanced Cancer Therapeutics LLC

100 Clinical Results associated with PFKFB3

100 Translational Medicine associated with PFKFB3

0 Patents (Medical) associated with PFKFB3

744

Literatures (Medical) associated with PFKFB3

01 Jul 2025·Biochemical Pharmacology

Increased SUMO-activating enzyme subunit 1 promotes glycolysis and fibrotic phenotype of diabetic nephropathy

Article

Author: Sailike, Ali ; Haimiti, Shayila ; Wang, Yitian ; Wusiman, Reziwanguli ; Yang, Miaoyan ; Abuduaini, Hanikezi ; Gu, Meijun ; Gao, Lei

Renal fibrosis is a prominent feature of diabetic nephropathy (DN), and the connection between renal fibrosis and abnormal glycolysis is not fully understood. SUMO-activating enzyme subunit 1 (SAE1) plays a crucial role in the SUMO modification process and is related to abnormal glycolysis. Despite this, the specific role of SAE1 in DN and its mechanism are not well defined. To investigate this, a streptozotocin-induced diabetic CD1 mice model was used, with SAE1 suppression achieved through systemic administration of SAE1 siRNA. In parallel, human renal proximal tubular tubule HK2 cells transfected with siSAE1 were exposed to high glucose for in vitro studies. The study revealed that SAE1 levels were elevated in diabetic kidney, and the deletion of SAE1 mitigated renal fibrosis in DN mice. Such suppression in SAE1 was associated with the lower expression of hypoxia inducible factor-1α (HIF-1α) and 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (PFKFB3), these alterations subsequently improved abnormal glycolysis and mesenchymal transformations in vivo and in vitro. Further experiments discovered that SAE1 stabilized transcription factor HIF-1α expression through SUMOylation, promoting PFKFB3 transcription, which enhanced glycolysis characterized by increased PFK1 activity and lactate production. Additionally, pharmacological inhibition of PFKFB3 reduced renal fibrosis in DN mice, while overexpression of PFKFB3 partly restored the glycolysis and mesenchymal transformations inhibited by SAE1 knockdown in vitro. These data demonstrate that SAE1 promotes abnormal glycolysis by HIF-1α/PFKFB3 which is responsible for the fibrotic phenotype of diabetic kidney. Inhibition of SAE1 could be an alternative strategy in combating diabetes associated-kidney fibrosis via improving aberrant glycolysis.

01 Jun 2025·Toxicology

H3K18 lactylation-mediated SIX1 upregulation contributes to silica-induced epithelial-mesenchymal transition in airway epithelial cells

Article

Author: Zhang, Qun ; He, Yiting ; Liu, Songtao ; Shi, Shuangshuang ; Jin, Linling ; Zhang, Jiayi ; Kong, Hui ; Xie, Weiping ; Yang, Mingxia

Silica exposure-induced airway epithelial-mesenchymal transition (EMT) is a critical pathological process in pulmonary fibrosis. This study investigated the role of NLRP3 inflammasome, glycolysis, and histone lactylation in silica-induced EMT of human bronchial epithelial cells (16HBE). Silica exposure activated NLRP3 inflammasome, enhanced glycolysis and H3K18 lactylation, as well as induced EMT in 16HBE cells. Selective inhibition of NLRP3 inflammasome with MCC950, blockade of the interleukin 1 (IL-1) receptor with AF12198, or suppression of lactate production with oxamate effectively reduced glycolysis-mediated histone lactylation and mitigated silica-induced EMT. Moreover, silica-induced upregulation of PFKFB3, a key enzyme of glycolysis, was significantly mitigated by MCC950 or AF12198. Cut&Tag analysis revealed silica treatment led to H3K18 lactylation enrichment at transcription start sites (TSS), particularly within the promoter region of the sine oculis homeobox 1 (SIX1), which enhanced transcription of SIX1, a key transcription factor involved in EMT. Consistently, inhibition of histone lactylation by the histone acetyltransferase P300 inhibitor A-485 suppressed silica-induced SIX1 expression and EMT. These findings indicate that silica activates NLRP3 inflammasome and promotes interleukin 1β (IL-1β) production, thereafter enhancing PFKFB3-mediated glycolysis by IL-1 receptor. Lactate accumulation by glycolysis enhances H3K18 lactylation at the TSS facilitating expression of SIX1. Together, this inflammation-glycolysis-lactylation cascade involved in EMT provides new insights into the molecular mechanisms underlying silica-induced pulmonary fibrosis.

01 Jun 2025·Phytomedicine

Soufeng Sanjie formula alleviates the progression of lupus and joint injury by regulating the ALKBH5-FoxO1-PFKFB3 axis in M-MDSCs

Article

Author: Dou, Huan ; Zhang, Tianshu ; Zhang, Lingyu ; Wang, Shuangan ; Wu, Zirou ; Hou, Yayi ; Cao, Peng ; Tan, Liping ; Wang, Xiuzhu

BACKGROUNDSystemic lupus erythematosus (SLE) cases present with impaired immune function and injured organs, with joint injury being one of the most common complications. Soufeng Sanjie formula (SF) is a traditional Chinese medicine (TCM) that alleviates rheumatoid arthritis and has a significant regulatory effect on T cells. Recently, myeloid-derived suppressor cells (MDSCs) have been considered an essential factor contributing to SLE pathogenesis, as they can mediate the abnormal amplification of Th17 cells. However, it remains unclear whether SF targets MDSCs to alleviate SLE and joint injury.PURPOSEWe aim to examine SF for therapeutic effects in lupus mice and the potential molecular mechanisms.STUDY DESIGN AND METHODSWe developed an IMQ-induced lupus mouse model for assessing the high and low doses of SF for their effects. The manifestations of joint injury were also examined. Changes in immune cell populations were analyzed by flow cytometry and in vitro co-culture experiments. The key targets and active components of the SF were identified through network pharmacological analysis. Moreover, SF-containing serum was prepared to stimulate TLR7 against R848-induced-MDSCs in vitro. We also developed a pristane-induced lupus model in myeloid FoxO1-deficient mice. ECAR and OCR detection, measurements of glucose and lactic acid levels, luciferase reporter gene assays and ChIP-qPCR were employed to assess the transcriptional regulatory mechanisms of FoxO1. Dot blot analysis in conjunction with RNA immunoprecipitation (RIP) was used to assess post-transcriptional regulation.RESULTSSF significantly alleviated the symptoms of IMQ-induced lupus in mice, including joint damage. SF decreased the proportion of monocytic MDSCs (M-MDSCs), with no significant effects on granulocytic MDSCs (G-MDSCs), in both blood and spleen. Network pharmacological analysis indicated that FoxO1 was a key target of SF in M-MDSCs. Expectedly, SF-containing serum enhanced the immunosuppressive effect of M-MDSCs on Th17 cells by increasing FoxO1. The therapeutic efficacy of SF was diminished in the pristane-induced lupus model with myeloid FoxO1-deficient mice. Mechanistically, FoxO1 impaired the glycolytic process in M-MDSCs by inhibiting PFKFB3 transcription, thereby enhancing their immunosuppressive effect on Th17 cells. Additionally, delphinidin chloride (DP), an important constituent of SF, increased FoxO1 mRNA stability by downregulating ALKBH5-m⁶A modification in M-MDSCs.CONCLUSIONThis study confirmed that SF enhanced glycolysis in M-MDSCs by regulating the ALKBH5-FoxO1-PFKFB3 axis, which decreased Th17 cells and alleviated lupus and joint injury. These data firstly indicate SF may represent a potential treatment option for SLE and joint damage, revealing regulatory effects of DP, the key active component of SF, at the post-transcriptional level.

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