Development of pyruvate dehydrogenase kinase inhibitors in medicinal chemistry with particular emphasis as anticancer agents

Zhang, Shaolin; Hu, Xiaohui; Zhang, Wen; Yao, Huankai; Tam, Kin Yip

doi:10.1016/j.drudis.2015.03.012

Cited by 73 publications

(46 citation statements)

References 53 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Indeed, we observed higher pPDH expression in our chemoresistant patient TMA which strongly correlates with lower PFS and MICU1 expression. The PDH is phosphorylated by the kinase PDK at ser293 and the later serves as a prognostic marker in many cancer types67. We determined a clinical correlation between MICU1 expression and overall survival in two separate clinical cohorts.…”

Section: Discussionmentioning

confidence: 99%

MICU1 drives glycolysis and chemoresistance in ovarian cancer

et al. 2017

View full text Add to dashboard Cite

Cancer cells actively promote aerobic glycolysis to sustain their metabolic requirements through mechanisms not always clear. Here, we demonstrate that the gatekeeper of mitochondrial Ca2+ uptake, Mitochondrial Calcium Uptake 1 (MICU1/CBARA1) drives aerobic glycolysis in ovarian cancer. We show that MICU1 is overexpressed in a panel of ovarian cancer cell lines and that MICU1 overexpression correlates with poor overall survival (OS). Silencing MICU1 in vitro increases oxygen consumption, decreases lactate production, inhibits clonal growth, migration and invasion of ovarian cancer cells, whereas silencing in vivo inhibits tumour growth, increases cisplatin efficacy and OS. Mechanistically, silencing MICU1 activates pyruvate dehydrogenase (PDH) by stimulating the PDPhosphatase-phosphoPDH-PDH axis. Forced-expression of MICU1 in normal cells phenocopies the metabolic aberrations of malignant cells. Consistent with the in vitro and in vivo findings we observe a significant correlation between MICU1 and pPDH (inactive form of PDH) expression with poor prognosis. Thus, MICU1 could serve as an important therapeutic target to normalize metabolic aberrations responsible for poor prognosis in ovarian cancer.

show abstract

Section: Discussionmentioning

confidence: 99%

MICU1 drives glycolysis and chemoresistance in ovarian cancer

et al. 2017

View full text Add to dashboard Cite

show abstract

“…In the case of PDK1, Akt phosphorylation took place exclusively in hypoxia, did not involve other PDK isoforms, and targeted a unique Thr346 site in the “ATP lid” (Zhang et al, 2015), ideally positioned to affect ATP loading, and kinase activation (Patel et al, 2014). Thr346 did not affect PDK1 binding to the PDC, thus differently from another proposed post-translational modification of PDK1 involving Tyr phosphorylation of the “ATP lid” (Hitosugi et al, 2011).…”

Section: Discussionmentioning

confidence: 99%

Mitochondrial Akt Regulation of Hypoxic Tumor Reprogramming

et al. 2016

View full text Add to dashboard Cite

SUMMARY Hypoxia is a universal driver of aggressive tumor behavior, but the underlying mechanisms are not completely understood. Using a phosphoproteomics screen, we now show that active Akt accumulates in the mitochondria during hypoxia and phosphorylates pyruvate dehydrogenase kinase 1 (PDK1) on Thr346 to inactivate the pyruvate dehydrogenase complex. In turn, this pathway switches tumor metabolism towards glycolysis, antagonizes apoptosis and autophagy, dampens oxidative stress, and maintains tumor cell proliferation in the face of severe hypoxia. Mitochondrial Akt-PDK1 signaling correlates with unfavorable prognostic markers and shorter survival in glioma patients and may provide an “actionable” therapeutic target in cancer.

show abstract

“…However, DCA suffers from some drawbacks as a therapeutic agent, such as low potency/selectivity and poor pharmacokinetics (91). The potential of PDK family members as therapeutic targets has prompted considerable interest in developing specific inhibitors against these enzymes (91)(92)(93).…”

Section: Distinct Metastatic Microenvironments Select For Specific Momentioning

confidence: 99%

Metabolic Plasticity as a Determinant of Tumor Growth and Metastasis

et al. 2016

View full text Add to dashboard Cite

Cancer cells must adapt their metabolism to meet the energetic and biosynthetic demands that accompany rapid growth of the primary tumor and colonization of distinct metastatic sites. Different stages of the metastatic cascade can also present distinct metabolic challenges to disseminating cancer cells. However, little is known regarding how changes in cellular metabolism, both within the cancer cell and the metastatic microenvironment, alter the ability of tumor cells to colonize and grow in distinct secondary sites. This review examines the concept of metabolic heterogeneity within the primary tumor, and how cancer cells are metabolically coupled with other cancer cells that comprise the tumor and cells within the tumor stroma. We examine how metabolic strategies, which are engaged by cancer cells in the primary site, change during the metastatic process. Finally, we discuss the metabolic adaptations that occur as cancer cells colonize foreign metastatic microenvironments and how cancer cells influence the metabolism of stromal cells at sites of metastasis. Through a discussion of these topics, it is clear that plasticity in tumor metabolic programs, which allows cancer cells to adapt and grow in hostile microenvironments, is emerging as an important variable that may change clinical approaches to managing metastatic disease. Cancer Res; 76(18); 5201-8. Ó2016 AACR.

show abstract

Development of pyruvate dehydrogenase kinase inhibitors in medicinal chemistry with particular emphasis as anticancer agents

Cited by 73 publications

References 53 publications

MICU1 drives glycolysis and chemoresistance in ovarian cancer

MICU1 drives glycolysis and chemoresistance in ovarian cancer

Mitochondrial Akt Regulation of Hypoxic Tumor Reprogramming

Metabolic Plasticity as a Determinant of Tumor Growth and Metastasis

Contact Info

Product

Resources

About