PDK1 as a potential prognostic and clinicopathological biomarker in various carcinomas: a meta-analysis
INTERNATIONAL JOURNAL OF CLINICAL AND EXPERIMENTAL MEDICINE
Authors: Yang, Lingyun; Zhu, Zhenghai; Zhou, Ying; Chen, Chaobo; Chen, Jie; Xu, Zipeng
Abstract
Introduction: Recent studies have confirmed that pyruvate dehydrogenase kinase 1 (PDK1) is dysregulated in various tumors and that PDK1 overexpression is associated with survival and clinicopathological features in patients with cancer. Therefore, this meta-analysis was performed to evaluate prognostic and clinicopathological roles of PDK1 in human tumors. Materials and methods: Electronic databases PubMed and Web of Science were searched (up to December 20, 2017). Results: A total of 2,676 patients from 14 eligible studies were collected and analyzed in this study. Results indicated high that PDK1 expression correlated with poor overall survival (OS) (HR=1.81, 95% CI: 1.42-2.31, P<0.001). Moreover, PDK1 was related to T grade (OR=1.72, 95% CI: 1.27-2.31, P<0.001). Conclusion: The present meta-analysis showed that high PDK1 expression predicts poor prognosis and T stage, serving as a promising biomarkers for patients with cancer.
The chemical diversity and structure-based discovery of allosteric modulators for the PIF-pocket of protein kinase PDK1
JOURNAL OF ENZYME INHIBITION AND MEDICINAL CHEMISTRY
Authors: Xu, Xinyuan; Chen, Yingyi; Fu, Qiang; Ni, Duan; Zhang, Jian; Li, Xiaolong; Lu, Shaoyong
Abstract
Phosphoinositide-dependent protein kinase-1 (PDK1) is an important protein in mediating the PI3K-AKT pathway and is thus identified as a promising target. The catalytic activity of PDK1 is tightly regulated by allosteric modulators, which bind to the PDK1 Interacting Fragment (PIF) pocket of the kinase domain that is topographically distinct from the orthosteric, ATP binding site. Allosteric modulators by attaching to the less conserved PIF-pocket have remarkable advantages such as higher selectivity, less side effect, and lower toxicity. Targeting allosteric PIF-pocket of PDK1 has become the focus of recent attention. In this review, we summarise the current advances in the structure-based discovery of PDK1 allosteric modulators. We will first present the three-dimensional structure of PDK1 and illustrate the allosteric regulatory mechanism of PDK1 through the modulation of the PIF-pocket. Then, the recent advances of PDK1 allosteric modulators targeting the PIF-pocket will be recapitulated detailly according to the structural similarity of allosteric modulators.
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