scholarly journals Globally Approved EGFR Inhibitors: Insights into Their Syntheses, Target Kinases, Biological Activities, Receptor Interactions, and Metabolism

Molecules ◽  
2021 ◽  
Vol 26 (21) ◽  
pp. 6677
Author(s):  
Mohammed A. S. Abourehab ◽  
Alaa M. Alqahtani ◽  
Bahaa G. M. Youssif ◽  
Ahmed M. Gouda

Targeting the EGFR with small-molecule inhibitors is a confirmed valid strategy in cancer therapy. Since the FDA approval of the first EGFR-TKI, erlotinib, great efforts have been devoted to the discovery of new potent inhibitors. Until now, fourteen EGFR small-molecule inhibitors have been globally approved for the treatment of different types of cancers. Although these drugs showed high efficacy in cancer therapy, EGFR mutations have emerged as a big challenge for these drugs. In this review, we focus on the EGFR small-molecule inhibitors that have been approved for clinical uses in cancer therapy. These drugs are classified based on their chemical structures, target kinases, and pharmacological uses. The synthetic routes of these drugs are also discussed. The crystal structures of these drugs with their target kinases are also summarized and their bonding modes and interactions are visualized. Based on their binding interactions with the EGFR, these drugs are also classified into reversible and irreversible inhibitors. The cytotoxicity of these drugs against different types of cancer cell lines is also summarized. In addition, the proposed metabolic pathways and metabolites of the fourteen drugs are discussed, with a primary focus on the active and reactive metabolites. Taken together, this review highlights the syntheses, target kinases, crystal structures, binding interactions, cytotoxicity, and metabolism of the fourteen globally approved EGFR inhibitors. These data should greatly help in the design of new EGFR inhibitors.

Author(s):  
Christina A. Kirby ◽  
Atwood Cheung ◽  
Aleem Fazal ◽  
Michael D. Shultz ◽  
Travis Stams

The crystal structures of tankyrase 1 (TNKS1) in complex with two small-molecule inhibitors, PJ34 and XAV939, both at 2.0 Å resolution, are reported. The structure of TNKS1 in complex with PJ34 reveals two molecules of PJ34 bound in the NAD+donor pocket. One molecule is in the nicotinamide portion of the pocket, as previously observed in other PARP structures, while the second molecule is bound in the adenosine portion of the pocket. Additionally, unlike the unliganded crystallization system, the TNKS1–PJ34 crystallization system has the NAD+donor site accessible to bulk solvent in the crystal, which allows displacement soaking. The TNKS1–PJ34 crystallization system was used to determine the structure of TNKS1 in complex with XAV939. These structures provide a basis for the start of a structure-based drug-design campaign for TNKS1.


2021 ◽  
Vol 12 ◽  
Author(s):  
Qiang Xie ◽  
Yi Chen ◽  
Huidan Tan ◽  
Bo Liu ◽  
Ling-Li Zheng ◽  
...  

Natural products are well-characterized to have pharmacological or biological activities that can be of therapeutic benefits for cancer therapy, which also provide an important source of inspiration for discovery of potential novel small-molecule drugs. In the past three decades, accumulating evidence has revealed that natural products can modulate a series of key autophagic signaling pathways and display therapeutic effects in different types of human cancers. In this review, we focus on summarizing some representative natural active compounds, mainly including curcumin, resveratrol, paclitaxel, Bufalin, and Ursolic acid that may ultimately trigger cancer cell death through the regulation of some key autophagic signaling pathways, such as RAS-RAF-MEK-ERK, PI3K-AKT-mTOR, AMPK, ULK1, Beclin-1, Atg5 and p53. Taken together, these inspiring findings would shed light on exploiting more natural compounds as candidate small-molecule drugs, by targeting the crucial pathways of autophagy for the future cancer therapy.


2014 ◽  
Vol 70 (a1) ◽  
pp. C631-C631
Author(s):  
Elena Boldyreva

Supramolecular interactions in the solid state attract much attention. Different experimental and computational approaches are used, to predict and to design crystal structures, to predict the properties based on molecular and crystal structures, to range different types of intermolecular interactions. Analysis of the crystal structures at fixed (e.g. ambient) temperature and pressure conditions is most common for experiments, whereas most DFT calculations are limited to 0 K, to minimize computational costs. At the same time, evolution of a crystal structure as a function of experimental conditions can contribute significantly to understanding the structure-forming role and relative energies of different types of intermolecular interactions in the same crystal structure and of similar interactions in a series of different but structurally or chemically related compounds. In the present invited contribution I attempt to illustrate this using several selected examples from my own practice and from the papers published by other research groups. I consider, in particular, the results of variable-temperature and variable-pressure studies of continuous lattice strain and phase transitions in small-molecule organic compounds, the results of variable-temperature and variable-pressure crystallization, the results of comparing the dissolution profiles of mono- and multi-component small-molecule organic crystals. I shall also discuss how variable-temperature and variable-pressure experimental diffraction data can assist in optimizing the calculations aimed at comparing the relative stability of polymorphs and predicting polymorph transitions. The study was supported by Russian Ministry of Science and Education and Russian Academy of Sciences.


Author(s):  
Roufen Chen ◽  
Dandan Yuan ◽  
JunJie Ma

Immunotherapy inhibiting the programmed death-1/programmed death ligand-1 (PD-1/PD-L1) interaction has emerged as one of the most attractive cancer treatment strategies. So far, the clinically used PD-1/PD-L1 inhibitors are monoclonal antibodies, but monoclonal antibodies have several limitations, such as poor pharmacokinetic properties, unchecked immune responses and high production cost. The development of small-molecule inhibitors targeting PD-1/PD-L1 interaction is showing great promise as a potential alternative or complementary therapeutic approach of monoclonal antibodies. In this article, the authors classify the reported biphenyl small-molecule inhibitors into symmetrical and asymmetrical types based on their structural features and further review their representative inhibitors and biological activities, as well as the binding models for providing insight into further exploration of more potent biphenyl small-molecule inhibitors targeting PD-1/PD-L1 interaction.


Author(s):  
Charlotte Dahlem ◽  
Ali Abuhaliema ◽  
Sonja M. Kessler ◽  
Tarek Kröhler ◽  
Ben G. E. Zoller ◽  
...  

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