Importance of protein flexibility in molecular recognition: a case study on Type-I1/2 inhibitors of ALK

2018 ◽  
Vol 20 (7) ◽  
pp. 4851-4863 ◽  
Author(s):  
Xiaotian Kong ◽  
Huiyong Sun ◽  
Peichen Pan ◽  
Feng Zhu ◽  
Shan Chang ◽  
...  
Keyword(s):  
Molecular Recognition ◽  
Anaplastic Lymphoma Kinase ◽  
Protein Flexibility ◽  
Anaplastic Lymphoma ◽  
Promising Target

Anaplastic lymphoma kinase (ALK) has been regarded as a promising target for the therapy of various cancers.

scholarly journals Inhibition of Plasmodium falciparum Lysyl-tRNA synthetase via an anaplastic lymphoma kinase inhibitor

2020 ◽  
Vol 48 (20) ◽  
pp. 11566-11576
Author(s):  
Jintong Zhou ◽  
Zhenghui Huang ◽  
Li Zheng ◽  
Zhoufei Hei ◽  
Zhiyong Wang ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Anaplastic Lymphoma Kinase ◽  
Kinase Inhibitor ◽  
B Cell Lymphoma ◽  
Trna Synthetase ◽  
Human Diseases ◽  
Anaplastic Lymphoma Kinase Inhibitor ◽  
Anaplastic Lymphoma ◽  
Mechanism Of Inhibition ◽  
Promising Target

Abstract Aminoacyl-tRNA synthetases are attractive targets for the development of antibacterial, antifungal, antiparasitic agents and for the treatment of other human diseases. Lysyl-tRNA synthetase (LysRS) from this family has been validated as a promising target for the development of antimalarial drugs. Here, we developed a high-throughput compatible assay and screened 1215 bioactive compounds to identify Plasmodium falciparum cytoplasmic LysRS (PfLysRS) inhibitor. ASP3026, an anaplastic lymphoma kinase inhibitor that was used in clinical trials for the treatment of B-cell lymphoma and solid tumors, was identified as a novel PfLysRS inhibitor. ASP3026 suppresses the enzymatic activity of PfLysRS at nanomolar potency, which is >380-fold more effective than inhibition of the human counterpart. In addition, the compound suppressed blood-stage P. falciparum growth. To understand the molecular mechanism of inhibition by ASP3026, we further solved the cocrystal structure of PfLysRS-ASP3026 at a resolution of 2.49 Å, providing clues for further optimization of the compound. Finally, primary structure-activity relationship analyses indicated that the inhibition of PfLysRS by ASP3026 is highly structure specific. This work not only provides a new chemical scaffold with good druggability for antimalarial development but also highlights the potential for repurposing kinase-inhibiting drugs to tRNA synthetase inhibitors to treat human diseases.

scholarly journals Sinonasal Inflammatory Myofibroblastic Tumor with Anaplastic Lymphoma Kinase 1 Rearrangement: Case Study and Literature Review

2016 ◽  
Vol 11 (2) ◽  
pp. 131-138 ◽  
Author(s):  
Ghizlene Lahlou ◽  
Marion Classe ◽  
Michel Wassef ◽  
Pierre-Alexandre Just ◽  
Nicolas Le Clerc ◽  
...  
Keyword(s):  
Literature Review ◽  
Anaplastic Lymphoma Kinase ◽  
Inflammatory Myofibroblastic Tumor ◽  
Anaplastic Lymphoma

Anaplastic Lymphoma Kinase in Human Cancer

2012 ◽  
Vol 17 (2) ◽  
pp. 123-143 ◽  
Author(s):  
Christina Schonherr ◽  
Bengt Hallberg ◽  
Ruth Palmer
Keyword(s):  
Anaplastic Lymphoma Kinase ◽  
Human Cancer ◽  
Anaplastic Lymphoma
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