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QSAR‐based targeting anaplastic lymphoma kinase (ALK) variants with noncognate inhibitors in pediatric acute lymphoblastic leukemia
Author(s) -
Wang Wei,
Zhuo QingCui,
Han ShiJie,
Liu Qian
Publication year - 2016
Publication title -
journal of chemometrics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.47
H-Index - 92
eISSN - 1099-128X
pISSN - 0886-9383
DOI - 10.1002/cem.2857
Subject(s) - anaplastic lymphoma kinase , alk inhibitor , kinase , lymphoma , cancer research , medicine , chemistry , oncology , lung cancer , biochemistry , malignant pleural effusion
Human anaplastic lymphoma kinase (ALK) is a potential target for the treatment of pediatric acute lymphoblastic leukemia. However, a number of residue mutations in ALK kinase domain have been observed to cause drug resistance in pediatric acute lymphoblastic leukemia chemotherapy. Here, a chemometrics quantitative structure‐activity relationship predictor was developed using a structure‐based panel of kinase‐inhibitor activity data. The predictor was validated rigorously through internal cross‐validation and external blind test to ensure its statistical reliability, which was then used to computationally construct a systematic activity profile of 13 noncognate kinase inhibitors against both wild‐type ALK wt and cancer‐related variants ALK vt . It is revealed that most noncognate inhibitors exhibit weak potency on ALK wt , but some of them are able to selectively target ALK vt over ALK wt . The chemometrics findings were then evaluated by using a kinase inhibition protocol; results showed that few noncognate inhibitors are 2‐ to 5‐fold higher potent against ALK variant than wild‐type kinase.