Details

Autor(en) / Beteiligte

• Wang, Wei
• Zhuo, Qing-Cui
• Han, Shi-Jie
• Liu, Qian

Titel

QSAR-based targeting anaplastic lymphoma kinase (ALK) variants with noncognate inhibitors in pediatric acute lymphoblastic leukemia

Ist Teil von

• Journal of chemometrics, 2016-12, Vol.30 (12), p.759-765

Ort / Verlag

Chichester: Blackwell Publishing Ltd

Erscheinungsjahr

2016

Quelle

Wiley Online Library

Beschreibungen/Notizen

• 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 ALKwt and cancer‐related variants ALKvt. It is revealed that most noncognate inhibitors exhibit weak potency on ALKwt, but some of them are able to selectively target ALKvt over ALKwt. 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. A chemometrics quantitative structure‐activity relationship predictor was developed to statistically construct a systematic activity profile of noncognate kinase inhibitors against both wild‐type ALKwt and cancer‐related variants ALKvt. Most noncognate inhibitors exhibit weak potency on ALKwt, but some of them are able to selectively target ALKvt over ALKwt. Kinase inhibition analysis reveals that few noncognate inhibitors have higher potency against ALKvt than ALKwt.