The anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase that is aberrant in a variety of malignancies. ALK tyrosine kinase is predominantly expressed in specific regions of the central and peripheral nervous systems and plays an important role in the genesis and differentiation of the nervous system. The ALK gene transforming rearrangements, mutation, and amplification have been discovered in cancers of 17 organs, including anaplastic large-cell lymphoma, papillary thyroid carcinoma, neuroblastoma, ovarian cancer, head and neck cancer, as well as non-small-cell lung cancer (neXtProt database). The activity of cancer-specific ALK variants is required for tumor maintenance and most of activating mutations occur within the TyrKc domain (SMART: SM000219). Furthermore, ALK TK inhibitors are used as first- or second-line treatment in metastatic NSCLC patients with ALK rearrangement, and some of them are in different phases of clinical trials.
Considering the above-mentioned evidence, Life Chemicals has designed its proprietary ALK Tyrosine Kinase Focused Library (2,500 compounds) of potential ALK inhibitors by the ligand-based approach.
At the first step, a reference set of 8,892 compounds with known activity against ALK tyrosine kinase (IC50, Ki, etc., ≤ 10 µM, Inhibition > 50 %) was prepared based on data from PubChem and ChEMBL databases. The Life Chemicals HTS Compound Collection was searched for structural analogs of the compounds from the reference set, using several 2D similarity methods (MDL public keys; long-range functional class fingerprint – FCFP) and the 75 % Tanimoto and Tversky similarity cut-off. Reactive, toxic or PAINS compounds were excluded and Ro5 compliance is indicated for each selected compound.
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