Anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase, predominantly expressed in specific regions of the central and peripheral nervous systems, that plays an important role in the genesis and differentiation of the nervous system. Aberrantly expressed ALK tyrosine kinase is involved in the pathogenesis of diverse malignancies. 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). Activity of cancer-specific ALK variants is a prerequisite for tumor maintenance and the majority 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 by the ligand-based approach. It comprises over 2,500 drug-like screening compounds of potential anaplastic lymphoma kinase inhibitors.
At the first step, a reference set of 8,892 bioactive compounds with reported activity against ALK (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 (Fig 1). Reactive, toxic, and PAINS molecules were excluded from the Screening Library. Ro5 compliance is indicated for each compound.
Figure 1. Example of representative analogues selected using the reference compound set for the ALK Tyrosine Kinase Focused Library.
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