Drug Discovery in the Kinase Inhibitory Field Using the Nested Chemical Library™ Technology

Abstract

Kinase inhibitors are at the forefront of modern drug research, where mostly three technologies are used for hit-and-lead finding: high throughput screening of random libraries, three-dimensional structure-based drug design based on X-ray data, and focused libraries around limited number of new cores. Our novel Nested Chemical Library (NCL) (Vichem Chemie Research Ltd., Budapest, Hungary) technology is based on a knowledge base approach, where focused libraries around selected cores are used to generate pharmacophore models. NCL was designed on the platform of a diverse kinase inhibitory library organized around 97 core structures. We have established a unique, proprietary kinase inhibitory chemistry around these core structures with small focused sublibraries around each core. All the compounds in our NCL library are stored in a big unified Structured Query Language database along with their measured and calculated physicochemical and ADME/toxicity (ADMET) properties, together with thousands of molecular descriptors calculated for each compound. Biochemical kinase inhibitory assays on selected, cloned kinase enzymes for a few hundred NCL compound sets can provide sufficient biological data for rational computerized design of new analogues, based on our pharmacophore model-generating 3DNET4W QSPAR (quantitative structure-property/activity relationships) approach. Using this pharmacophore modeling approach and the ADMET filters, we can preselect synthesizable compounds for hit-and-lead optimization. Starting from this point and integrating the information from QSPAR, high-quality leads can be generated within a small number of optimization cycles. Applying NCL technology we have developed lead compounds for several validated kinase targets.

AXL Is a Potential Target for Therapeutic Intervention in Breast Cancer Progression

“…Based on the results of the target validation experiments with breast cancer cell lines, we initiated efforts to identify small molecular kinase inhibitors with selective activity on the AXL tyrosine kinase. In attempts to identify lead compounds, we applied the Nested Chemical Library technology, which is a novel hit and lead finding method for rational drug design of kinase inhibitors, developed by Keri et al (29). The Nested Chemical Library was designed on the and invasivity (right ) of MCF7 breast cancer cells stably overexpressing wtAXL or control vector were analyzed by Boyden chamber migration and invasion assays, respectively, for 36 h toward medium containing 10% FCS as a chemoattractant.…”

Lead selection and characterization of antitubercular compounds using the Nested Chemical Library

“…All the compounds screened in this study belong to the Nested Chemical Library™ (NCL) of Vichem Chemie Research Ltd., which contains more than 19,000 molecules organized around 110 core structures and more than 600 scaffolds, including most of the published clinically and pre-clinically relevant kinase inhibitors and new, patentable compounds as well [17,18].…”

“…The lysosomal transfer assay and the macrophages infection assay were performed as previously described [16,17].…”

Novel compounds reducing IRS-1 serine phosphorylation for treatment of diabetes

“…18 We have screened Vichem's EVL library for JNK inhibition. Two compound families were identified to be druglike and suitable for optimization.…”

“…The stress response of RINm5F rat insulinoma cells, including JNK, c-Jun and IRS-1 Ser307 phosphorylations, to short term saturated fatty acid treatment, has been studied earlier in our laboratory. 18 In this study, the levels of P-JNK and P-IRS-1 were assessed in the cells after incubation in the presence of 500 µM albumin-conjugated palmitate for 8 hr. JNK phosphorylation was inhibited to less than 50% of palmitate only treatment by two of the investigated kinase inhibitors, 27 and 18 (54% and 59% inhibition, respectively) (Fig 3).…”