LASSBio Chemical Library Diversity and FLT3 New Ligand Identification

Abstract

This account describes the analysis of the Laboratory of Evaluation and Synthesis of Bioactive Substances (LASSBio) chemical library as a valuable resource for early drug discovery studies. LASSBio has been using medicinal chemistry strategies for almost 30 years to design new prototype compounds with a focus on pharmacological activity. The LASSBio Chemical Library (LCL) is a collection of more than 2000 compounds, and the aim of this work was to characterize its chemical diversity and to perform a molecular repositioning study to identify ligands of feline McDonough sarcoma (FMS)-like tyrosine kinase 3 (FLT3), a validated target for leukemia treatment. To achieve this, cheminformatic tools were utilized to analyze the chemical diversity of the LCL. The analysis allowed the identification of the most representative compounds of this collection, showing that the N-acylhydrazone chemotype is present in approximately 50% of the compounds. Furthermore, the compounds in this chemical library demonstrated remarkable compliance with both the Lipinski’s (93% of the compounds) and Veber’s (96% of the compounds) rules. In the study on molecular repositioning, 10 compounds were selected through virtual screening to test their enzymatic inhibition of FLT3 kinase. Among them, 4-((6,7-dimethoxyquinazolin-4-yl)amino) benzamide (LASSBio-2166) (31) showed a half-maximal inhibitory concentration (IC50) = 194 nM. Optimization of the identified hit and further studies to compare the diversity of the LCL with other libraries are perspectives of this work.