TAK-020

This publication details the successful use of FBDD (fragment-based drug discovery) principles in the invention of a novel covalent Bruton's tyrosine kinase inhibitor, which ultimately became the Takeda Pharmaceuticals clinical candidate TAK-020. Described herein are the discovery of the fragment 5-phenyl-2,4-dihydro-3H-1,2,4-triazol-3-one, the subsequent optimization of this hit molecule to the candidate, and synthesis and performance in pharmacodynamic and efficacy models along with direct biophysical comparison of TAK-020 with other clinical-level assets and the marketed drug Ibrutinib.

An anal. of 156 published/clin. candidates from the Journal of Medicinal Chem. between 2018 and 2021 was conducted to identify lead generation strategies most frequently employed leading to drug candidates.As in a previous publication, the most frequent lead generation strategies resulting in clin. candidates were from known compounds (59%) followed by random screening approaches (21%).The remainder of the approaches included directed screening, fragment screening, DNA-encoded library screening (DEL), and virtual screening.An anal. of similarity was also conducted based on Tanimoto-MCS and revealed most clin. candidates were distant from their original hits; however, most shared a key pharmacophore that translated from hit-to-clin. candidate.An examination of frequency of oxygen, nitrogen, fluorine, chlorine, and sulfur incorporation in clin. candidates was also conducted.The three most similar and least similar hit-to-clin. pairs from random screening were examined to provide perspective on changes that occur that lead to successful clin. candidates.