The discovery & development of new drugs is a highly costly and slow process, while repositioning old drugs to treat other diseases is increasingly becoming an attractive proposition1. In this context and at the interface between drug repositioning and drug design, we have applied our integrative multidisciplinary fragment-based drug design approach, ‘DOTS’. We have deconstructed an existing drug -masitinib- originally targeting a protein tyrosine kinase, c-kit, and (re)optimized it against a new target, the deoxycytidine kinase (dCK), a nucleotide kinase involved in the pyrimidine biosynthesis (salvage) pathway. Our lead compound -OR0642- in combination with a physiological inhibitor of the de novo pathway, deoxythymidin (dT), doubled the survival rate in a human T-cell Acute Lymphoblastic Leukemia patient-derived xenograft mouse model, demonstrating the proof-of-concept of this mixed strategy2.
1- Hammam K, Saez-Ayala M et al. Nature Communications 2017. (PMID 29127277)
2- Saez-Ayala M et al. Nature Communications, in press.
Published on May 2, 2023