From a drug repositioning to a structure-based drug design approach to tackle acute lymphoblastic leukemia

Abstract

Cancer cells utilize the main de novo pathway and the alternative salvage pathway for deoxyribonucleotide biosynthesis to achieve adequate nucleotide pools. Deoxycytidine kinase is the rate-limiting enzyme of the salvage pathway and it has recently emerged as a target for anti-proliferative therapies for cancers where it is essential. Here, we present the development of a potent inhibitor applying an iterative multidisciplinary approach, which relies on computational design coupled with experimental evaluations. This strategy allows an acceleration of the hit-to-lead process by gradually implementing key chemical modifications to increase affinity and activity. Our lead compound, OR0642, is more than 1000 times more potent than its initial parent compound, masitinib, previously identified from a drug repositioning approach. OR0642 in combination with a physiological inhibitor of the de novo pathway doubled the survival rate in a human T-cell acute lymphoblastic leukemia patient-derived xenograft mouse model, demonstrating the proof-of-concept of this drug design strategy.

Therapies from Thiopeptides

“…It was thus necessary to enhance the anti-dCK potency of masitinib almost 10,000 fold! A medicinal chemistry effort relying on advanced computational, crystallographic, and calorimetric methods, as well as a great deal of sophisticated organic synthesis, transmogrified masitinib into 56, a 2 nM dCK inhibitor with appropriate pharmacological, toxicity, and selectivity properties [40]. The progression from 50 to 56 is summarized in Scheme 13.…”

ChemoDOTS: a web server to design chemistry-driven focused libraries

“…The final library undergoes virtual screening with the S4MPLE tool ( 37 , 38 ) to identify the best putative optimizations, aiming to create additional favorable contacts while maintaining the original binding mode. The DOTS approach has been successfully applied to various targets including the zika virus NS5 protein ( 39 ), syntenin PDZ domain protein ( 40–42 ), bromodomain-containing protein 4, BRD4 ( 43 ) and, more recently, a nucleotide kinase, dCK ( 44 ).…”