Deoxyribonucleotide triphosphates (dNTPs) are essential for tumor growth, and DNA replication and repair also is essential dNTPs. Parallel and convergent de novo and salvage pathways redundantly produce the same dNTPs using different substrates. The de novo pathway produces dNTPs from glucose and amino acids and is dependent upon ribonucleotide reductase (RNR). 3AP can block RNR for anticancer therapy. However, tumors develop resistance through upregulation of salvage pathways which produce dNTPs from preformed deoxyribonucleosides present in the extracellular environment. Deoxycytidine kinase (dCK), a salvage pathway enzyme, phosphorylates preformed deoxycytidine to its monophosphate form (dCMP). It is a key precursor for the production of both deoxycytidine triphosphate (dCTP) and thymidine triphosphate (dTTP). DI-39 can inhibit tumor growth when given in combination therapy with thymidine to mice with acute lymphoblastic leukemia (ALL) xenografts. In this study, DI-87 is a dCK inhibitor and is more soluble and metabolically stable than DI-39.
DI-87 rescues human cell line CCRF-CEM (CEM) cells from the anti-proliferative effects of gemcitabine, a dCK-dependent nucleoside analog prodrug, with an EC50 of 10.2 nM. (S)-DI-87 exhibits a much higher IC50 value (468 nM) relative to DI-87 (3.15 nM) in CEM T-ALL cells for the inhibition of dCK activity. DI-87 also exhibits full dCK inhibition for 27 hours, and enzyme activity fully recovered by 36 hours with 25 mg/kg dose. Meanwhile, DI-87 has plasma concentrations of between 1 and 3 hours and plasma half-life of 4 hours. In addition, it with thymidine results in reduced tumor growth in male NSG mice implanted with CEM tumors.
In summary, dCK is an intriguing target in anti-cancer therapy. DI-87, as a dCK inhibitor, is a promising new compound for use in combination therapy against tumors expressing dCK.
Reference:
Soumya Poddar, et al.Biochem Pharmacol. 2020 Feb;172:113742.