Piperazin-1-ylpyridazine Derivatives Are a Novel Class of Human dCTP Pyrophosphatase 1 Inhibitors

The
dCTP pyrophosphatase 1 (dCTPase) is a nucleotide pool “housekeeping”
enzyme responsible for the catabolism of canonical and noncanonical
nucleoside triphosphates (dNTPs) and has been associated with cancer
progression and cancer cell stemness. We have identified a series
of piperazin-1-ylpyridazines as a new class of potent dCTPase inhibitors.
Lead compounds increase dCTPase thermal and protease stability, display
outstanding selectivity over related enzymes and synergize with a
cytidine analogue against leukemic cells. This new class of dCTPase
inhibitors lays the first stone toward the development of drug-like
probes for the dCTPase enzyme.