Identification of Triazolothiadiazoles as Potent Inhibitors of the dCTP Pyrophosphatase 1.
The dCTP pyrophosphatase 1 (dCTPase) is involved in the regulation of the cellular dNTP pool and has been linked to cancer progression. Here we report on the discovery of a series of 3,6-disubstituted triazolothiadiazoles as potent dCTPase inhibitors. Compounds 16 and 18 display good correlation between enzymatic inhibition and target engagement, together with efficacy in a cellular synergy model, deeming them as a promising starting point for hit-to-lead development.
Department of Medical Biochemistry and Biophysics, Science for Life Laboratory, Division of Translational Medicine and Chemical Biology, Karolinska Institutet , 17121 Stockholm, Sweden.
Sabin
0000-0003-3187-722X
S
Llona-Minguez
Department of Medical Biochemistry and Biophysics, Science for Life Laboratory, Division of Translational Medicine and Chemical Biology, Karolinska Institutet , 17121 Stockholm, Sweden.
Andreas
A
Höglund
Department of Medical Biochemistry and Biophysics, Science for Life Laboratory, Division of Translational Medicine and Chemical Biology, Karolinska Institutet , 17121 Stockholm, Sweden.
Elisee
E
Wiita
Department of Medical Biochemistry and Biophysics, Science for Life Laboratory, Division of Translational Medicine and Chemical Biology, Karolinska Institutet , 17121 Stockholm, Sweden.
Ingrid
I
Almlöf
Uppsala University Drug Optimization and Pharmaceutical Profiling Platform (UDOPP), Department of Pharmacy, Science for Life Laboratory, Uppsala University , 75123 Uppsala, Sweden.
André
A
Mateus
Department of Medical Biochemistry and Biophysics, Science for Life Laboratory, Division of Translational Medicine and Chemical Biology, Karolinska Institutet , 17121 Stockholm, Sweden.
José Manuel
JM
Calderón-Montaño
Department of Medical Biochemistry and Biophysics, Science for Life Laboratory, Division of Translational Medicine and Chemical Biology, Karolinska Institutet , 17121 Stockholm, Sweden.
Cindy
C
Cazares-Körner
Department of Medical Biochemistry and Biophysics, Science for Life Laboratory, Division of Translational Medicine and Chemical Biology, Karolinska Institutet , 17121 Stockholm, Sweden.
Evert
E
Homan
Department of Medical Biochemistry and Biophysics, Science for Life Laboratory, Division of Translational Medicine and Chemical Biology, Karolinska Institutet , 17121 Stockholm, Sweden.
Olga
O
Loseva
Department of Medical Biochemistry and Biophysics, Science for Life Laboratory, Division of Translational Medicine and Chemical Biology, Karolinska Institutet , 17121 Stockholm, Sweden.|Uppsala University Drug Optimization and Pharmaceutical Profiling Platform (UDOPP), Department of Pharmacy, Science for Life Laboratory, Uppsala University , 75123 Uppsala, Sweden.
Pawel
P
Baranczewski
Department of Medical Biochemistry and Biophysics, Science for Life Laboratory, Division of Translational Medicine and Chemical Biology, Karolinska Institutet , 17121 Stockholm, Sweden.
Ann-Sofie
AS
Jemth
RNAi Cell Screening Facility, Department of Biochemistry and Biophysics, Science for Life Laboratory, Stockholm University , S-10691 Stockholm, Sweden.
Maria
M
Häggblad
RNAi Cell Screening Facility, Department of Biochemistry and Biophysics, Science for Life Laboratory, Stockholm University , S-10691 Stockholm, Sweden.
Ulf
U
Martens
RNAi Cell Screening Facility, Department of Biochemistry and Biophysics, Science for Life Laboratory, Stockholm University , S-10691 Stockholm, Sweden.
Bo
B
Lundgren
Uppsala University Drug Optimization and Pharmaceutical Profiling Platform (UDOPP), Department of Pharmacy, Science for Life Laboratory, Uppsala University , 75123 Uppsala, Sweden.
Per
P
Artursson
Department of Medical Biochemistry and Biophysics, Science for Life Laboratory, Division of Translational Medicine and Chemical Biology, Karolinska Institutet , 17121 Stockholm, Sweden.|Chemical Biology Consortium Sweden, and Department of Medical Biochemistry and Biophysics, Science for Life Laboratory, Division of Translational Medicine and Chemical Biology, Karolinska Institutet, 17121 Stockholm, Sweden.
Thomas
T
Lundbäck
Department of Medical Biochemistry and Biophysics, Science for Life Laboratory, Division of Translational Medicine and Chemical Biology, Karolinska Institutet , 17121 Stockholm, Sweden.|Chemical Biology Consortium Sweden, and Department of Medical Biochemistry and Biophysics, Science for Life Laboratory, Division of Translational Medicine and Chemical Biology, Karolinska Institutet, 17121 Stockholm, Sweden.
Annika
A
Jenmalm Jensen
Department of Medical Biochemistry and Biophysics, Science for Life Laboratory, Division of Translational Medicine and Chemical Biology, Karolinska Institutet , 17121 Stockholm, Sweden.
Ulrika
U
Warpman Berglund
Department of Medical Biochemistry and Biophysics, Science for Life Laboratory, Division of Translational Medicine and Chemical Biology, Karolinska Institutet , 17121 Stockholm, Sweden.
Martin
M
Scobie
Department of Medical Biochemistry and Biophysics, Science for Life Laboratory, Division of Translational Medicine and Chemical Biology, Karolinska Institutet , 17121 Stockholm, Sweden.
Thomas
T
Helleday
D004791:Enzyme Inhibitors / Q000494:pharmacology*; D057166:High-Throughput Screening Assays; D006801:Humans; D062105:Molecular Docking Simulation; D011755:Pyrophosphatases / Q000037:antagonists & inhibitors*; D013830:Thiadiazoles / Q000494:pharmacology*
D004791:Enzyme Inhibitors; D013830:Thiadiazoles; D011755:Pyrophosphatases; C020007:dCTP pyrophosphatase