Journal of Medicinal Chemistry p. 3915 - 3934 (2020)
Update date:2022-08-15
Topics:
Popova, Gergana
Ladds, Marcus J. G. W.
Johansson, Lars
Saleh, Aljona
Larsson, Johanna
Sandberg, Lars
Sahlberg, Sara H?ggblad
Qian, Weixing
Gullberg, Hjalmar
Garg, Neeraj
Gustavsson, Anna-Lena
Haraldsson, Martin
Lane, David
Yngve, Ulrika
Lain, Sonia
Human dihydroorotate dehydrogenase (DHODH), an enzyme in the de novo pyrimidine synthesis pathway, is a target for the treatment of rheumatoid arthritis and multiple sclerosis and is re-emerging as an attractive target for cancer therapy. Here we describe the optimization of recently identified tetrahydroindazoles (HZ) as DHODH inhibitors. Several of the HZ analogues synthesized in this study are highly potent inhibitors of DHODH in an enzymatic assay, while also inhibiting cancer cell growth and viability and activating p53-dependent transcription factor activity in a reporter cell assay. Furthermore, we demonstrate the specificity of the compounds toward the de novo pyrimidine synthesis pathway through supplementation with an excess of uridine. We also show that induction of the DNA damage marker γ-H2AX after DHODH inhibition is preventable by cotreatment with the pan-caspase inhibitor Z-VAD-FMK. Additional solubility and in vitro metabolic stability profiling revealed compound 51 as a favorable candidate for preclinical efficacy studies.
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