2. Academic Validation
  3. Discovery of small molecule inhibitors of human uridine-cytidine kinase 2 by high-throughput screening

Discovery of small molecule inhibitors of human uridine-cytidine kinase 2 by high-throughput screening

  • Bioorg Med Chem Lett. 2019 Sep 15;29(18):2559-2564. doi: 10.1016/j.bmcl.2019.08.010.
Ayse Okesli-Armlovich 1,  Amita Gupta 2,  Marta Jimenez 3,  Douglas Auld 3,  Qi Liu 1,  Michael C Bassik 4,  Chaitan Khosla 5
Affiliations

Affiliations

  • 1 Department of Chemistry, Stanford University, Stanford, CA 94305, USA; Stanford ChEM-H, Stanford, CA 94305, USA.
  • 2 Stanford ChEM-H, Stanford, CA 94305, USA; Department of Chemical Engineering, Stanford University, Stanford, CA 94305, USA.
  • 3 Facilitated Access to Screening Technologies (FAST) Laboratory, Novartis Institutes for Biomedical Research, Cambridge, MA 02139, USA.
  • 4 Stanford ChEM-H, Stanford, CA 94305, USA; Department of Genetics, Stanford University, Stanford, CA 94305, USA.
  • 5 Department of Chemistry, Stanford University, Stanford, CA 94305, USA; Stanford ChEM-H, Stanford, CA 94305, USA; Department of Chemical Engineering, Stanford University, Stanford, CA 94305, USA. Electronic address: [email protected].
PMID: 31420268 DOI: 10.1016/j.bmcl.2019.08.010
Abstract

Clinically relevant inhibitors of Dihydroorotate Dehydrogenase (DHODH), a rate-limiting Enzyme in mammalian de novo pyrimidine synthesis, have strong Antiviral and Anticancer activity in vitro. However, they are ineffective in vivo due to efficient uridine salvage by infected or rapidly dividing cells. The pyrimidine salvage Enzyme uridine-cytidine kinase 2 (UCK2), a ∼29 kDa protein that forms a tetramer in its active state, is necessary for uridine salvage. Notwithstanding the pharmacological potential of this target, no medicinally tractable inhibitors of the human Enzyme have been reported to date. We therefore established and miniaturized an in vitro assay for UCK2 activity and undertook a high-throughput screen against a ∼40,000-compound library to generate drug-like leads. The structures, activities, and modes of inhibition of the most promising hits are described. Notably, our screen yielded non-competitive UCK2 inhibitors which were able to suppress nucleoside salvage in cells both in the presence and absence of DHODH inhibitors.

Keywords

DHODH inhibitor; De novo pyrimidine synthesis; GSK983; High-throughput screening; Pyrimidine processing inhibitors; Pyrimidine salvage; Uridine; Uridine-cytidine kinase.

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