TY - JOUR
T1 - Small-Molecule Allosteric Inhibitors of Human Aspartate Transcarbamoylase Suppress Proliferation of Bone Osteosarcoma Epithelial Cells
AU - Wang, Chao
AU - Zhang, Bidong
AU - Cong, Yingying
AU - Du, Xiaochen
AU - Chen, Siyao
AU - Visser, Lidia
AU - Ruiz-Moreno, Angel
AU - Zhang, Lili
AU - Reggiori, Fulvio
AU - Alexander, Domling
AU - Groves, Matthew Robert
N1 - © 2024 Wiley‐VCH GmbH.
PY - 2024/7/2
Y1 - 2024/7/2
N2 - Aspartate transcarbamoylase (ATC) is the first committed step in de novo pyrimidine biosynthesis in eukaryotes and plants. A potent transition state analog of human ATCase (PALA) has previously been assessed in clinical trials for the treatment of cancer, but was ultimately unsuccessful. Additionally, inhibition of this pathway has been proposed to be a target to suppress cell proliferation in E. coli, the malarial parasite and tuberculosis. In this manuscript we screened a 70-member library of ATC inhibitors developed against the malarial and tubercular ATCases for inhibitors of the human ATC. Four compounds showed low nanomolar inhibition (IC50 30-120 nM) in an in vitro activity assay. These compounds significantly outperform PALA, which has a triphasic inhibition response under identical conditions, in which significant activity remains at PALA concentrations above 10 μM. Evidence for a druggable allosteric pocket in human ATC is provided by both in vitro enzyme kinetic, homology modeling and in silico docking. These compounds also suppress the proliferation of U2OS osteoblastoma cells by promoting cell cycle arrest in G0/G1 phase. This report provides the first evidence for an allosteric pocket in human ATC, which greatly enhances its druggability and demonstrates the potential of this series in cancer therapy.
AB - Aspartate transcarbamoylase (ATC) is the first committed step in de novo pyrimidine biosynthesis in eukaryotes and plants. A potent transition state analog of human ATCase (PALA) has previously been assessed in clinical trials for the treatment of cancer, but was ultimately unsuccessful. Additionally, inhibition of this pathway has been proposed to be a target to suppress cell proliferation in E. coli, the malarial parasite and tuberculosis. In this manuscript we screened a 70-member library of ATC inhibitors developed against the malarial and tubercular ATCases for inhibitors of the human ATC. Four compounds showed low nanomolar inhibition (IC50 30-120 nM) in an in vitro activity assay. These compounds significantly outperform PALA, which has a triphasic inhibition response under identical conditions, in which significant activity remains at PALA concentrations above 10 μM. Evidence for a druggable allosteric pocket in human ATC is provided by both in vitro enzyme kinetic, homology modeling and in silico docking. These compounds also suppress the proliferation of U2OS osteoblastoma cells by promoting cell cycle arrest in G0/G1 phase. This report provides the first evidence for an allosteric pocket in human ATC, which greatly enhances its druggability and demonstrates the potential of this series in cancer therapy.
KW - Aspartate Transcarbamoylase
KW - Molecular Docking
KW - Non-competitive Inhibition
KW - Osteosarcoma
KW - Pyrimidine Biosynthesis
UR - http://www.scopus.com/inward/record.url?scp=85193727434&partnerID=8YFLogxK
U2 - 10.1002/cmdc.202300688
DO - 10.1002/cmdc.202300688
M3 - Journal article
C2 - 38602859
SN - 1860-7179
VL - 19
SP - e202300688
JO - ChemMedChem
JF - ChemMedChem
IS - 13
M1 - e202300688
ER -