Publication — IRIC

Discovery of Benzodiazepine-Based Inhibitors of the E2 Enzyme UBCH10 from a Cell-Based p21 Degradation Screen.

p21Cip1 (p21) is a universal cyclin-dependent kinase (CDK) inhibitor that halts cell proliferation and tumor growth by multiple mechanisms. The expression of p21 is often downregulated in cancer cells as a result of the loss of function of transcriptional activators, such as p53, or the increased degradation rate of the protein. To identify small molecules that block the ubiquitin-mediated degradation of p21 as a future avenue for cancer drug discovery, we have screened a compound library using a cell-based reporter assay of p21 degradation. This led to the identification of a benzodiazepine series of molecules that induce the accumulation of p21 in cells. Using a chemical proteomic strategy, we identified the ubiquitin-conjugating enzyme UBCH10 as a cellular target of this benzodiazepine series. We show that an optimized benzodiazepine analogue inhibits UBCH10 ubiquitin-conjugating activity and substrate proteolysis by the anaphase-promoting complex.

Date de publication
19 mai 2023
Pelletier B, Duhamel S, Tambutet G, Jarvis S, Cléroux P, David M, Tanguay PL, Voisin L, James C, Lavoie R, Gareau Y, Flynn-Robitaille J, Lorca T, Ruel R, Marinier A, Meloche S
Référence PubMed
ACS Chem Biol 2023;18(5):1039-1046
ID PubMed
Institute for Research in Immunology and Cancer, Montreal, Quebec H3C 3J7, Canada.