UPCDC-30245 is an allosteric p97 inhibitor with an IC50 of approximately 27 nM[1]. UPCDC-30245 inhibits the p97 mutant N660K similar to wild type (WT; IC50=300 nM) and shows 3-fold resistance for p97 mutant T688A[2]. UPCDC-30245 can be used in the research of cancer[1][2][3].
UPCDC-30245 binds at the junction between the D1 dan D2 domains of p97[1]. UPCDC-30245 inhibits cell proliferation in HeLa, A549, BxPC-3, PRMI8226, MM1S, HCT116 cells, and appears more potent in HT29 cells[2].UPCDC-30245 (0.01-100 μM) shows anti-proliferative effects on parental and CB-5083 resistant HCT116 cell lines that harbor a new p97 double mutation (D649A/T688A)[2].UPCDC-30245 (4 μm; 2, 6, 10, 18, 24 hours; functional enrichment analysis) is not linked to pathways typically impacted by p97 inhibition, such as protein processing in the ER, UPR, and asparagine N-linked glycosylation[3].
[1]. Banerjee S, et al. 2.3 Å resolution cryo-EM structure of human p97 and mechanism of allosteric inhibition. Science. 2016 Feb 19;351(6275):871-5.
[2]. Wang F, et al. Allosteric p97 Inhibitors Can Overcome Resistance to ATP-Competitive p97 Inhibitors for Potential Anticancer Therapy. ChemMedChem. 2020 Apr 20;15(8):685-694.
[3]. Wang F, et al. Temporal proteomics reveal specific cell cycle oncoprotein downregulation by p97/VCP inhibition. Cell Chem Biol. 2021 Nov 23:S2451-9456(21)00482-7.