UPCDC30245

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].

UPCDC30245 is an allosteric inhibitor of AAA ATPase p97, also called valosine containing protein (VCP). p97 is an integral component of the ubiquitin fusion degradation (UFD) pathway. It plays a role in degradation of misfolded proteins, Golgi membrane reassembly, membrane transport, myofibril assembly, autophagosome maturation, and cell division, and is overexpressed in many tumor types. UPCDC30245 has an IC50 value of 27 nM, and has been shown to bind at the junction between the D1 and D2 domains of p97. UPCDC30245 has been used in cryo-ECM to show how such inhibitor binding prevents the confomational changes necessary for p97 function.

allosteric p97: 27 nM (IC₅₀); wild type p97: 300 nM (IC₅₀)

[1] Banerjee S, et al. 2.3 resolution cryo-EM structure of human p97 and mechanism of allosteric inhibition. Science. 2016 Feb 19;351(6275):871-5. DOI:10.1126/science.aad7974
[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. DOI:10.1002/cmdc.201900722
[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. DOI:10.1016/j.chembiol.2021.11.005