PYR41

PYR41 is an irreversible inhibitor of ubiquitin-activating enzyme (E1) with an IC₅₀ value of less than 10 µM.¹ PYR41 specifically inhibits ubiquitin-thioester bond formation (IC₅₀ = 6.4 µM) and not adenylation.² It is selective for E1 over ubiquitin-conjugating enzyme (E2) but does inhibit autoubiquitination of the HECT domain ubiquitin protein ligase (E3) Nedd4 at a concentration of 50 µM in an autoubiquitination assay.¹ It inhibits proteasome-dependent and -independent ubiquitination and protein degradation when used at a concentration of 50 µM. PYR41 prevents activation of NF-κB, ubiquitination of TNF receptor-associated factor 6 (TRAF6), and proteasomal degradation of IκBα. It prevents degradation and induces transcriptional activity of the tumor suppressor p53 and preferentially induces apoptosis of E1A-transformed RPE cells expressing wild-type p53 over non-transformed RPE cells when used at concentrations ranging from 1 to 20 µM. PYR41 also increases net cellular sumoylation and irreversibly cross-links proteins such as JAK2 and Bcr-Abl.^1,3

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1. Yang, Y., Kitagaki, J., Dai, R.M., et al. Inhibitors of ubiquitin-activating enzyme (E₁), a new class of potential cancer therapeutics. Cancer Res. 67(19), 9472-9481 (2007).

2. Ungermannova, D., Parker, P.J., Nasveschuk, C.G., et al. Identification and mechanistic studies of a novel ubiquitin E₁ inhibitor. J. Biomol. Screen. 17(4), 421-434 (2012).

3. Kapuria, V., Peterson, L.F., Showalter, H.D., et al. Protein cross-linking as a novel mechanism of action of a ubiquitin-activating enzyme inhibitor with anti-tumor activity. Biochem. Pharmacol. 83(4), 341-349 (2011).