RPN13 Inhibitor, RA190

A cell-permeable bis-benzylidine piperidone that covalently modifies RPN13/ADRM1 via Michael addition between its electrophilic enone and the nucleophilic RPN13 Cys88, most likely freeing pleckstrin-like receptor for ubiquitin (Pru) domain from intramolecular interaction with the UCH37-binding domain and thereby allowing non-proteasome-associated RPN13 to compete against proteasome 19S regulatory particle- (RP-) incorporated RPN13 for ubiquitinated substrates binding, without affecting RPN13 RP assembly, 20S core particle (CP) proteolytic activities, or the deubiquitinase activity of UCH37 or RP. RPN13 blockage not only prevents many pro-apoptotic factors from degradation, the buildup of cellular ubiquitinated proteins in general also effectively triggers ER unfold protein response (UPR), accounting for the observed RA190 anticancer activity, notably in Multiple Myeloma (IC₅₀ in nM = 35/MM.1S, 50/NCI-H929, 75/ANBL6,100/RPMI-8226), HPV+ cervical cancer (IC₅₀ in nM = 150/HeLa, 300/CasKi, 750/HiHa), and HPV16-transformed oral keratinocyte HOK-16B (IC₅₀ = 600 nM) cultures. RA190 is bioavailable via either oral or intraperitoneal administration in mice with tissue distribution in blood and major organs except brain and effectively inhibits NCI-H929 (20 mg/kg/d, i.p.), ES-2 (10 mg/kg/d, i.p.), and TC-1 (40 mg/kg/72 h, p.o.) tumor growths, as well as prevents 4UbFL reporter degradation in skin via topical application in mice in vivo without signs of adverse effects to animals or compromised host immune response. Synergizes with the 20S CP proteolytic activity inhibitor Bortezomib (Cat. No. 504314 ) in HeLa killing and is active against Bortezomib-resistant RPMI-8226-V10R and ANBL6-V10R cultures.

Cell permeable: yes

Primary Target
RPN13/ADRM1

Reversible: no

Following reconstitution, aliquot and freeze (-20°C). Stock solutions are stable for up to 3 months at -20°C.

Use only fresh DMSO for reconstitution

Anchoori, R.K., et al. 2013. Cancer Cell.24, 791.

CALBIOCHEM is a registered trademark of Merck KGaA, Darmstadt, Germany

Toxicity: Standard Handling (A)