RA190 forms a covalent bond with cysteine 88 on the RPN13 ubiquitin receptor within the 19S regulatory particle, leading to proteasome inhibition and a swift build-up of polyubiquitinated proteins. It is effective against multiple myeloma (MM) cell lines, including those that are bortezomib-resistant, by inducing apoptosis through endoplasmic reticulum stress. Additionally, RA190 impedes the degradation of human papillomavirus (HPV) E6 oncoprotein targets, resulting in the selective elimination of HPV-transformed cells[1].
RA190 细胞实验
Cell Line
Concentration
Treated Time
Description
References
MM.1S cells
0.5 µM
6 hours
RA190 treatment elevated Bax protein levels
Cancer Cell. 2013 Dec 9;24(6):791-805
SK-MEL-5 cells
30 µM
1 hour
To assess the alkylation activity of RA190 in cell lysates, results showed that RA190 can alkylate multiple proteins, exhibiting broad alkylation activity.
Cell Chem Biol. 2020 Nov 19;27(11):1371-1382. e6
HeLa cells
1 µM
1 hour
To assess the alkylation of Rpn13 by RA190, results showed that RA190 can alkylate Rpn13 but not selectively at the C88 site.
Cell Chem Biol. 2020 Nov 19;27(11):1371-1382. e6
MM.1S cells
300 nM
12 hours
RA190 triggered caspase-3, caspase-8, and caspase-9-mediated apoptotic signaling cascades.
Leukemia. 2016 Sep;30(9):1877-86
ANBL6.BR cells
300 nM
12 hours
RA190 decreased expression of G2/M-phase cell-cycle regulatory proteins CDC25C, CDC2, and cyclin B1.
Leukemia. 2016 Sep;30(9):1877-86
HepG2
1 µM or 2 µM
12 hours
To evaluate the effect of RA190 on the levels of polyubiquitinated proteins in HepG2 cells, the results showed that RA190 treatment significantly increased the levels of polyubiquitinated proteins in a dose-dependent manner.
BMC Cancer. 2020 May 6;20(1):386
HeLa cells
1 µM
12 hours
RA190 treatment leads to a block in DNA replication and cell cycle arrest in G2, and induces apoptosis.
J Biol Chem. 2016 Apr 15;291(16):8773-83
ANBL6.BR cells
500 nM
16 hours
To evaluate the effect of WL40 in bortezomib-resistant cells. Results showed that WL40 induced RPN13 degradation.
Leukemia. 2019 Nov;33(11):2685-2694
RPMI-8226 cells
500 nM
16 hours
To evaluate the effect of WL40 in p53-mutated cells. Results showed that WL40 induced RPN13 degradation.
Leukemia. 2019 Nov;33(11):2685-2694
CRBN-knockout MM.1S cells
500 nM
16 hours
To confirm the requirement of CRBN for WL40 function. Results showed that WL40 did not decrease Rpn13 levels in CRBN-KO cells.
Leukemia. 2019 Nov;33(11):2685-2694
MM.1S cells
500 nM
16 hours
To analyze intracellular alterations in Rpn13 using flow cytometry. Results showed that WL40 treatment significantly reduced Rpn13 expression.
Leukemia. 2019 Nov;33(11):2685-2694
HCT116 ΔUCHL5
1 µM
24 hours
Evaluate the effect of RA190 on ubiquitinated protein accumulation, showing RA190 treatment caused accumulation in ΔUCHL5 cells
Mol Cell Biol. 2020 Aug 28;40(18):e00122-20
HCT116
1 µM
24 hours
Evaluate the effect of RA190 on ubiquitinated protein accumulation, showing RA190 treatment caused accumulation in WT cells but was attenuated in trRpn13 cells
Mol Cell Biol. 2020 Aug 28;40(18):e00122-20
MM.1S cells
300 nM
24 hours
RA190 significantly increased both early and late apoptotic cell populations, as assessed by Annexin V/PI double staining.
Leukemia. 2016 Sep;30(9):1877-86
MM.1S cells
300 nM
24 hours
RA190 induced significant G2/M-phase growth arrest, with a concomitant increase in the S phase, and decreased expression of G2/M-phase cell-cycle regulatory proteins CDC25C, CDC2, and cyclin B1.
Leukemia. 2016 Sep;30(9):1877-86
U266
>10 µM
24 hours
To evaluate the antiproliferative effects of RA190 on multiple myeloma cell lines
Front Immunol. 2023 Mar 2;14:982720
OPM-2
>10 µM
24 hours
To evaluate the antiproliferative effects of RA190 on multiple myeloma cell lines
Front Immunol. 2023 Mar 2;14:982720
KMS12BM
>10 µM
24 hours
To evaluate the antiproliferative effects of RA190 on multiple myeloma cell lines
Front Immunol. 2023 Mar 2;14:982720
NCI-H929
>10 µM
24 hours
To evaluate the antiproliferative effects of RA190 on multiple myeloma cell lines
Front Immunol. 2023 Mar 2;14:982720
MM1S
>10 µM
24 hours
To evaluate the antiproliferative effects of RA190 on multiple myeloma cell lines
Front Immunol. 2023 Mar 2;14:982720
RPMI-R5
>10 µM
24 hours
To evaluate the antiproliferative effects of RA190 on multiple myeloma cell lines
Front Immunol. 2023 Mar 2;14:982720
RPMI-8226
>10 µM
24 hours
To evaluate the antiproliferative effects of RA190 on multiple myeloma cell lines
Front Immunol. 2023 Mar 2;14:982720
ANBL6-WT and ANBL6-BR cells
1.25 µM
24 hours
RA190 showed anti-MM activity in both bortezomib-sensitive and -resistant cells and reduced SOD1 levels
Leukemia. 2021 Feb;35(2):550-561
MM.1S cells
0.25 µM
24 hours
RA190 significantly downregulated SOD1 expression (2.6-fold decrease) and triggered cytotoxicity
Leukemia. 2021 Feb;35(2):550-561
CaSki cells
1 µM
4 hours
RA190 treatment caused accumulation of K48-linked polyubiquitinated proteins
Cancer Cell. 2013 Dec 9;24(6):791-805
HeLa cells
1 µM
4 hours
RA190 treatment caused accumulation of K48-linked polyubiquitinated proteins
Cancer Cell. 2013 Dec 9;24(6):791-805
Ovarian cancer cell lines
1.2–2.3 µM (IC50)
48 hours
Evaluate sensitivity of RA190 across ovarian cancer cell lines, all lines were sensitive to RA190
J Ovarian Res. 2017 Aug 7;10(1):53
HepG2
0.15 µM
72 hours
To evaluate the cytotoxic effect of RA190 on HepG2 cells, the results showed that the IC50 of RA190 was 0.15 μM, significantly lower than that of sorafenib (9.7 μM).
BMC Cancer. 2020 May 6;20(1):386
RA190 动物实验
Species
Animal Model
Administration
Dosage
Frequency
Description
References
CB-17 SCID mice
Human plasmacytoma MM.1S xenograft model
Intraperitoneal injection
15 mg/kg
Two times weekly for 18 days
RA190 inhibited MM tumor growth and prolonged survival of mice, with good tolerability. Tumor analysis showed increased PARP cleavage, caspase-7 activation, and polyubiquitylation.
Leukemia. 2016 Sep;30(9):1877-86
Mice
NOG mice carrying NCI-H929-GFP-luc human tumor cells
Intraperitoneal injection
20 mg/kg
Once per day for 7 days
RA190 significantly inhibited tumor growth
Cancer Cell. 2013 Dec 9;24(6):791-805
Nude mice
Orthotopic HCC xenograft model
Intraperitoneal injection
20 mg/kg
Once daily for 21 days
To evaluate the therapeutic effect of RA190 in an orthotopic HCC xenograft model, the results showed that RA190 significantly reduced tumor growth.
BMC Cancer. 2020 May 6;20(1):386
RA190 动物研究
Animal study
RA190 is distributed throughout the plasma and most major organs, with the exception of the brain, and it disrupts proteasome activity in the skin and muscle. The administration of RA190 significantly diminishes the growth of multiple myeloma and ovarian cancer xenografts. Moreover, oral administration of RA190 slows down the growth of HPV16+ syngeneic mouse tumors without affecting the natural HPV-specific CD8+ T cell responses[1].
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