RA190 | CAS#1617495-03-0 | Rpn13 inhibitor

MedKoo Cat#: 533301 | Name: RA190 HCl

Description:

WARNING: This product is for research use only, not for human or veterinary use.

RA190 is a potent Rpn13 inhibitor and ADRM1 inhibitor, suppressing intrahepatic cholangiocarcinoma by inducing NF-kappaB-mediated cell apoptosis.

Chemical Structure

RA190 HCl

CAS#1617495-03-0 (HCl)

Theoretical Analysis

MedKoo Cat#: 533301

Name: RA190 HCl

CAS#: 1617495-03-0 (HCl)

Chemical Formula: C28H23Cl5N2O2

Exact Mass: 0.0000

Molecular Weight: 596.75

Elemental Analysis: C, 56.36; H, 3.89; Cl, 29.70; N, 4.69; O, 5.36

Price and Availability

Size	Price	Availability
50mg	USD 550.00	2 Weeks
100mg	USD 1,050.00	2 Weeks
200mg	USD 1,850.00	2 Weeks
500mg	USD 3,650.00	2 Weeks

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Related CAS #

1617572-02-7 (free base) 1617495-03-0 (HCl)

Synonym

RA190; RA-190; RA 190; RA190 HCl; RA190 hydrochloride

IUPAC/Chemical Name

1-(L-Phenylalanyl)-3,5-bis((E)-3,4-dichlorobenzylidene)piperidin-4-one hydrochloride

InChi Key

UMWXLEVUBFNYIK-VXWDMQPRSA-N

InChi Code

InChI=1S/C28H22Cl4N2O2.ClH/c29-22-8-6-18(12-24(22)31)10-20-15-34(28(36)26(33)14-17-4-2-1-3-5-17)16-21(27(20)35)11-19-7-9-23(30)25(32)13-19;/h1-13,26H,14-16,33H2;1H/b20-10+,21-11+;/t26-;/m0./s1

SMILES Code

O=C1/C(CN(C([C@H](CC2=CC=CC=C2)N)=O)C/C1=C\C3=CC=C(Cl)C(Cl)=C3)=C/C4=CC=C(Cl)C(Cl)=C4.[H]Cl

Appearance

Solid powder

Purity

>98% (or refer to the Certificate of Analysis)

Shipping Condition

Shipped under ambient temperature as non-hazardous chemical. This product is stable enough for a few weeks during ordinary shipping and time spent in Customs.

Storage Condition

Dry, dark and at 0 - 4 C for short term (days to weeks) or -20 C for long term (months to years).

Solubility

To be determined

Shelf Life

>3 years if stored properly

Drug Formulation

To be determined

Stock Solution Storage

0 - 4 C for short term (days to weeks), or -20 C for long term (months).

HS Tariff Code

2934.99.9001

More Info

Product Data

Product Data

Instruction

View handling instruction

Biological target:

RA190 HCl is a salt. RA190 treatment inhibits proteasome function by covalently binding to cysteine 88 of RPN1, causing rapid accumulation of polyubiquitinated proteins. RA190 has therapeutic activity in a xenograft model, and with sorafenib exhibited synergetic killing of HCC cells in vitro.

In vitro activity:

This study found that RA190 triggers rapid accumulation of polyubiquitinated proteins, unresolved endoplasmic reticulum stress, and cell death via apoptosis. Treatment of mice bearing an orthotopic HCC model with RA190 significantly reduced tumor growth. Further exploration of RA190/ sorafenib combination treatment of HCC is warranted. Reference: BMC Cancer. 2020 May 6;20(1):386. https://pubmed.ncbi.nlm.nih.gov/32375699/

In vivo activity:

A190 suppressed cell proliferation and colony formation by hepatocellular carcinoma (HCC) cells in a concentration-dependent manner. This study revealed that targeting ADRM1 blocked the G2/M transition in the cell cycle and induced apoptosis of HCC cells. The results indicated that ADRM1 inhibitors, such as RA190, have the potential for clinical application in the treatment of HCC. Reference: J Med Sci. 2021 Jan;37(1):47-54. https://pubmed.ncbi.nlm.nih.gov/32916039/

Preparing Stock Solutions

The following data is based on the product molecular weight 596.75 Batch specific molecular weights may vary from batch to batch due to the degree of hydration, which will affect the solvent volumes required to prepare stock solutions.

Concentration / Solvent Volume / Mass	1 mg	5 mg	10 mg
1 mM	1.15 mL	5.76 mL	11.51 mL
5 mM	0.23 mL	1.15 mL	2.3 mL
10 mM	0.12 mL	0.58 mL	1.15 mL
50 mM	0.02 mL	0.12 mL	0.23 mL

Formulation protocol:

1. Soong RS, Anchoori RK, Roden RBS, Cho RL, Chen YC, Tseng SC, Huang YL, Liao PC, Shyu YC. Bis-benzylidine Piperidone RA190 treatment of hepatocellular carcinoma via binding RPN13 and inhibiting NF-κB signaling. BMC Cancer. 2020 May 6;20(1):386. doi: 10.1186/s12885-020-06896-0. PMID: 32375699; PMCID: PMC7201939. 2. Dickson P, Abegg D, Vinogradova E, Takaya J, An H, Simanski S, Cravatt BF, Adibekian A, Kodadek T. Physical and Functional Analysis of the Putative Rpn13 Inhibitor RA190. Cell Chem Biol. 2020 Nov 19;27(11):1371-1382.e6. doi: 10.1016/j.chembiol.2020.08.007. Epub 2020 Aug 27. PMID: 32857985; PMCID: PMC7680414. 3. Liang YC, Wang JL, Wang HT, Liu H, Zhang HL, Liang YX. ADRM1 as a therapeutic target in hepatocellular carcinoma. Kaohsiung J Med Sci. 2021 Jan;37(1):47-54. doi: 10.1002/kjm2.12298. Epub 2020 Sep 11. PMID: 32916039. 4. Du T, Song Y, Ray A, Chauhan D, Anderson KC. Proteomic analysis identifies mechanism(s) of overcoming bortezomib resistance via targeting ubiquitin receptor Rpn13. Leukemia. 2021 Feb;35(2):550-561. doi: 10.1038/s41375-020-0865-2. Epub 2020 May 18. PMID: 32424294; PMCID: PMC7988682.

In vitro protocol:

In vivo protocol:

1. Liang YC, Wang JL, Wang HT, Liu H, Zhang HL, Liang YX. ADRM1 as a therapeutic target in hepatocellular carcinoma. Kaohsiung J Med Sci. 2021 Jan;37(1):47-54. doi: 10.1002/kjm2.12298. Epub 2020 Sep 11. PMID: 32916039. 2. Du T, Song Y, Ray A, Chauhan D, Anderson KC. Proteomic analysis identifies mechanism(s) of overcoming bortezomib resistance via targeting ubiquitin receptor Rpn13. Leukemia. 2021 Feb;35(2):550-561. doi: 10.1038/s41375-020-0865-2. Epub 2020 May 18. PMID: 32424294; PMCID: PMC7988682.

1: Zhu M, Cao Z, Mo F, Shi S, Hu J, Xu Q, Quan K, Liang J, Li W, Hong X, Zhang B, Liu X, Dai M. ADRM1/RPN13 attenuates cartilage extracellular matrix degradation via enhancing UCH37-mediated ALK5 deubiquitination. Int J Biol Macromol. 2023 Aug 30;247:125670. doi: 10.1016/j.ijbiomac.2023.125670. Epub 2023 Jul 3. PMID: 37406898. 2: Anchoori RK, Anchoori V, Lam B, Tseng SH, Das S, Velasquez FC, Karanam B, Poddatoori D, Patnam R, Rudek MA, Chang YN, Roden RBS. Development and anticancer properties of Up284, a spirocyclic candidate ADRM1/RPN13 inhibitor. PLoS One. 2023 Jun 14;18(6):e0285221. doi: 10.1371/journal.pone.0285221. PMID: 37315065; PMCID: PMC10266688. 3: Waad Sadiq Z, Brioli A, Al-Abdulla R, Çetin G, Schütt J, Murua Escobar H, Krüger E, Ebstein F. Immunogenic cell death triggered by impaired deubiquitination in multiple myeloma relies on dysregulated type I interferon signaling. Front Immunol. 2023 Mar 2;14:982720. doi: 10.3389/fimmu.2023.982720. PMID: 36936919; PMCID: PMC10018035. 4: Lee D, Goldberg AL. 26S proteasomes become stably activated upon heat shock when ubiquitination and protein degradation increase. Proc Natl Acad Sci U S A. 2022 Jun 21;119(25):e2122482119. doi: 10.1073/pnas.2122482119. Epub 2022 Jun 15. PMID: 35704754; PMCID: PMC9231471. 5: Anchoori RK, George L, Tseng SH, Lam B, Polkampally S, Amiano AD, Foran P, Tsingine H, Samanapally H, Carrizo Velasquez F, Das S, Xing D, Bin Salam A, Karanam B, Hung CF, Roden RBS. Chirality and asymmetry increase the potency of candidate ADRM1/RPN13 inhibitors. PLoS One. 2021 Sep 10;16(9):e0256937. doi: 10.1371/journal.pone.0256937. PMID: 34506530; PMCID: PMC8432795. 6: Bazzaro M, Linder S. Dienone Compounds: Targets and Pharmacological Responses. J Med Chem. 2020 Dec 24;63(24):15075-15093. doi: 10.1021/acs.jmedchem.0c00812. Epub 2020 Nov 4. PMID: 33146523; PMCID: PMC7770821. 7: Liang YC, Wang JL, Wang HT, Liu H, Zhang HL, Liang YX. ADRM1 as a therapeutic target in hepatocellular carcinoma. Kaohsiung J Med Sci. 2021 Jan;37(1):47-54. doi: 10.1002/kjm2.12298. Epub 2020 Sep 11. PMID: 32916039. 8: Dickson P, Abegg D, Vinogradova E, Takaya J, An H, Simanski S, Cravatt BF, Adibekian A, Kodadek T. Physical and Functional Analysis of the Putative Rpn13 Inhibitor RA190. Cell Chem Biol. 2020 Nov 19;27(11):1371-1382.e6. doi: 10.1016/j.chembiol.2020.08.007. Epub 2020 Aug 27. PMID: 32857985; PMCID: PMC7680414. 9: Osei-Amponsa V, Sridharan V, Tandon M, Evans CN, Klarmann K, Cheng KT, Lack J, Chari R, Walters KJ. Impact of Losing hRpn13 Pru or UCHL5 on Proteasome Clearance of Ubiquitinated Proteins and RA190 Cytotoxicity. Mol Cell Biol. 2020 Aug 28;40(18):e00122-20. doi: 10.1128/MCB.00122-20. PMID: 32631902; PMCID: PMC7459265. 10: Du T, Song Y, Ray A, Chauhan D, Anderson KC. Proteomic analysis identifies mechanism(s) of overcoming bortezomib resistance via targeting ubiquitin receptor Rpn13. Leukemia. 2021 Feb;35(2):550-561. doi: 10.1038/s41375-020-0865-2. Epub 2020 May 18. PMID: 32424294; PMCID: PMC7988682. 11: Soong RS, Anchoori RK, Roden RBS, Cho RL, Chen YC, Tseng SC, Huang YL, Liao PC, Shyu YC. Bis-benzylidine Piperidone RA190 treatment of hepatocellular carcinoma via binding RPN13 and inhibiting NF-κB signaling. BMC Cancer. 2020 May 6;20(1):386. doi: 10.1186/s12885-020-06896-0. PMID: 32375699; PMCID: PMC7201939. 12: Sherman DJ, Li J. Proteasome Inhibitors: Harnessing Proteostasis to Combat Disease. Molecules. 2020 Feb 5;25(3):671. doi: 10.3390/molecules25030671. PMID: 32033280; PMCID: PMC7037493. 13: Anchoori RK, Tan M, Tseng SH, Peng S, Soong RS, Algethami A, Foran P, Das S, Wang C, Wang TL, Liang H, Hung CF, Roden RBS. Structure-function analyses of candidate small molecule RPN13 inhibitors with antitumor properties. PLoS One. 2020 Jan 15;15(1):e0227727. doi: 10.1371/journal.pone.0227727. PMID: 31940398; PMCID: PMC6961910. 14: Ray A, Song Y, Chauhan D, Anderson KC. Blockade of ubiquitin receptor Rpn13 in plasmacytoid dendritic cells triggers anti-myeloma immunity. Blood Cancer J. 2019 Aug 12;9(8):64. doi: 10.1038/s41408-019-0224-6. PMID: 31406111; PMCID: PMC6690908. 15: Song Y, Park PMC, Wu L, Ray A, Picaud S, Li D, Wimalasena VK, Du T, Filippakopoulos P, Anderson KC, Qi J, Chauhan D. Development and preclinical validation of a novel covalent ubiquitin receptor Rpn13 degrader in multiple myeloma. Leukemia. 2019 Nov;33(11):2685-2694. doi: 10.1038/s41375-019-0467-z. Epub 2019 Apr 8. PMID: 30962579; PMCID: PMC6783320. 16: Anchoori RK, Jiang R, Peng S, Soong RS, Algethami A, Rudek MA, Anders N, Hung CF, Chen X, Lu X, Kayode O, Dyba M, Walters KJ, Roden RBS. Covalent Rpn13-Binding Inhibitors for the Treatment of Ovarian Cancer. ACS Omega. 2018 Sep 30;3(9):11917-11929. doi: 10.1021/acsomega.8b01479. Epub 2018 Sep 27. PMID: 30288466; PMCID: PMC6166221. 17: Yu GY, Wang X, Zheng SS, Gao XM, Jia QA, Zhu WW, Lu L, Jia HL, Chen JH, Dong QZ, Lu M, Qin LX. RA190, a Proteasome Subunit ADRM1 Inhibitor, Suppresses Intrahepatic Cholangiocarcinoma by Inducing NF-KB-Mediated Cell Apoptosis. Cell Physiol Biochem. 2018;47(3):1152-1166. doi: 10.1159/000490210. Epub 2018 Jun 15. PMID: 29913454. 18: Jiang RT, Yemelyanova A, Xing D, Anchoori RK, Hamazaki J, Murata S, Seidman JD, Wang TL, Roden RBS. Early and consistent overexpression of ADRM1 in ovarian high-grade serous carcinoma. J Ovarian Res. 2017 Aug 7;10(1):53. doi: 10.1186/s13048-017-0347-y. PMID: 28784174; PMCID: PMC5547474. 19: Lu X, Nowicka U, Sridharan V, Liu F, Randles L, Hymel D, Dyba M, Tarasov SG, Tarasova NI, Zhao XZ, Hamazaki J, Murata S, Burke TR Jr, Walters KJ. Structure of the Rpn13-Rpn2 complex provides insights for Rpn13 and Uch37 as anticancer targets. Nat Commun. 2017 Jun 9;8:15540. doi: 10.1038/ncomms15540. PMID: 28598414; PMCID: PMC5494190. 20: Soong RS, Anchoori RK, Yang B, Yang A, Tseng SH, He L, Tsai YC, Roden RB, Hung CF. RPN13/ADRM1 inhibitor reverses immunosuppression by myeloid-derived suppressor cells. Oncotarget. 2016 Oct 18;7(42):68489-68502. doi: 10.18632/oncotarget.12095. PMID: 27655678; PMCID: PMC5340091.