WARNING: This product is for research use only, not for human or veterinary use.
MedKoo CAT#: 202421
Description: RO5045337, also known as RG7112, is a MDM2 antagonist with potential antineoplastic activity. RO5045337 binds to MDM2, thereby preventing the binding of the MDM2 protein to the transcriptional activation domain of the tumor suppressor protein p53. By preventing this MDM2-p53 interaction, the proteosome-mediated enzymatic degradation of p53 is inhibited and the transcriptional activity of p53 is restored, which may result in the restoration of p53 signaling and thus the p53-mediated induction of tumor cell apoptosis. MDM2, a zinc finger protein, is a negative regulator of the p53 pathway; often overexpressed in cancer cells, it has been implicated in cancer cell proliferation and survival.
MedKoo Cat#: 202421
Chemical Formula: C38H48Cl2N4O4S
Exact Mass: 726.27733
Molecular Weight: 726.28
Elemental Analysis: C, 62.71; H, 6.65; Cl, 9.74; N, 7.70; O, 8.79; S, 4.41
Synonym: R7112 RG7112 RG 7112; RG7112; RO5045337; RO 5045337; RO5045337
IUPAC/Chemical Name: ((4S,5R)-2-(4-(tert-butyl)-2-ethoxyphenyl)-4,5-bis(4-chlorophenyl)-4,5-dimethyl-4,5-dihydro-1H-imidazol-1-yl)(4-(3-(methylsulfonyl)propyl)piperazin-1-yl)methanone
InChi Key: QBGKPEROWUKSBK-QPPIDDCLSA-N
InChi Code: InChI=1S/C38H48Cl2N4O4S/c1-8-48-33-26-29(36(2,3)4)14-19-32(33)34-41-37(5,27-10-15-30(39)16-11-27)38(6,28-12-17-31(40)18-13-28)44(34)35(45)43-23-21-42(22-24-43)20-9-25-49(7,46)47/h10-19,26H,8-9,20-25H2,1-7H3/t37-,38+/m0/s1
SMILES Code: O=C(N1[C@](C)(C2=CC=C(Cl)C=C2)[C@](C)(C3=CC=C(Cl)C=C3)N=C1C4=CC=C(C(C)(C)C)C=C4OCC)N5CCN(CCCS(=O)(C)=O)CC5
Appearance: White to off-white 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: Soluble in DMSO, not in water
Shelf Life: >2 years if stored properly
Drug Formulation: This drug may be formulated in DMSO
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
|Biological target:||RG7112 is a potent, selective, first clinical, orally active and blood-brain barrier crossed MDM2-p53 inhibitor, with an IC50 of 18 nM and a KD of 11 nM for binding to MDM2.|
|In vitro activity:||The efficacy of RG7112 in vitro using NB cell lines was examined. Two wild-type (WT)-p53 NB cell lines IMR5 and LAN-5, a mutant p53 cell line SK-N-BE(2), and a WT-p53/p14 deleted cell line SH-EP were employed. Data showed that RG7112 significantly reduced cellular viability of IMR5 (IC50, 562 nM) and LAN-5 (IC50, 430 nM), but not SK-N-BE(2) and SH-EP cells. Further, RG7112 restores p53 and p21 protein levels in IMR5 and LAN-5 in a dose-dependent manner. RG7112 induces cell cycle arresting (60% G1 arresting) in WT-p53 cells (IMR5), but no pronounced effect observed in SK-N-BE(2). Reference: Cancer Biother Radiopharm. 2019 May;34(4):252-257. https://www.liebertpub.com/doi/10.1089/cbr.2018.2732?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%20%200pubmed|
|In vivo activity:||To assess the ability of RG7112 to activate p53 response in vivo, SJSA1 tumor-bearing mice were treated with a single dose of vehicle or 50 to 200 mg/kg RG7112 for 4 to 24 hours (Fig. 5A). Western blot analysis showed a dose-dependent increase in p53 protein and its targets, p21 and MDM2. The p53 protein levels were highest at 4 hours after dose and continue to persist at 24 hours at the highest dose level (200 mg/kg), whereas the duration of p53 modulation was shorter at lower dose levels. In vivo, cell-cycle arrest was assessed by measuring bromodeoxyuridine (BrdUrd) incorporation. SJSA1 tumor-bearing animals were treated with a single dose of vehicle or 50 to 200 mg/kg RG7112 for 8 to 24 hours, and BrdUrd was administered 2 hours before tumor collection. Immunohistochemical detection of BrdUrd incorporation indicated a statistically significant and dose-dependent decrease in proliferating cells at 16 and 24 hours postdosing with RG7112 as compared with vehicle controls (Fig. 5B.). At the highest dose level of RG7112 (200 mg/kg), only 1.2% (± 0.89 SD) of cells incorporated BrdUrd at 24 hours postdosing versus 14% (± 1.83 SD) of vehicle treated tumors, suggesting that RG7112 effectively arrests DNA replication and tumor cell proliferation. To evaluate the ability of RG7112 to elicit apoptosis in vivo, bioluminescent detection of activated caspases 3/7 was monitored in SJSA1-luc2 tumor-bearing mice using Z-DEVD-aminoluciferin as a substrate for activated caspases 3 and 7. When the DEVD peptide sequence is cleaved by activated caspases, aminoluciferin is liberated and can then serve as a substrate for luciferase enzyme produced by SJSA1-luc2 cells. Luminescent signal is thereby emitted only in apoptotic cells. Representative bioluminescent images from mice bearing vehicle and RG7112-treated tumors are shown in Fig. 5C (left). Tumors from mice treated with a single dose of 100 or 200 mg/kg RG7112 produced a statistically significant time-dependent induction in luciferase signal as compared with vehicle controls, indicating that apoptosis was occurring within the tumors (Fig. 5C, right). Daily oral administration of RG7112 inhibited both human osteosarcoma xenografts in a dose-dependent manner with 74% and 69% tumor growth inhibition elicited, respectively, at a daily dose of 50 mg/kg (Fig. 6A and B). At the high dose of 100 mg/kg, the majority of SJSA1 and MHM tumors regressed and the average tumor volume was below the starting volume. Reference: Cancer Res. 2013 Apr 15;73(8):2587-97. http://cancerres.aacrjournals.org/cgi/pmidlookup?view=long&pmid=23400593|
|Solvent||Max Conc. mg/mL||Max Conc. mM|
The following data is based on the product molecular weight 726.28 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|
|In vitro protocol:||1. Al-Ghabkari A, Narendran A. In Vitro Characterization of a Potent p53-MDM2 Inhibitor, RG7112 in Neuroblastoma Cancer Cell Lines. Cancer Biother Radiopharm. 2019 May;34(4):252-257. doi: 10.1089/cbr.2018.2732. Epub 2019 Feb 6. PMID: 30724592. 2. Iancu-Rubin C, Mosoyan G, Glenn K, Gordon RE, Nichols GL, Hoffman R. Activation of p53 by the MDM2 inhibitor RG7112 impairs thrombopoiesis. Exp Hematol. 2014 Feb;42(2):137-45.e5. doi: 10.1016/j.exphem.2013.11.012. Epub 2013 Dec 3. PMID: 24309210.|
|In vivo protocol:||1. Tovar C, Graves B, Packman K, Filipovic Z, Higgins B, Xia M, Tardell C, Garrido R, Lee E, Kolinsky K, To KH, Linn M, Podlaski F, Wovkulich P, Vu B, Vassilev LT. MDM2 small-molecule antagonist RG7112 activates p53 signaling and regresses human tumors in preclinical cancer models. Cancer Res. 2013 Apr 15;73(8):2587-97. doi: 10.1158/0008-5472.CAN-12-2807. Epub 2013 Feb 11. PMID: 23400593. 2. Iancu-Rubin C, Mosoyan G, Glenn K, Gordon RE, Nichols GL, Hoffman R. Activation of p53 by the MDM2 inhibitor RG7112 impairs thrombopoiesis. Exp Hematol. 2014 Feb;42(2):137-45.e5. doi: 10.1016/j.exphem.2013.11.012. Epub 2013 Dec 3. PMID: 24309210.|
1: Ding Q, Zhang Z, Liu JJ, Jiang N, Zhang J, Ross TM, Chu XJ, Bartkovitz D, Podlaski F, Janson C, Tovar C, Filipovic ZM, Higgins B, Glenn K, Packman K, Vassilev LT, Graves B. Discovery of RG7388, a Potent and Selective p53-MDM2 Inhibitor in Clinical Development. J Med Chem. 2013 Jul 16. [Epub ahead of print] PubMed PMID: 23808545.
2: Tovar C, Graves B, Packman K, Filipovic Z, Higgins B, Xia M, Tardell C, Garrido R, Lee E, Kolinsky K, To KH, Linn M, Podlaski F, Wovkulich P, Vu B, Vassilev LT. MDM2 small-molecule antagonist RG7112 activates p53 signaling and regresses human tumors in preclinical cancer models. Cancer Res. 2013 Apr 15;73(8):2587-97. doi: 10.1158/0008-5472.CAN-12-2807. Epub 2013 Feb 11. PubMed PMID: 23400593.
3: Ray-Coquard I, Blay JY, Italiano A, Le Cesne A, Penel N, Zhi J, Heil F, Rueger R, Graves B, Ding M, Geho D, Middleton SA, Vassilev LT, Nichols GL, Bui BN. Effect of the MDM2 antagonist RG7112 on the P53 pathway in patients with MDM2-amplified, well-differentiated or dedifferentiated liposarcoma: an exploratory proof-of-mechanism study. Lancet Oncol. 2012 Nov;13(11):1133-40. doi: 10.1016/S1470-2045(12)70474-6. Epub 2012 Oct 17. PubMed PMID: 23084521.
4: Carol H, Reynolds CP, Kang MH, Keir ST, Maris JM, Gorlick R, Kolb EA, Billups CA, Geier B, Kurmasheva RT, Houghton PJ, Smith MA, Lock RB. Initial testing of the MDM2 inhibitor RG7112 by the Pediatric Preclinical Testing Program. Pediatr Blood Cancer. 2013 Apr;60(4):633-41. doi: 10.1002/pbc.24235. Epub 2012 Jul 2. PubMed PMID: 22753001; PubMed Central PMCID: PMC3495996.
5: Millard M, Pathania D, Grande F, Xu S, Neamati N. Small-molecule inhibitors of p53-MDM2 interaction: the 2006-2010 update. Curr Pharm Des. 2011;17(6):536-59. Review. PubMed PMID: 21391905.