Idasanutlin | RG7388 | CAS#1229705-06-9 | p53-MDM2 Inhibitor

MedKoo Cat#: 205917 | Name: Idasanutlin (RG7388)

Description:

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

Idasanutlin, also known as RG7388 and RO5503781, is a highly potent and selective MDM2 antagonist with potential anticancer activity. RG7388 binds to MDM2 blocking the interaction between the MDM2 protein and the transcriptional activation domain of the tumor suppressor protein p53. By preventing the MDM2-p53 interaction, p53 is not enzymatically degraded and the transcriptional activity of p53 is restored. This may lead to p53-mediated induction of tumor cell apoptosis. MDM2, a zinc finger nuclear phosphoprotein and negative regulator of the p53 pathway, is often overexpressed in cancer cells and has been implicated in cancer cell proliferation and survival.

Chemical Structure

Idasanutlin (RG7388)

CAS#1229705-06-9

Theoretical Analysis

MedKoo Cat#: 205917

Name: Idasanutlin (RG7388)

CAS#: 1229705-06-9

Chemical Formula: C31H29Cl2F2N3O4

Exact Mass: 615.1503

Molecular Weight: 616.48

Elemental Analysis: C, 60.40; H, 4.74; Cl, 11.50; F, 6.16; N, 6.82; O, 10.38

Price and Availability

Size	Price	Availability
10mg	USD 90.00	Ready to ship
50mg	USD 250.00	Ready to ship
100mg	USD 450.00	Ready to ship
200mg	USD 750.00	Ready to ship
500mg	USD 1,650.00	Ready to ship
1g	USD 2,950.00	Ready to ship
2g	USD 5,250.00	Ready to Ship

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Related CAS #

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Synonym

RG7388; RG 7388; RG-7388; RO5503781; RO-5503781; RO 5503781; Idasanutlin.

IUPAC/Chemical Name

4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoic acid.

InChi Key

TVTXCJFHQKSQQM-LJQIRTBHSA-N

InChi Code

InChI=1S/C31H29Cl2F2N3O4/c1-30(2,3)14-24-31(15-36,19-10-9-17(32)13-21(19)34)25(18-6-5-7-20(33)26(18)35)27(38-24)28(39)37-22-11-8-16(29(40)41)12-23(22)42-4/h5-13,24-25,27,38H,14H2,1-4H3,(H,37,39)(H,40,41)/t24-,25-,27+,31-/m0/s1

SMILES Code

O=C(O)C1=CC=C(NC([C@@H]2N[C@@H](CC(C)(C)C)[C@](C#N)(C3=CC=C(Cl)C=C3F)[C@H]2C4=CC=CC(Cl)=C4F)=O)C(OC)=C1

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

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

More Info

Product Data

Product Data

Certificate of Analysis

View CoA: current batch, Lot#A21T12K04

View CoA: current batch, Lot#A8T04K17

QC Data

View QC data: current batch, Lot#A8T04K17

View QC data: current batch, Lot#A21T12K04

Safety Data Sheet (SDS)

View Safety Data Sheet (SDS)

Instruction

View handling instruction

Biological target:

Idasanutlin (RG-7388) is a potent and selective p53-MDM2 inhibitor with IC50 of 6 nM showing improved in vitro binding as well as cellular potency/selectivity.

In vitro activity:

Short-term treatment with 100 nmol/L RG7388 inhibited clonogenicity in p53 wild-type glioblastoma cell lines (U87MG and A172, Fig. 1A and Supplementary Fig. S1A) and p53 wild-type glioma-initiating cell cultures (GICs; Supplementary T1, Supplementary Fig. S24, Fig. 1A), whereas p53 mutant (LN18, LN428, U318, U373; Supplementary Fig. S1A) and p53-deficient cell lines (LN308) were primary resistant against RG7388 treatment in a concentration of 100 nmol/L (Supplementary Fig. S1A). In p53 wild-type glioblastoma cell lines (U87MG, A172) and GICs (T1, S24), RG7388 led to a significant and dose-dependent reduction of clonogenicity and proliferation [Fig. 1A; Supplementary Fig. S2, left panel (“no RT”) of each graph]. In U87MG cells, RG7388 induced protein levels of p53 target genes, such as p21 and MDM2 (Supplementary Fig. S1B), apoptosis (Supplementary Fig. S1C), and a G1 arrest (Supplementary Fig. S1D). Reference: Clin Cancer Res. 2019 Jan 1;25(1):253-265. http://clincancerres.aacrjournals.org/cgi/pmidlookup?view=long&pmid=30274984

In vivo activity:

As shown in Figure 5a,b, the group treated with RG7388 for 12 days showed significantly suppressed tumor growth from 0.17 to 1.88 cm3, whereas the group treated with vehicle grew from 0.16 to 1.28 cm3. The tumor weights in the RG7388 group were approximately 40% less than those in the vehicle group. The HE staining of tumor tissue sections was revealed a clear difference of proliferating tumor cells in vivo. The data (Figure 5c) showed that the number of nuclear fission tumor cells in RG7388 group was decreased significantly than the control group. The ability of RG7388 to induce cellular arrest or apoptosis was also examined. The levels of the cell proliferation marker Ki-67 and apoptotic marker cleaved caspase-3 were measured in 5-8F tumors after dosing with a single 25 mg/kg dose and compared to the results following vehicle treatment alone. The results (Figure 5d,e) revealed significantly reduced numbers of Ki-67+-positive tumor cells and cleaved caspase-3+- stained cells were significantly increased in RG7388-treated tumors compareing in the controls. Reference: Cancer Biol Ther. 2019;20(10):1328-1336. https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/31311404/

	Solvent	mg/mL	mM
Solubility
	DMSO	45.0	73.00

Note: There can be variations in solubility for the same chemical from different vendors or different batches from the same vendor. The following factors can affect the solubility of the same chemical: solvent used for crystallization, residual solvent content, polymorphism, salt versus free form, degree of hydration, solvent temperature. Please use the solubility data as a reference only. Warming and sonication will facilitate dissolving. Still have questions? Please contact our Technical Support scientists.

Preparing Stock Solutions

The following data is based on the product molecular weight 616.48 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. Fan X, Wang Y, Song J, Wu H, Yang M, Lu L, Weng X, Liu L, Nie G. MDM2 inhibitor RG7388 potently inhibits tumors by activating p53 pathway in nasopharyngeal carcinoma. Cancer Biol Ther. 2019;20(10):1328-1336. doi: 10.1080/15384047.2019.1638677. Epub 2019 Jul 16. PMID: 31311404; PMCID: PMC6783115. 2. Berberich A, Kessler T, Thomé CM, Pusch S, Hielscher T, Sahm F, Oezen I, Schmitt LM, Ciprut S, Hucke N, Ruebmann P, Fischer M, Lemke D, Breckwoldt MO, von Deimling A, Bendszus M, Platten M, Wick W. Targeting Resistance against the MDM2 Inhibitor RG7388 in Glioblastoma Cells by the MEK Inhibitor Trametinib. Clin Cancer Res. 2019 Jan 1;25(1):253-265. doi: 10.1158/1078-0432.CCR-18-1580. Epub 2018 Oct 1. PMID: 30274984. 3. Higgins B, Glenn K, Walz A, Tovar C, Filipovic Z, Hussain S, Lee E, Kolinsky K, Tannu S, Adames V, Garrido R, Linn M, Meille C, Heimbrook D, Vassilev L, Packman K. Preclinical optimization of MDM2 antagonist scheduling for cancer treatment by using a model-based approach. Clin Cancer Res. 2014 Jul 15;20(14):3742-52. doi: 10.1158/1078-0432.CCR-14-0460. Epub 2014 May 8. PMID: 24812409.

In vitro protocol:

In vivo protocol:

1: Alzahrani A, Natarajan U, Rathinavelu A. Enhancement of MDM2 inhibitory effects through blocking nuclear export mechanisms in ovarian cancer cells. Cancer Genet. 2022 Aug;266-267:57-68. doi: 10.1016/j.cancergen.2022.06.003. Epub 2022 Jun 11. PMID: 35785714. 2: Wang Q, Li J, Zhu J, Mao J, Duan C, Liang X, Zhu L, Zhu M, Zhang Z, Lin F, Guo R. Genome-wide CRISPR/Cas9 screening for therapeutic targets in NSCLC carrying wild-type TP53 and receptor tyrosine kinase genes. Clin Transl Med. 2022 Jun;12(6):e882. doi: 10.1002/ctm2.882. PMID: 35692096; PMCID: PMC9189421. 3: Bortot B, Romani A, Ricci G, Biffi S. Exploiting Extracellular Vesicles Strategies to Modulate Cell Death and Inflammation in COVID-19. Front Pharmacol. 2022 May 20;13:877422. doi: 10.3389/fphar.2022.877422. PMID: 35668941; PMCID: PMC9164251. 4: Smiley SB, Zarrinmayeh H, Das SK, Pollok KE, Vannier MW, Veronesi MC. Novel therapeutics and drug-delivery approaches in the modulation of glioblastoma stem cell resistance. Ther Deliv. 2022 Apr;13(4):249-273. doi: 10.4155/tde-2021-0086. Epub 2022 May 26. PMID: 35615860. 5: Chang X, Cheng X, Wang CJ. Catalytic asymmetric synthesis of enantioenriched α-deuterated pyrrolidine derivatives. Chem Sci. 2022 Mar 17;13(14):4041-4049. doi: 10.1039/d2sc00826b. PMID: 35440992; PMCID: PMC8985513. 6: Zhang S, Yan Z, Li Y, Gong Y, Lyu X, Lou J, Zhang D, Meng X, Zhao Y. Structure-Based Discovery of MDM2/4 Dual Inhibitors that Exert Antitumor Activities against MDM4-Overexpressing Cancer Cells. J Med Chem. 2022 Apr 28;65(8):6207-6230. doi: 10.1021/acs.jmedchem.2c00095. Epub 2022 Apr 14. PMID: 35420431. 7: Konopleva MY, Röllig C, Cavenagh J, Deeren D, Girshova L, Krauter J, Martinelli G, Montesinos P, Schäfer JA, Ottmann O, Petrini M, Pigneux A, Rambaldi A, Recher C, Rodriguez-Veiga R, Taussig D, Vey N, Yoon SS, Ott M, Muehlbauer S, Beckermann BM, Catalani O, Genevray M, Mundt K, Jamois C, Fenaux P, Wei AH. Idasanutlin plus cytarabine in relapsed or refractory acute myeloid leukemia: results of the MIRROS trial. Blood Adv. 2022 Jul 26;6(14):4147-4156. doi: 10.1182/bloodadvances.2021006303. PMID: 35413116; PMCID: PMC9327534. 8: Hohtari H, Kankainen M, Adnan-Awad S, Yadav B, Potdar S, Ianevski A, Dufva O, Heckman C, Sexl V, Kytölä S, Mustjoki S, Porkka K. Targeting Apoptosis Pathways With BCL2 and MDM2 Inhibitors in Adult B-cell Acute Lymphoblastic Leukemia. Hemasphere. 2022 Feb 24;6(3):e701. doi: 10.1097/HS9.0000000000000701. PMID: 35233509; PMCID: PMC8878725. 9: Alimova I, Wang D, Danis E, Pierce A, Donson A, Serkova N, Madhavan K, Lakshmanachetty S, Balakrishnan I, Foreman NK, Mitra S, Venkataraman S, Vibhakar R. Targeting the TP53/MDM2 axis enhances radiation sensitivity in atypical teratoid rhabdoid tumors. Int J Oncol. 2022 Mar;60(3):32. doi: 10.3892/ijo.2022.5322. Epub 2022 Feb 18. PMID: 35179215; PMCID: PMC8878716. 10: Chamberlain V, Drew Y, Lunec J. Tipping Growth Inhibition into Apoptosis by Combining Treatment with MDM2 and WIP1 Inhibitors in p53WT Uterine Leiomyosarcoma. Cancers (Basel). 2021 Dec 21;14(1):14. doi: 10.3390/cancers14010014. PMID: 35008180; PMCID: PMC8750798. 11: Umehara K, Cleary Y, Fowler S, Parrott N, Tuerck D. Accelerating Clinical Development of Idasanutlin through a Physiologically Based Pharmacokinetic Modeling Risk Assessment for CYP450 Isoenzyme-Related Drug-Drug Interactions. Drug Metab Dispos. 2022 Mar;50(3):214-223. doi: 10.1124/dmd.121.000720. Epub 2021 Dec 22. PMID: 34937801. 12: Mascarenhas J, Passamonti F, Burbury K, El-Galaly TC, Gerds A, Gupta V, Higgins B, Wonde K, Jamois C, Kovic B, Huw LY, Katakam S, Maffioli M, Mesa R, Palmer J, Bellini M, Ross DM, Vannucchi AM, Yacoub A. The MDM2 antagonist idasanutlin in patients with polycythemia vera: results from a single-arm phase 2 study. Blood Adv. 2022 Feb 22;6(4):1162-1174. doi: 10.1182/bloodadvances.2021006043. PMID: 34933330; PMCID: PMC8864654. 13: Zhang X, Zhang R, Ren C, Xu Y, Wu S, Meng C, Pataer A, Song X, Zhang J, Yao Y, He H, Chen H, Ma W, Wang J, Meric-Bernstam F, Champlin RE, Heymach JV, Rooney CM, Swisher SG, Vaporciyan AA, Roth JA, You MJ, Wang M, Fang B. Epstein Barr virus-positive B-cell lymphoma is highly vulnerable to MDM2 inhibitors in vivo. Blood Adv. 2022 Feb 8;6(3):891-901. doi: 10.1182/bloodadvances.2021006156. PMID: 34861697; PMCID: PMC8945299. 14: Xu C, Liu H, Pirozzi CJ, Chen LH, Greer PK, Diplas BH, Zhang L, Waitkus MS, He Y, Yan H. TP53 wild-type/PPM1D mutant diffuse intrinsic pontine gliomas are sensitive to a MDM2 antagonist. Acta Neuropathol Commun. 2021 Nov 3;9(1):178. doi: 10.1186/s40478-021-01270-y. PMID: 34732238; PMCID: PMC8565061. 15: Zhou Z, Zalutsky MR, Chitneni SK. Fluorine-18 Labeling of the MDM2 Inhibitor RG7388 for PET Imaging: Chemistry and Preliminary Evaluation. Mol Pharm. 2021 Oct 4;18(10):3871-3881. doi: 10.1021/acs.molpharmaceut.1c00531. Epub 2021 Sep 15. PMID: 34523337; PMCID: PMC8775362. 16: Yuan S, Wang X, Hou S, Guo T, Lan Y, Yang S, Zhao F, Gao J, Wang Y, Chu Y, Shi J, Cheng T, Yuan W. PHF6 and JAK3 mutations cooperate to drive T-cell acute lymphoblastic leukemia progression. Leukemia. 2022 Feb;36(2):370-382. doi: 10.1038/s41375-021-01392-1. Epub 2021 Aug 31. PMID: 34465864; PMCID: PMC8807395. 17: Italiano A, Miller WH Jr, Blay JY, Gietema JA, Bang YJ, Mileshkin LR, Hirte HW, Higgins B, Blotner S, Nichols GL, Chen LC, Petry C, Yang QJ, Schmitt C, Jamois C, Siu LL. Phase I study of daily and weekly regimens of the orally administered MDM2 antagonist idasanutlin in patients with advanced tumors. Invest New Drugs. 2021 Dec;39(6):1587-1597. doi: 10.1007/s10637-021-01141-2. Epub 2021 Jun 28. PMID: 34180037; PMCID: PMC8541972. 18: Toutah K, Nawar N, Timonen S, Sorger H, Raouf YS, Bukhari S, von Jan J, Ianevski A, Gawel JM, Olaoye OO, Geletu M, Abdeldayem A, Israelian J, Radu TB, Sedighi A, Bhatti MN, Hassan MM, Manaswiyoungkul P, Shouksmith AE, Neubauer HA, de Araujo ED, Aittokallio T, Krämer OH, Moriggl R, Mustjoki S, Herling M, Gunning PT. Development of HDAC Inhibitors Exhibiting Therapeutic Potential in T-Cell Prolymphocytic Leukemia. J Med Chem. 2021 Jun 24;64(12):8486-8509. doi: 10.1021/acs.jmedchem.1c00420. Epub 2021 Jun 8. PMID: 34101461; PMCID: PMC8237267. 19: Smiley SB, Yun Y, Ayyagari P, Shannon HE, Pollok KE, Vannier MW, Das SK, Veronesi MC. Development of CD133 Targeting Multi-Drug Polymer Micellar Nanoparticles for Glioblastoma - In Vitro Evaluation in Glioblastoma Stem Cells. Pharm Res. 2021 Jun;38(6):1067-1079. doi: 10.1007/s11095-021-03050-8. Epub 2021 Jun 7. PMID: 34100216. 20: Arya Y, Syal A, Gupta M, Gaba S. Advances in the Treatment of Polycythemia Vera: Trends in Disease Management. Cureus. 2021 Mar 30;13(3):e14193. doi: 10.7759/cureus.14193. PMID: 33936902; PMCID: PMC8084584.

Eirew P, O'Flanagan C, Ting J, Salehi S, Brimhall J, Wang B, Biele J, Algara T, Lee SR, Hoang C, Yap D, McKinney S, Bates C, Kong E, Lai D, Beatty S, Andronescu M, Zaikova E, Funnell T, Ceglia N, Chia S, Gelmon K, Mar C, Shah S, Roth A, Bouchard-Côté A, Aparicio S. Accurate determination of CRISPR-mediated gene fitness in transplantable tumours. Nat Commun. 2022 Aug 4;13(1):4534. doi: 10.1038/s41467-022-31830-2. PMID: 35927228; PMCID: PMC9352714.