Idasanutlin (RG7388)
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MedKoo CAT#: 205917

CAS#: 1229705-06-9

Description: 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

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Idasanutlin (RG7388)
CAS# 1229705-06-9

Theoretical Analysis

MedKoo Cat#: 205917
Name: Idasanutlin (RG7388)
CAS#: 1229705-06-9
Chemical Formula: C31H29Cl2F2N3O4
Exact Mass: 615.15032
Molecular Weight: 616.48247
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 Quantity
10.0mg USD 150.0 Ready to ship
25.0mg USD 250.0 Ready to ship
50.0mg USD 450.0 Ready to ship
100.0mg USD 750.0 Ready to ship
200.0mg USD 1350.0 Ready to ship
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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

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/

Solubility Data

Solvent Max Conc. mg/mL Max Conc. mM
Solubility
DMSO 45.0 73.0

Preparing Stock Solutions

The following data is based on the product molecular weight 616.48247 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.

Recalculate based on batch purity %
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: 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.
In vivo 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. 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.

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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.



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