MI-77301
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MedKoo CAT#: 407971

CAS#: 1303607-60-4

Description: MI-77301, also known as SAR405838, is a MDM2 inhibitor. MI-77301 binds to MDM2 with a Ki value of 0.88 nM and blocks the MDM2-p53 interaction. It activates wild-type p53 in vitro and in xenograft tumor tissue of leukemia and solid tumors, leading to p53-dependent cell cycle arrest and/or apoptosis.

Chemical Structure

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MI-77301
CAS# 1303607-60-4
Product data Instruction

Theoretical Analysis

MedKoo Cat#: 407971
Name: MI-77301
CAS#: 1303607-60-4
Chemical Formula: C29H34Cl2FN3O3
Exact Mass: 561.20
Molecular Weight: 562.507
Elemental Analysis: C, 61.92; H, 6.09; Cl, 12.60; F, 3.38; N, 7.47; O, 8.53

Price and Availability

Size Price Availability Quantity
25mg USD 450 2 Weeks
50mg USD 750 2 Weeks
100mg USD 1250 2 Weeks
200mg USD 1950 2 Weeks
500mg USD 2950 2 Weeks
1g USD 4650 2 Weeks
2g USD 6750 2 Weeks
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Related CAS #: 1303607-07-9   1303607-60-4    

Synonym: MI773; MI-773; MI 773; MI-77301; MI 77301; MI77301; SAR405838; SAR-405838; SAR 405838;

IUPAC/Chemical Name: (2'S,3R,4'S,5'R)-6-Chloro-4'-(3-chloro-2-fluorophenyl)-2'-(2,2-dimethylpropyl)-1,2-dihydro-N-(trans-4-hydroxycyclohexyl)-2-oxospiro[3H-indole-3,3'-pyrrolidine]-5'-carboxamide

InChi Key: IDKAKZRYYDCJDU-HBMMIIHUSA-N

InChi Code: InChI=1S/C29H34Cl2FN3O3/c1-28(2,3)14-22-29(19-12-7-15(30)13-21(19)34-27(29)38)23(18-5-4-6-20(31)24(18)32)25(35-22)26(37)33-16-8-10-17(36)11-9-16/h4-7,12-13,16-17,22-23,25,35-36H,8-11,14H2,1-3H3,(H,33,37)(H,34,38)/t16-,17-,22-,23-,25+,29+/m0/s1

SMILES Code: O=C([C@H](N[C@H]1CC(C)(C)C)[C@H](C2=CC=CC(Cl)=C2F)[C@@]31C(NC4=C3C=CC(Cl)=C4)=O)N[C@H]5CC[C@H](O)CC5

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

Shelf Life: >3 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
Instruction:
View handling instruction
Biological target: SAR405838 (MI-77301), an analog of MI-773, is a highly potent and selective MDM2-p53 interaction inhibitor.
In vitro activity: This study reports on the preclinical effects of SAR405838, a novel and highly selective MDM2 small-molecule inhibitor, in both in vitro and in vivo DDLPS models. SAR405838 effectively stabilized p53 and activated the p53 pathway, resulting in abrogated cellular proliferation, cell-cycle arrest, and apoptosis. Similar results were observed with Nutlin-3a and MI-219; however, significantly higher concentrations were required. Reference: Clin Cancer Res. 2016 Mar 1;22(5):1150-60. https://pubmed.ncbi.nlm.nih.gov/26475335/
In vivo activity: Treatment of the parental SJSA-1 xenograft tumors with SAR405838 in mice yields rapid tumor regression but the tumors eventually regrow. Harvesting and culturing tumors obtained from a prolonged treatment with SAR405838 in mice established additional in vivo sublines, which all contain a single heterozygous C176F mutation with no additional p53 mutation detected. Reference: PLoS One. 2015 Jun 12;10(6):e0128807. https://pubmed.ncbi.nlm.nih.gov/26070072/

Solubility Data

Solvent Max Conc. mg/mL Max Conc. mM
Solubility
Ethanol:PBS (pH 7.2) (1:3) 0.3 0.44

Preparing Stock Solutions

The following data is based on the product molecular weight 562.51 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. Lu J, McEachern D, Li S, Ellis MJ, Wang S. Reactivation of p53 by MDM2 Inhibitor MI-77301 for the Treatment of Endocrine-Resistant Breast Cancer. Mol Cancer Ther. 2016 Dec;15(12):2887-2893. doi: 10.1158/1535-7163.MCT-16-0028. Epub 2016 Oct 7. PMID: 27765850; PMCID: PMC5367629. 2. Bill KL, Garnett J, Meaux I, Ma X, Creighton CJ, Bolshakov S, Barriere C, Debussche L, Lazar AJ, Prudner BC, Casadei L, Braggio D, Lopez G, Zewdu A, Bid H, Lev D, Pollock RE. SAR405838: A Novel and Potent Inhibitor of the MDM2:p53 Axis for the Treatment of Dedifferentiated Liposarcoma. Clin Cancer Res. 2016 Mar 1;22(5):1150-60. doi: 10.1158/1078-0432.CCR-15-1522. Epub 2015 Oct 16. Erratum in: Clin Cancer Res. 2022 Jan 15;28(2):431. PMID: 26475335; PMCID: PMC4775372. 3. Hoffman-Luca CG, Yang CY, Lu J, Ziazadeh D, McEachern D, Debussche L, Wang S. Significant Differences in the Development of Acquired Resistance to the MDM2 Inhibitor SAR405838 between In Vitro and In Vivo Drug Treatment. PLoS One. 2015 Jun 12;10(6):e0128807. doi: 10.1371/journal.pone.0128807. PMID: 26070072; PMCID: PMC4466389.
In vitro protocol: 1. Lu J, McEachern D, Li S, Ellis MJ, Wang S. Reactivation of p53 by MDM2 Inhibitor MI-77301 for the Treatment of Endocrine-Resistant Breast Cancer. Mol Cancer Ther. 2016 Dec;15(12):2887-2893. doi: 10.1158/1535-7163.MCT-16-0028. Epub 2016 Oct 7. PMID: 27765850; PMCID: PMC5367629. 2. Bill KL, Garnett J, Meaux I, Ma X, Creighton CJ, Bolshakov S, Barriere C, Debussche L, Lazar AJ, Prudner BC, Casadei L, Braggio D, Lopez G, Zewdu A, Bid H, Lev D, Pollock RE. SAR405838: A Novel and Potent Inhibitor of the MDM2:p53 Axis for the Treatment of Dedifferentiated Liposarcoma. Clin Cancer Res. 2016 Mar 1;22(5):1150-60. doi: 10.1158/1078-0432.CCR-15-1522. Epub 2015 Oct 16. Erratum in: Clin Cancer Res. 2022 Jan 15;28(2):431. PMID: 26475335; PMCID: PMC4775372.
In vivo protocol: 1. Lu J, McEachern D, Li S, Ellis MJ, Wang S. Reactivation of p53 by MDM2 Inhibitor MI-77301 for the Treatment of Endocrine-Resistant Breast Cancer. Mol Cancer Ther. 2016 Dec;15(12):2887-2893. doi: 10.1158/1535-7163.MCT-16-0028. Epub 2016 Oct 7. PMID: 27765850; PMCID: PMC5367629. 2. Hoffman-Luca CG, Yang CY, Lu J, Ziazadeh D, McEachern D, Debussche L, Wang S. Significant Differences in the Development of Acquired Resistance to the MDM2 Inhibitor SAR405838 between In Vitro and In Vivo Drug Treatment. PLoS One. 2015 Jun 12;10(6):e0128807. doi: 10.1371/journal.pone.0128807. PMID: 26070072; PMCID: PMC4466389.

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1: de Weger VA, de Jonge M, Langenberg MHG, Schellens JHM, Lolkema M, Varga A, Demers B, Thomas K, Hsu K, Tuffal G, Goodstal S, Macé S, Deutsch E. A phase I study of the HDM2 antagonist SAR405838 combined with the MEK inhibitor pimasertib in patients with advanced solid tumours. Br J Cancer. 2019 Feb;120(3):286-293. doi: 10.1038/s41416-018-0355-8. Epub 2018 Dec 26. PubMed PMID: 30585255.

2: Liao G, Yang D, Ma L, Li W, Hu L, Zeng L, Wu P, Duan L, Liu Z. The development of piperidinones as potent MDM2-P53 protein-protein interaction inhibitors for cancer therapy. Eur J Med Chem. 2018 Nov 5;159:1-9. doi: 10.1016/j.ejmech.2018.09.044. Epub 2018 Sep 18. Review. PubMed PMID: 30253242.

3: Kim M, Ma DJ, Calligaris D, Zhang S, Feathers RW, Vaubel RA, Meaux I, Mladek AC, Parrish KE, Jin F, Barriere C, Debussche L, Watters J, Tian S, Decker PA, Eckel-Passow JE, Kitange GJ, Johnson AJ, Parney IF, Anastasiadis PZ, Agar NYR, Elmquist WF, Sarkaria JN. Efficacy of the MDM2 Inhibitor SAR405838 in Glioblastoma Is Limited by Poor Distribution Across the Blood-Brain Barrier. Mol Cancer Ther. 2018 Sep;17(9):1893-1901. doi: 10.1158/1535-7163.MCT-17-0600. Epub 2018 Jul 3. PubMed PMID: 29970480; PubMed Central PMCID: PMC6125211.

4: Krasavin M, Gureyev MA, Dar'in D, Bakulina O, Chizhova M, Lepikhina A, Novikova D, Grigoreva T, Ivanov G, Zhumagalieva A, Garabadzhiu AV, Tribulovich VG. Design, in silico prioritization and biological profiling of apoptosis-inducing lactams amenable by the Castagnoli-Cushman reaction. Bioorg Med Chem. 2018 May 15;26(9):2651-2673. doi: 10.1016/j.bmc.2018.04.036. Epub 2018 Apr 18. PubMed PMID: 29691156.

5: Hata AN, Rowley S, Archibald HL, Gomez-Caraballo M, Siddiqui FM, Ji F, Jung J, Light M, Lee JS, Debussche L, Sidhu S, Sadreyev RI, Watters J, Engelman JA. Synergistic activity and heterogeneous acquired resistance of combined MDM2 and MEK inhibition in KRAS mutant cancers. Oncogene. 2017 Nov 23;36(47):6581-6591. doi: 10.1038/onc.2017.258. Epub 2017 Aug 7. PubMed PMID: 28783173; PubMed Central PMCID: PMC5700857.

6: Tisato V, Voltan R, Gonelli A, Secchiero P, Zauli G. MDM2/X inhibitors under clinical evaluation: perspectives for the management of hematological malignancies and pediatric cancer. J Hematol Oncol. 2017 Jul 3;10(1):133. doi: 10.1186/s13045-017-0500-5. Review. PubMed PMID: 28673313; PubMed Central PMCID: PMC5496368.

7: Chen H, Luo D, Zhang L, Lin X, Luo Q, Yi H, Wang J, Yan X, Li B, Chen Y, Liu X, Zhang H, Liu S, Qiu M, Yang D, Jiang N. Restoration of p53 using the novel MDM2-p53 antagonist APG115 suppresses dedifferentiated papillary thyroid cancer cells. Oncotarget. 2017 Jun 27;8(26):43008-43022. doi: 10.18632/oncotarget.17398. PubMed PMID: 28498808; PubMed Central PMCID: PMC5522123.

8: de Jonge M, de Weger VA, Dickson MA, Langenberg M, Le Cesne A, Wagner AJ, Hsu K, Zheng W, Macé S, Tuffal G, Thomas K, Schellens JH. A phase I study of SAR405838, a novel human double minute 2 (HDM2) antagonist, in patients with solid tumours. Eur J Cancer. 2017 May;76:144-151. doi: 10.1016/j.ejca.2017.02.005. Epub 2017 Mar 17. PubMed PMID: 28324749.

9: Wang S, Zhao Y, Aguilar A, Bernard D, Yang CY. Targeting the MDM2-p53 Protein-Protein Interaction for New Cancer Therapy: Progress and Challenges. Cold Spring Harb Perspect Med. 2017 May 1;7(5). pii: a026245. doi: 10.1101/cshperspect.a026245. Review. PubMed PMID: 28270530.

10: Lu J, McEachern D, Li S, Ellis MJ, Wang S. Reactivation of p53 by MDM2 Inhibitor MI-77301 for the Treatment of Endocrine-Resistant Breast Cancer. Mol Cancer Ther. 2016 Dec;15(12):2887-2893. Epub 2016 Oct 7. PubMed PMID: 27765850; PubMed Central PMCID: PMC5367629.

11: Lu J, Guan S, Zhao Y, Yu Y, Wang Y, Shi Y, Mao X, Yang KL, Sun W, Xu X, Yi JS, Yang T, Yang J, Nuchtern JG. Novel MDM2 inhibitor SAR405838 (MI-773) induces p53-mediated apoptosis in neuroblastoma. Oncotarget. 2016 Dec 13;7(50):82757-82769. doi: 10.18632/oncotarget.12634. PubMed PMID: 27764791; PubMed Central PMCID: PMC5347730.

12: Jung J, Lee JS, Dickson MA, Schwartz GK, Le Cesne A, Varga A, Bahleda R, Wagner AJ, Choy E, de Jonge MJ, Light M, Rowley S, Macé S, Watters J. TP53 mutations emerge with HDM2 inhibitor SAR405838 treatment in de-differentiated liposarcoma. Nat Commun. 2016 Aug 31;7:12609. doi: 10.1038/ncomms12609. PubMed PMID: 27576846; PubMed Central PMCID: PMC5013668.

13: Mahfoudhi E, Lordier L, Marty C, Pan J, Roy A, Roy L, Rameau P, Abbes S, Debili N, Raslova H, Chang Y, Debussche L, Vainchenker W, Plo I. P53 activation inhibits all types of hematopoietic progenitors and all stages of megakaryopoiesis. Oncotarget. 2016 May 31;7(22):31980-92. doi: 10.18632/oncotarget.7881. PubMed PMID: 26959882; PubMed Central PMCID: PMC5077990.

14: Yu B, Zheng YC, Shi XJ, Qi PP, Liu HM. Natural Product-Derived Spirooxindole Fragments Serve as Privileged Substructures for Discovery of New Anticancer Agents. Anticancer Agents Med Chem. 2016;16(10):1315-24. Review. PubMed PMID: 26522954.

15: Bill KL, Garnett J, Meaux I, Ma X, Creighton CJ, Bolshakov S, Barriere C, Debussche L, Lazar AJ, Prudner BC, Casadei L, Braggio D, Lopez G, Zewdu A, Bid H, Lev D, Pollock RE. SAR405838: A Novel and Potent Inhibitor of the MDM2:p53 Axis for the Treatment of Dedifferentiated Liposarcoma. Clin Cancer Res. 2016 Mar 1;22(5):1150-60. doi: 10.1158/1078-0432.CCR-15-1522. Epub 2015 Oct 16. PubMed PMID: 26475335; PubMed Central PMCID: PMC4775372.

16: Hoffman-Luca CG, Yang CY, Lu J, Ziazadeh D, McEachern D, Debussche L, Wang S. Significant Differences in the Development of Acquired Resistance to the MDM2 Inhibitor SAR405838 between In Vitro and In Vivo Drug Treatment. PLoS One. 2015 Jun 12;10(6):e0128807. doi: 10.1371/journal.pone.0128807. eCollection 2015. PubMed PMID: 26070072; PubMed Central PMCID: PMC4466389.

17: Hoffman-Luca CG, Ziazadeh D, McEachern D, Zhao Y, Sun W, Debussche L, Wang S. Elucidation of Acquired Resistance to Bcl-2 and MDM2 Inhibitors in Acute Leukemia In Vitro and In Vivo. Clin Cancer Res. 2015 Jun 1;21(11):2558-68. doi: 10.1158/1078-0432.CCR-14-2506. Epub 2015 Mar 9. PubMed PMID: 25754349; PubMed Central PMCID: PMC4957562.

18: Wang S, Sun W, Zhao Y, McEachern D, Meaux I, Barrière C, Stuckey JA, Meagher JL, Bai L, Liu L, Hoffman-Luca CG, Lu J, Shangary S, Yu S, Bernard D, Aguilar A, Dos-Santos O, Besret L, Guerif S, Pannier P, Gorge-Bernat D, Debussche L. SAR405838: an optimized inhibitor of MDM2-p53 interaction that induces complete and durable tumor regression. Cancer Res. 2014 Oct 15;74(20):5855-65. doi: 10.1158/0008-5472.CAN-14-0799. Epub 2014 Aug 21. PubMed PMID: 25145672; PubMed Central PMCID: PMC4247201.