NVP-CGM097 sulfate | CAS#1313367-56-4 | MDM2 inhibitor

MedKoo Cat#: 462431 | Name: NVP-CGM097 sulfate

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Description:

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

NVP-CGM097 is a potent and selective MDM2 inhibitor. P53 wild type GOT1 cells were sensitive to NVP-CGM097, p53mutated BON1 and p53mutated NCI-H727 cells were resistant to NVP-CGM097. Incubation of GOT1 cells with NVP-CGM097 at 100, 500, and 2,500 nM for 96 h caused a significant decline in cell viability to 84.9 ± 9.2% (p < 0.05), 77.4 ± 6.6% (p < 0.01), and 47.7 ± 9.2% (p < 0.01). NVP-CGM097 can inhibit the proliferation of tumor cells. NVP-CGM097 could reverse ABCB1-mediated MDR by directly blocking the ABCB1-mediated drug efflux and raising the accumulation of chemotherapeutic drugs in cancer cells. NVP-CGM097 tended to bind to the inhibitory site, which led to slight but critical conformational changes in the transporter and reduced the ATPase activity.

Chemical Structure

NVP-CGM097 sulfate

CAS#1313367-56-4 (sulfate)

Theoretical Analysis

MedKoo Cat#: 462431

Name: NVP-CGM097 sulfate

CAS#: 1313367-56-4 (sulfate)

Chemical Formula: C38H49ClN4O8S

Exact Mass: 0.0000

Molecular Weight: 757.34

Elemental Analysis: C, 60.27; H, 6.52; Cl, 4.68; N, 7.40; O, 16.90; S, 4.23

Price and Availability

Size	Price	Availability	Quantity
5mg	USD 485.00	2 Weeks
10mg	USD 850.00	2 Weeks

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Related CAS #

1313363-54-0 (free base) 1313367-56-4 (sulfate)

Synonym

NVP-CGM097 sulfate; NVP CGM097; NVP-CGM 097; NVP-CGM-097; NVPCGM097; NVPCGM 097; NVPCGM-097; CGM 097; CGM-097; CGM097;

IUPAC/Chemical Name

(S)-1-(4-chlorophenyl)-7-isopropoxy-6-methoxy-2-(4-(methyl(((1r,4S)-4-(4-methyl-3-oxopiperazin-1-yl)cyclohexyl)methyl)amino)phenyl)-1,4-dihydroisoquinolin-3(2H)-one sulfate

InChi Key

YFLKIFVIZIALIA-KSUDFVIKSA-N

InChi Code

InChI=1S/C38H47ClN4O4.H2O4S/c1-25(2)47-35-22-33-28(20-34(35)46-5)21-36(44)43(38(33)27-8-10-29(39)11-9-27)32-16-14-30(15-17-32)41(4)23-26-6-12-31(13-7-26)42-19-18-40(3)37(45)24-42;1-5(2,3)4/h8-11,14-17,20,22,25-26,31,38H,6-7,12-13,18-19,21,23-24H2,1-5H3;(H2,1,2,3,4)/t26-,31-,38-;/m0./s1

SMILES Code

ClC(C=C1)=CC=C1[C@@H](C2=CC(OC(C)C)=C(OC)C=C2C3)N(C4=CC=C(N(C[C@@H]5CC[C@@H](N6CC(N(C)CC6)=O)CC5)C)C=C4)C3=O.O=S(O)(O)=O

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

Multidrug resistance (MDR) is a major challenge in the treatment of tumors. It refers to cancer cells become resistant to not only the therapeutic drug, but also cross-resistant to multiple drugs with distinct structures and mechanisms of action when they are exposed to a drug for a period of time. An essential mechanism of MDR is the aberrant expression and function of ATP-binding cassette (ABC) transporters. Therefore, blocking the function of ABC transporters has the therapeutic potential in reversing MDR. The hdm2 oncogene product, HDM2 (also known as MDM2), is an important negative regulator of the p53 tumor suppressor. N

Product Data

Product Data

Instruction

View handling instruction

Biological target:

NVP-CGM097 sulfate is a potent and selective MDM2 inhibitor with IC50 of 1.7±0.1 nM for hMDM2.

In vitro activity:

This study evaluated whether NVP-CGM097 could reverse ABCB1-mediated MDR. The results of reversal experiment showed that NVP-CGM097 remarkably reversed ABCB1-mediated MDR but not ABCG2-mediated MDR. The results of Western blot and immunofluorescence suggested that the level of expression and subcellular localization of ABCB1 protein were not significantly altered by NVP-CGM097. Mechanism studies indicated that NVP-CGM097 could reverse ABCB1-mediated MDR by directly blocking the ABCB1-mediated drug efflux and raising the accumulation of chemotherapeutic drugs in cancer cells. Reference: Front Oncol. 2020 Jul 23;10:1219. https://pubmed.ncbi.nlm.nih.gov/32793491/

In vivo activity:

A single oral dose of NVP-CGM097, 100 mg/kg, led to stabilization of p53 and elevation of p53 target genes such as CDKN1A (p21) at the mRNA level (Figure 5A, left) and at the protein level (Figure 5A, right). Treatment of SJSA-1 xenografted tumors with NVP-CGM097 led to dose-dependent tumor growth inhibition with 65% tumor regression at 100 mg/kg daily (Figure 5B, left) and was well tolerated as measured by body weight (Figure 5B, right). The anti-tumor activity of NVP-CGM097 correlated well with a dose-dependent induction in tumors of p21 and HDM2 at the mRNA level and/or protein levels (Figure 5C,D). Reference: Elife. 2015 May 12;4:e06498. https://pubmed.ncbi.nlm.nih.gov/25965177/

	Solvent	mg/mL	mM
Solubility
	DMSO	100.0	132.04
	Water	100.0	132.04

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 757.34 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. Zhang M, Chen XY, Dong XD, Wang JQ, Feng W, Teng QX, Cui Q, Li J, Li XQ, Chen ZS. NVP-CGM097, an HDM2 Inhibitor, Antagonizes ATP-Binding Cassette Subfamily B Member 1-Mediated Drug Resistance. Front Oncol. 2020 Jul 23;10:1219. doi: 10.3389/fonc.2020.01219. PMID: 32793491; PMCID: PMC7390918. 2. Reuther C, Heinzle V, Nölting S, Herterich S, Hahner S, Halilovic E, Jeay S, Wuerthner JU, Aristizabal Prada ET, Spöttl G, Maurer J, Auernhammer CJ. The HDM2 (MDM2) Inhibitor NVP-CGM097 Inhibits Tumor Cell Proliferation and Shows Additive Effects with 5-Fluorouracil on the p53-p21-Rb-E2F1 Cascade in the p53wild type Neuroendocrine Tumor Cell Line GOT1. Neuroendocrinology. 2018;106(1):1-19. doi: 10.1159/000453369. Epub 2016 Nov 21. PMID: 27871087. 3. Weisberg E, Halilovic E, Cooke VG, Nonami A, Ren T, Sanda T, Simkin I, Yuan J, Antonakos B, Barys L, Ito M, Stone R, Galinsky I, Cowens K, Nelson E, Sattler M, Jeay S, Wuerthner JU, McDonough SM, Wiesmann M, Griffin JD. Inhibition of Wild-Type p53-Expressing AML by the Novel Small Molecule HDM2 Inhibitor CGM097. Mol Cancer Ther. 2015 Oct;14(10):2249-59. doi: 10.1158/1535-7163.MCT-15-0429. Epub 2015 Jul 23. PMID: 26206331; PMCID: PMC4596780. 4. Jeay S, Gaulis S, Ferretti S, Bitter H, Ito M, Valat T, Murakami M, Ruetz S, Guthy DA, Rynn C, Jensen MR, Wiesmann M, Kallen J, Furet P, Gessier F, Holzer P, Masuya K, Würthner J, Halilovic E, Hofmann F, Sellers WR, Graus Porta D. A distinct p53 target gene set predicts for response to the selective p53-HDM2 inhibitor NVP-CGM097. Elife. 2015 May 12;4:e06498. doi: 10.7554/eLife.06498. Erratum in: Elife. 2016 Nov 17;5:null. PMID: 25965177; PMCID: PMC4468608.

In vitro protocol:

In vivo protocol:

1. Weisberg E, Halilovic E, Cooke VG, Nonami A, Ren T, Sanda T, Simkin I, Yuan J, Antonakos B, Barys L, Ito M, Stone R, Galinsky I, Cowens K, Nelson E, Sattler M, Jeay S, Wuerthner JU, McDonough SM, Wiesmann M, Griffin JD. Inhibition of Wild-Type p53-Expressing AML by the Novel Small Molecule HDM2 Inhibitor CGM097. Mol Cancer Ther. 2015 Oct;14(10):2249-59. doi: 10.1158/1535-7163.MCT-15-0429. Epub 2015 Jul 23. PMID: 26206331; PMCID: PMC4596780. 2. Jeay S, Gaulis S, Ferretti S, Bitter H, Ito M, Valat T, Murakami M, Ruetz S, Guthy DA, Rynn C, Jensen MR, Wiesmann M, Kallen J, Furet P, Gessier F, Holzer P, Masuya K, Würthner J, Halilovic E, Hofmann F, Sellers WR, Graus Porta D. A distinct p53 target gene set predicts for response to the selective p53-HDM2 inhibitor NVP-CGM097. Elife. 2015 May 12;4:e06498. doi: 10.7554/eLife.06498. Erratum in: Elife. 2016 Nov 17;5:null. PMID: 25965177; PMCID: PMC4468608.

1: Wang S, Zhao Y, Yao F, Wei P, Ma L, Zhang S. An anti-GD2 aptamer-based bifunctional spherical nucleic acid nanoplatform for synergistic therapy targeting MDM2 for retinoblastoma. Biomed Pharmacother. 2024 May;174:116437. doi: 10.1016/j.biopha.2024.116437. Epub 2024 Mar 24. PMID: 38522240. 2: Blazhynska M, Goulard Coderc de Lacam E, Chen H, Chipot C. Improving Speed and Affordability without Compromising Accuracy: Standard Binding Free-Energy Calculations Using an Enhanced Sampling Algorithm, Multiple-Time Stepping, and Hydrogen Mass Repartitioning. J Chem Theory Comput. 2023 Jun 13;19(11):3091-3101. doi: 10.1021/acs.jctc.3c00141. Epub 2023 May 17. PMID: 37196198. 3: Blazhynska M, Goulard Coderc de Lacam E, Chen H, Roux B, Chipot C. Hazardous Shortcuts in Standard Binding Free Energy Calculations. J Phys Chem Lett. 2022 Jul 14;13(27):6250-6258. doi: 10.1021/acs.jpclett.2c01490. Epub 2022 Jun 30. PMID: 35771686. 4: Bauer S, Demetri GD, Halilovic E, Dummer R, Meille C, Tan DSW, Guerreiro N, Jullion A, Ferretti S, Jeay S, Van Bree L, Hourcade-Potelleret F, Wuerthner JU, Fabre C, Cassier PA. Pharmacokinetic-pharmacodynamic guided optimisation of dose and schedule of CGM097, an HDM2 inhibitor, in preclinical and clinical studies. Br J Cancer. 2021 Aug;125(5):687-698. doi: 10.1038/s41416-021-01444-4. Epub 2021 Jun 17. PMID: 34140638; PMCID: PMC8405607. 5: Dalton KM, Krytska K, Lochmann TL, Sano R, Casey C, D'Aulerio A, Khan QA, Crowther GS, Coon C, Cai J, Jacob S, Kurupi R, Hu B, Dozmorov M, Greninger P, Souers AJ, Benes CH, Mossé YP, Faber AC. Venetoclax-based Rational Combinations are Effective in Models of MYCN-amplified Neuroblastoma. Mol Cancer Ther. 2021 Aug;20(8):1400-1411. doi: 10.1158/1535-7163.MCT-20-0710. Epub 2021 Jun 4. PMID: 34088831; PMCID: PMC10350345. 6: Maser T, Zagorski J, Kelly S, Ostrander A, Goodyke A, Nagulapally A, Bond J, Park Y, Saulnier Sholler G. The MDM2 inhibitor CGM097 combined with the BET inhibitor OTX015 induces cell death and inhibits tumor growth in models of neuroblastoma. Cancer Med. 2020 Nov;9(21):8144-8158. doi: 10.1002/cam4.3407. Epub 2020 Oct 9. PMID: 33034426; PMCID: PMC7643634. 7: Fang Y, Liao G, Yu B. Small-molecule MDM2/X inhibitors and PROTAC degraders for cancer therapy: advances and perspectives. Acta Pharm Sin B. 2020 Jul;10(7):1253-1278. doi: 10.1016/j.apsb.2020.01.003. Epub 2020 Jan 14. PMID: 32874827; PMCID: PMC7452049. 8: Zhang M, Chen XY, Dong XD, Wang JQ, Feng W, Teng QX, Cui Q, Li J, Li XQ, Chen ZS. NVP-CGM097, an HDM2 Inhibitor, Antagonizes ATP-Binding Cassette Subfamily B Member 1-Mediated Drug Resistance. Front Oncol. 2020 Jul 23;10:1219. doi: 10.3389/fonc.2020.01219. PMID: 32793491; PMCID: PMC7390918. 9: Portman N, Milioli HH, Alexandrou S, Coulson R, Yong A, Fernandez KJ, Chia KM, Halilovic E, Segara D, Parker A, Haupt S, Haupt Y, Tilley WD, Swarbrick A, Caldon CE, Lim E. MDM2 inhibition in combination with endocrine therapy and CDK4/6 inhibition for the treatment of ER-positive breast cancer. Breast Cancer Res. 2020 Aug 12;22(1):87. doi: 10.1186/s13058-020-01318-2. PMID: 32787886; PMCID: PMC7425060. 10: Konopleva M, Martinelli G, Daver N, Papayannidis C, Wei A, Higgins B, Ott M, Mascarenhas J, Andreeff M. MDM2 inhibition: an important step forward in cancer therapy. Leukemia. 2020 Nov;34(11):2858-2874. doi: 10.1038/s41375-020-0949-z. Epub 2020 Jul 10. PMID: 32651541. 11: de Koning L, Decaudin D, El Botty R, Nicolas A, Carita G, Schuller M, Ouine B, Cartier A, Naguez A, Fleury J, Cooke V, Wylie A, Smith P, Marangoni E, Gentien D, Meseure D, Mariani P, Cassoux N, Piperno-Neumann S, Roman-Roman S, Némati F. PARP Inhibition Increases the Response to Chemotherapy in Uveal Melanoma. Cancers (Basel). 2019 May 29;11(6):751. doi: 10.3390/cancers11060751. PMID: 31146482; PMCID: PMC6628115. 12: Kallen J, Izaac A, Chau S, Wirth E, Schoepfer J, Mah R, Schlapbach A, Stutz S, Vaupel A, Guagnano V, Masuya K, Stachyra TM, Salem B, Chene P, Gessier F, Holzer P, Furet P. Structural States of Hdm2 and HdmX: X-ray Elucidation of Adaptations and Binding Interactions for Different Chemical Compound Classes. ChemMedChem. 2019 Jul 17;14(14):1305-1314. doi: 10.1002/cmdc.201900201. Epub 2019 May 27. PMID: 31066983. 13: Tan B, Tong C, Yuan Y, Xu P, Wen L, Zhang C, Zheng Y, Lin L, Zhu F, Gui S, Wang L, Gao R, Li J, Qi H, Baker PN. The Regulation of Trophoblastic p53 Homeostasis by the p38-Wip1 Feedback Loop is Disturbed in Placentas from Pregnancies Complicated by Preeclampsia. Cell Physiol Biochem. 2019;52(2):315-335. doi: 10.33594/000000023. Epub 2019 Feb 28. PMID: 30816677. 14: 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. PMID: 30253242. 15: Vaupel A, Holzer P, Ferretti S, Guagnano V, Kallen J, Mah R, Masuya K, Ruetz S, Rynn C, Schlapbach A, Stachyra T, Stutz S, Todorov M, Jeay S, Furet P. In vitro and in vivo characterization of a novel, highly potent p53-MDM2 inhibitor. Bioorg Med Chem Lett. 2018 Nov 1;28(20):3404-3408. doi: 10.1016/j.bmcl.2018.08.027. Epub 2018 Aug 26. PMID: 30217415. 16: Holzer P. Discovery of Potent and Selective p53-MDM2 Protein-Protein Interaction Inhibitors as Anticancer Drugs. Chimia (Aarau). 2017 Oct 25;71(10):716-721. doi: 10.2533/chimia.2017.716. PMID: 29070416. 17: Reuther C, Heinzle V, Nölting S, Herterich S, Hahner S, Halilovic E, Jeay S, Wuerthner JU, Aristizabal Prada ET, Spöttl G, Maurer J, Auernhammer CJ. The HDM2 (MDM2) Inhibitor NVP-CGM097 Inhibits Tumor Cell Proliferation and Shows Additive Effects with 5-Fluorouracil on the p53-p21-Rb-E2F1 Cascade in the p53wild type Neuroendocrine Tumor Cell Line GOT1. Neuroendocrinology. 2018;106(1):1-19. doi: 10.1159/000453369. Epub 2016 Nov 21. PMID: 27871087. 18: Jeay S, Gaulis S, Ferretti S, Bitter H, Ito M, Valat T, Murakami M, Ruetz S, Guthy DA, Rynn C, Jensen MR, Wiesmann M, Kallen J, Furet P, Gessier F, Holzer P, Masuya K, Würthner J, Halilovic E, Hofmann F, Sellers WR, Graus Porta D. Correction: A distinct p53 target gene set predicts for response to the selective p53-HDM2 inhibitor NVP-CGM097. Elife. 2016 Nov 17;5:e19317. doi: 10.7554/eLife.19317. Erratum for: Elife. 2015 May 12;4:e06498. doi: 10.7554/eLife.06498. PMID: 27852439; PMCID: PMC5114012. 19: Furet P, Masuya K, Kallen J, Stachyra-Valat T, Ruetz S, Guagnano V, Holzer P, Mah R, Stutz S, Vaupel A, Chène P, Jeay S, Schlapbach A. Discovery of a novel class of highly potent inhibitors of the p53-MDM2 interaction by structure-based design starting from a conformational argument. Bioorg Med Chem Lett. 2016 Oct 1;26(19):4837-4841. doi: 10.1016/j.bmcl.2016.08.010. Epub 2016 Aug 9. PMID: 27542305. 20: Carita G, Frisch-Dit-Leitz E, Dahmani A, Raymondie C, Cassoux N, Piperno- Neumann S, Némati F, Laurent C, De Koning L, Halilovic E, Jeay S, Wylie A, Emery C, Roman-Roman S, Schoumacher M, Decaudin D. Dual inhibition of protein kinase C and p53-MDM2 or PKC and mTORC1 are novel efficient therapeutic approaches for uveal melanoma. Oncotarget. 2016 Jun 7;7(23):33542-56. doi: 10.18632/oncotarget.9552. PMID: 27507190; PMCID: PMC5085101.