A-1210477 | CAS#1668553-26-1 | MCL-1 inhibitor

MedKoo Cat#: 407156 | Name: A-1210477

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Description:

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

A-1210477 is a potent and selective MCL-1 inhibitor. A-1210477 induces the hallmarks of intrinsic apoptosis and demonstrates single agent killing of multiple myeloma and non-small cell lung cancer cell lines. A-1210477 synergizes with the BCL-2/BCL-XL inhibitor navitoclax to kill a variety of cancer cell lines. A-1210477 is a potential therapeutics for the treatment of cancer. The anti-apoptotic protein MCL-1 is a key regulator of cancer cell survival and a known resistance factor for small-molecule BCL-2 family inhibitors such as ABT-263 (navitoclax), making it an attractive therapeutic target.

Chemical Structure

A-1210477

CAS#1668553-26-1

Theoretical Analysis

MedKoo Cat#: 407156

Name: A-1210477

CAS#: 1668553-26-1

Chemical Formula: C46H55N7O7S

Exact Mass: 849.3884

Molecular Weight: 850.05

Elemental Analysis: C, 65.00; H, 6.52; N, 11.53; O, 13.17; S, 3.77

Price and Availability

Size	Price	Availability
5mg	USD 90.00	Ready to ship
10mg	USD 150.00	Ready to ship
25mg	USD 300.00	Ready to ship
50mg	USD 500.00	Ready to ship
100mg	USD 850.00	Ready to ship
200mg	USD 1,450.00	Ready to ship

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Related CAS #

No Data

Synonym

A-1210477; A 1210477; A1210477.

IUPAC/Chemical Name

7-(5-((4-(4-(N,N-dimethylsulfamoyl)piperazin-1-yl)phenoxy)methyl)-1,3-dimethyl-1H-pyrazol-4-yl)-1-(2-morpholinoethyl)-3-(3-(naphthalen-1-yloxy)propyl)-1H-indole-2-carboxylic acid

InChi Key

XMVAWGSQPHFXKU-UHFFFAOYSA-N

InChi Code

InChI=1S/C46H55N7O7S/c1-33-43(41(49(4)47-33)32-60-36-19-17-35(18-20-36)51-22-24-52(25-23-51)61(56,57)48(2)3)40-14-8-13-38-39(15-9-29-59-42-16-7-11-34-10-5-6-12-37(34)42)45(46(54)55)53(44(38)40)26-21-50-27-30-58-31-28-50/h5-8,10-14,16-20H,9,15,21-32H2,1-4H3,(H,54,55)

SMILES Code

O=C(C(N1CCN2CCOCC2)=C(CCCOC3=C(C=CC=C4)C4=CC=C3)C5=C1C(C6=C(COC7=CC=C(N8CCN(S(=O)(N(C)C)=O)CC8)C=C7)N(C)N=C6C)=CC=C5)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, 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#CRB51111

QC Data

View QC data: current batch, Lot#CRB51111

Safety Data Sheet (SDS)

View Safety Data Sheet (SDS)

Instruction

View handling instruction

Biological target:

A-1210477 is a MCL-1 inhibitor with an IC50 of 26.2 nM.

In vitro activity:

Esophageal cell proliferation was reduced markedly following A-1210477 treatment. The apoptotic cells of these ESCC (esophageal squamous cell carcinoma) were evaluated after A-1210477 treatment by detecting cleaved caspase3 expression with quantitative IHC (immunohistochemistry). There was a statistically significant increase in labeling indices when control ESCC (1.2 ± 0.8) was compared with low dose (8.0 ± 3.1) and high dose ones (14.0 ± 4.5) (Figure 4A–4D). The percentage of TUNEL positive cells increased dose dependently from 1.9 % in DMSO mice to 8.9 % (p < 0.05) in low-dose A-1210477 mice and 19.0 % (p < 0.05) in high-dose A-1210477 mice (Figure 4E–4N). These data clearly demonstrated A-1210477 treatment led to increased cell death in mouse ESCC. Reference: Oncotarget. 2017 Jun 28;8(70):114457-114462. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5777705/

In vivo activity:

To test whether MCL-1 plays a role in ESCC cancer progression, mice at 20 weeks after initial 4NQO exposure were injected with control vehicle, lose dose and high dose of A-1210477 daily for 4 weeks. A-1210477-treated mice had developed fewer tumors than the vehicle-treated mice did in a dose dependent manner (Figure 2A). Similarly, there was significant less body weight loss in the A-1210477-treatment group mice compared with the control ones (Figure 2B). Microscopically, there was also less malignancy formation in the esophagus following A-1210477-treatment (Figure 2C–2E). Reference: Oncotarget. 2017 Jun 28;8(70):114457-114462. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5777705/

	Solvent	mg/mL	mM
Solubility
	DMSO	5.9	6.94

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 850.05 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. Lin J, Fu D, Dai Y, Lin J, Xu T. Mcl-1 inhibitor suppresses tumor growth of esophageal squamous cell carcinoma in a mouse model. Oncotarget. 2017 Jun 28;8(70):114457-114462. doi: 10.18632/oncotarget.18772. PMID: 29383093; PMCID: PMC5777705.

In vitro protocol:

In vivo protocol:

1: Wang Q, Hao S. A-1210477, a selective MCL-1 inhibitor, overcomes ABT-737 resistance in AML. Oncol Lett. 2019 Nov;18(5):5481-5489. doi: 10.3892/ol.2019.10891. Epub 2019 Sep 19. PMID: 31612056; PMCID: PMC6781566. 2: Mallick DJ, Soderquist RS, Bates D, Eastman A. Confounding off-target effects of BH3 mimetics at commonly used concentrations: MIM1, UMI-77, and A-1210477. Cell Death Dis. 2019 Feb 22;10(3):185. doi: 10.1038/s41419-019-1426-3. PMID: 30796196; PMCID: PMC6385300. 3: Song S, Kim S, El-Sawy ER, Cerella C, Orlikova-Boyer B, Kirsch G, Christov C, Dicato M, Diederich M. Anti-Leukemic Properties of Aplysinopsin Derivative EE-84 Alone and Combined to BH3 Mimetic A-1210477. Mar Drugs. 2021 May 21;19(6):285. doi: 10.3390/md19060285. PMID: 34063867; PMCID: PMC8224038. 4: Lian BSX, Yek AEH, Shuvas H, Abdul Rahman SF, Muniandy K, Mohana-Kumaran N. Synergistic anti-proliferative effects of combination of ABT-263 and MCL-1 selective inhibitor A-1210477 on cervical cancer cell lines. BMC Res Notes. 2018 Mar 27;11(1):197. doi: 10.1186/s13104-018-3302-0. PMID: 29580266; PMCID: PMC5870236. 5: Lin J, Fu D, Dai Y, Lin J, Xu T. Mcl-1 inhibitor suppresses tumor growth of esophageal squamous cell carcinoma in a mouse model. Oncotarget. 2017 Jun 28;8(70):114457-114462. doi: 10.18632/oncotarget.18772. PMID: 29383093; PMCID: PMC5777705. 6: Milani M, Byrne DP, Greaves G, Butterworth M, Cohen GM, Eyers PA, Varadarajan S. DRP-1 is required for BH3 mimetic-mediated mitochondrial fragmentation and apoptosis. Cell Death Dis. 2017 Jan 12;8(1):e2552. doi: 10.1038/cddis.2016.485. PMID: 28079887; PMCID: PMC5386385. 7: Meister MT, Boedicker C, Linder B, Kögel D, Klingebiel T, Fulda S. Concomitant targeting of Hedgehog signaling and MCL-1 synergistically induces cell death in Hedgehog-driven cancer cells. Cancer Lett. 2019 Nov 28;465:1-11. doi: 10.1016/j.canlet.2019.08.012. Epub 2019 Aug 26. PMID: 31465840. 8: Wang Q, Wan J, Zhang W, Hao S. MCL-1 or BCL-xL-dependent resistance to the BCL-2 antagonist (ABT-199) can be overcome by specific inhibitor as single agents and in combination with ABT-199 in acute myeloid leukemia cells. Leuk Lymphoma. 2019 Sep;60(9):2170-2180. doi: 10.1080/10428194.2018.1563694. Epub 2019 Jan 10. PMID: 30626241. 9: Wang LJ, Liou LR, Shi YJ, Chiou JT, Lee YC, Huang CH, Huang PW, Chang LS. Albendazole-Induced SIRT3 Upregulation Protects Human Leukemia K562 Cells from the Cytotoxicity of MCL1 Suppression. Int J Mol Sci. 2020 May 30;21(11):3907. doi: 10.3390/ijms21113907. PMID: 32486166; PMCID: PMC7312678. 10: Melo G, Silva CAB, Hague A, Parkinson EK, Rivero ERC. Anticancer effects of putative and validated BH3-mimetic drugs in head and neck squamous cell carcinomas: An overview of current knowledge. Oral Oncol. 2022 Sep;132:105979. doi: 10.1016/j.oraloncology.2022.105979. Epub 2022 Jul 8. PMID: 35816876. 11: Phillips DC, Xiao Y, Lam LT, Litvinovich E, Roberts-Rapp L, Souers AJ, Leverson JD. Loss in MCL-1 function sensitizes non-Hodgkin's lymphoma cell lines to the BCL-2-selective inhibitor venetoclax (ABT-199). Blood Cancer J. 2015 Nov 13;5(11):e368. doi: 10.1038/bcj.2015.88. Erratum in: Blood Cancer J. 2016;6:e403. PMID: 26565405; PMCID: PMC4670945. 12: Luedtke DA, Niu X, Pan Y, Zhao J, Liu S, Edwards H, Chen K, Lin H, Taub JW, Ge Y. Inhibition of Mcl-1 enhances cell death induced by the Bcl-2-selective inhibitor ABT-199 in acute myeloid leukemia cells. Signal Transduct Target Ther. 2017 Apr 7;2:17012. doi: 10.1038/sigtrans.2017.12. PMID: 29263915; PMCID: PMC5661618. 13: Leverson JD, Zhang H, Chen J, Tahir SK, Phillips DC, Xue J, Nimmer P, Jin S, Smith M, Xiao Y, Kovar P, Tanaka A, Bruncko M, Sheppard GS, Wang L, Gierke S, Kategaya L, Anderson DJ, Wong C, Eastham-Anderson J, Ludlam MJ, Sampath D, Fairbrother WJ, Wertz I, Rosenberg SH, Tse C, Elmore SW, Souers AJ. Potent and selective small-molecule MCL-1 inhibitors demonstrate on-target cancer cell killing activity as single agents and in combination with ABT-263 (navitoclax). Cell Death Dis. 2015 Jan 15;6(1):e1590. doi: 10.1038/cddis.2014.561. PMID: 25590800; PMCID: PMC4669759. 14: Guo Z, Song T, Xue Z, Liu P, Zhang M, Zhang X, Zhang Z. Using CETSA assay and a mathematical model to reveal dual Bcl-2/Mcl-1 inhibition and on-target mechanism for ABT-199 and S1. Eur J Pharm Sci. 2020 Jan 15;142:105105. doi: 10.1016/j.ejps.2019.105105. Epub 2019 Oct 25. PMID: 31669390. 15: Ow TJ, Thomas C, Fulcher CD, Chen J, López A, Reyna DE, Prystowsky MB, Smith RV, Schiff BA, Rosenblatt G, Belbin TJ, Harris TM, Childs GC, Kawachi N, Schlecht NF, Gavathiotis E. Apoptosis signaling molecules as treatment targets in head and neck squamous cell carcinoma. Laryngoscope. 2020 Nov;130(11):2643-2649. doi: 10.1002/lary.28441. Epub 2020 Jan 2. PMID: 31894587; PMCID: PMC8142150. 16: Fiskus W, Cai T, DiNardo CD, Kornblau SM, Borthakur G, Kadia TM, Pemmaraju N, Bose P, Masarova L, Rajapakshe K, Perera D, Coarfa C, Mill CP, Saenz DT, Saenz DN, Sun B, Khoury JD, Shen Y, Konopleva M, Bhalla KN. Superior efficacy of cotreatment with BET protein inhibitor and BCL2 or MCL1 inhibitor against AML blast progenitor cells. Blood Cancer J. 2019 Jan 15;9(2):4. doi: 10.1038/s41408-018-0165-5. PMID: 30647404; PMCID: PMC6333829. 17: Shukla S, Saxena S, Singh BK, Kakkar P. BH3-only protein BIM: An emerging target in chemotherapy. Eur J Cell Biol. 2017 Dec;96(8):728-738. doi: 10.1016/j.ejcb.2017.09.002. Epub 2017 Sep 23. PMID: 29100606. 18: Kawakami H, Huang S, Pal K, Dutta SK, Mukhopadhyay D, Sinicrope FA. Mutant BRAF Upregulates MCL-1 to Confer Apoptosis Resistance that Is Reversed by MCL-1 Antagonism and Cobimetinib in Colorectal Cancer. Mol Cancer Ther. 2016 Dec;15(12):3015-3027. doi: 10.1158/1535-7163.MCT-16-0017. Epub 2016 Oct 7. PMID: 27765849; PMCID: PMC5136313. 19: Xiao Y, Nimmer P, Sheppard GS, Bruncko M, Hessler P, Lu X, Roberts-Rapp L, Pappano WN, Elmore SW, Souers AJ, Leverson JD, Phillips DC. MCL-1 Is a Key Determinant of Breast Cancer Cell Survival: Validation of MCL-1 Dependency Utilizing a Highly Selective Small Molecule Inhibitor. Mol Cancer Ther. 2015 Aug;14(8):1837-47. doi: 10.1158/1535-7163.MCT-14-0928. Epub 2015 May 26. PMID: 26013319. 20: De Blasio A, Pratelli G, Drago-Ferrante R, Saliba C, Baldacchino S, Grech G, Tesoriere G, Scerri C, Vento R, Di Fiore R. Loss of MCL1 function sensitizes the MDA-MB-231 breast cancer cells to rh-TRAIL by increasing DR4 levels. J Cell Physiol. 2019 Aug;234(10):18432-18447. doi: 10.1002/jcp.28479. Epub 2019 Mar 25. PMID: 30912136.