A3935-5mg | WEHI-539 [1431866-33-9] Biotrend

Background

WEHI-539 is a small-molecule inhibitor of BCLXLwith an IC50 value of 1.1 nM [1].

WEHI-539 was designed as a BCL-XLinhibitor with high affinity. It interacted the with the binding groove of BCL-XLwith a Kd value of 0.6 nM. In MEF cells lacking MCL-1, WEHI-539 induced apoptosis which was evidenced by the release of mitochondrial cytochrome cand caspase-3 processing. In BCL-XLoverexpressed MEF cells, WEHI-539 showed EC50 value of 0.48 μM. WEHI-539 also significantly induced apoptosis of the platelets purified from mice. Besides that, WEHI-539can not kill MEF cells lacking BAK because the cell death mediator BAK is regulated by BCL-XLand MCL-1. [1].

References:
[1] Lessene G, Czabotar P E, Sleebs B E, et al. Structure-guided design of a selective BCL-XL inhibitor. Nature chemical biology, 2013, 9(6): 390-397.

Product Citation

1. Iseghohimen, Adesuwa. "Overcoming drug resistance: targeting the BCL-2 family and the long non-coding RNA HCP5 in medulloblastoma and colorectal cancer." University of Salford Manchester, Jul 3, 2023.
2. Venneker, S. "Exploiting vulnerabilities induced by recurrent mutations in chondrosarcoma and giant cell tumour of bone: therapeutic targeting of the altered epigenome and beyond." Leiden University Scholarly Publications. Jan 01, 2023.
3. Loo, Larry Sai Weng. "Dynamics of BCL-2 family of proteins in early pancreatic progenitors and β-cells." Nanyang Technological University.
4. Boccellato, Chiara, et al. "Overcoming glioblastoma intractability: pre-clinical characterisation of TRAIL sensitisation by marizomib and novel treatment perspectives." Universität Stuttgart. 2022.
5. Yasmeen A. Albalawi, Srinivas D. Narasipura, et al. "Wnt/β-Catenin Protects Lymphocytes from HIV-Mediated Apoptosis via Induction of Bcl-xL." Viruses. 2022 Jul 2;14(7):1469. PMID: 35891449
6. Nadine Pollak, Aline Lindner, et al. "Cell cycle progression and transmitotic apoptosis resistance promote escape from extrinsic apoptosis." J Cell Sci. 2021 Dec 15;134(24):jcs258966. PMID: 34806752
7. Kirsteen J. Campbell, Susan M. Mason, et al. "Breast cancer dependence on MCL-1 is due to its canonical anti-apoptotic function." Cell Death Differ. 2021 Sep;28(9):2589-2600. PMID: 33785871
8. Sanne Venneker, Alwine B. Kruisselbrink, et al. "Beyond the influence of idh mutations: Exploring epigenetic vulnerabilities in chondrosarcoma." Cancers (Basel). 2020 Nov 30;12(12):E3589. PMID: 33266275
9. Enyuan Shang, Trang T. T. Nguyen, et al. "Epigenetic Targeting of Mcl-1 Is Synthetically Lethal with Bcl-xL/Bcl-2 Inhibition in Model Systems of Glioblastoma." Cancers 2020, 12(8), 2137;1 August 2020. PMID: 32752193
10. Meyer L, Verbist KC, et al. "JAK/STAT pathway inhibition sensitizes CD8 T cells to dexamethasone-induced apoptosis in hyperinflammation." Blood. 2020;blood.2020006075. PMID: 32530039
11. Loo LSW, Soetedjo AAP, et al. "BCL-xL/BCL2L1 is a critical anti-apoptotic protein that promotes the survival of differentiating pancreatic cells from human pluripotent stem cells." Cell Death Dis. 2020;11(5):378. PMID: 32424151
12. Villalobos-Ortiz M, Ryan J, et al. "BH3 profiling discriminates on-target small molecule BH3 mimetics from putative mimetics." Cell Death Differ. 2019 Jul 22. PMID: 31332296
13. de Jong Y, Monderer D, et al. "Bcl-xl as the most promising Bcl-2 family member in targeted treatment of chondrosarcoma." Oncogenesis. 2018 Sep 21;7(9):74. PMID: 30242253
14. Soderquist RS, Crawford L, et al. "Systematic mapping of BCL-2 gene dependencies in cancer reveals molecular determinants of BH3 mimetic sensitivity." Nat Commun. 2018 Aug 29;9(1):3513. PMID: 30158527
15. Wilson Xuan Mai."Comprehensive Characterization of the Apoptotic Machinery in Glioblastoma Identifies New Therapeutic Strategies." UNIVERSITY OF CALIFORNIA.2018-01-01.
16. Dai J, Luftig MA. "Intracellular BH3 Profiling Reveals Shifts in Antiapoptotic Dependency in Human B Cell Maturation and Mitogen-Stimulated Proliferation." J Immunol. 2018 Mar 1;200(5):1727-1736. PMID: 29358277
17. Vuillier C, Lohard S, et al. "E2F1 interacts with BCL-xL and regulates its subcellular localization dynamics to trigger cell death." EMBO Rep. 2017 Dec 12. PMID: 29233828
18. Mai WX, Gosa L, et al. "Cytoplasmic p53 couples oncogene-driven glucose metabolism to apoptosis and is a therapeutic target in glioblastoma." Nat Med. 2017 Nov;23(11):1342-1351. PMID: 29035366
19. Park HA, Licznerski P, et al. "Inhibition of Bcl-xL prevents pro-death actions of ΔN-Bcl-xL at the mitochondrial inner membrane during glutamate excitotoxicity."Cell Death Differ. 2017 Nov;24(11):1963-1974. PMID: 28777375
20. Tan Y, Lin Y, et al. "Selective Antagonism of Bcl-xL Potentiates M1 Oncolysis by Enhancing Mitochondrial Apoptosis." Hum Gene Ther. 2017 Jul 27. PMID: 28750564
21. Rose JC, Stephany JJ, et al. "Rapidly inducible Cas9 and DSB-ddPCR to probe editing kinetics." Nat Methods. 2017 Sep;14(9):891-896. PMID: 28737741
22. Russo M, Milito A, et al. "CK2 and PI3K are direct molecular targets of quercetin in chronic lymphocytic leukaemia." Oncotarget. 2017 Jun 27;8(26):42571-42587. PMID: 28489572
23. Bi C, Zhang X, et al."Inhibition of 4EBP phosphorylation mediates the cytotoxic effect of mechanistic target of rapamycin kinase inhibitors in aggressive B-cell lymphomas."Haematologica. 2017 Apr;102(4):755-764. PMID: 28104700
24. Pécot J, Maillet L, et al. "Tight Sequestration of BH3 Proteins by BCL-xL at Subcellular Membranes Contributes to Apoptotic Resistance." Cell Rep. 2016 Dec 20;17(12):3347-3358. PMID: 28009301
25. Bennett A, Sloss O, et al. "Inhibition of Bcl-xL sensitizes cells to mitotic blockers, but not mitotic drivers." Open Biol. 2016 Aug;6(8). PMID: 27512141
26. Kris Cameron Wood,Peter Saville Winter. "Compositions and Methods for Treating Cancer with JAK2 Activity." US Patent App. 15/027,216, 2016.
27. Winter PS, et al. "RAS signaling promotes resistance to JAK inhibitors by suppressing BAD-mediated apoptosis." Sci Signal. 2014 Dec 23. PMID: 25538080

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Chemical Properties

Physical Appearance	A solid
Storage	Store at -20°C
M.Wt	583.72
Cas No.	1431866-33-9
Formula	C₃₁H₂₉N₅O₃S₂
Synonyms	WEHI539,WEHI 539
Solubility	insoluble in DMSO; insoluble in H2O; insoluble in EtOH
Chemical Name	5-[3-[4-(aminomethyl)phenoxy]propyl]-2-[(8E)-8-(1,3-benzothiazol-2-ylhydrazinylidene)-6,7-dihydro-5H-naphthalen-2-yl]-1,3-thiazole-4-carboxylic acid
SDF	Download SDF
Canonical SMILES	C1CC2=C(C=C(C=C2)C3=NC(=C(S3)CCCOC4=CC=C(C=C4)CN)C(=O)O)C(=NNC5=NC6=CC=CC=C6S5)C1
Shipping Condition	Small Molecules with Blue Ice, Modified Nucleotides with Dry Ice.
General tips	We do not recommend long-term storage for the solution, please use it up soon.

Protocol

Cell experiment[1]:
Cell lines	Human colon cancer cell
Reaction Conditions	1 μM, 24h
Applications	Limiting dilution analysis with CSCs that were pre-treated with ABT-737, ABT-199 or WEHI-539 revealed that ABT-737 and WEHI-539 both were sufficient to decrease clonogenic capacity, whereas ABT-199 did not affect clonogenic growth. As WEHI-539 is selective for BCLXL, this points to a dependency of CSCs on BCLXL for survival. Importantly, ABT-737- or WEHI-539-induced loss of clonogenicity could be restored when BCLXL was ectopically overexpressed. When spheroid cultures were treated with ABT-737 or WEHI-539 compounds, CSCs were effectively sensitized toward oxaliplatin and other chemotherapeutic agents.
References: 1. Colak S, Zimberlin CD, Fessler E et al. Decreased mitochondrial priming determines chemoresistance of colon cancer stem cells. Cell Death Differ. 2014 Jul;21(7):1170-7.

Biological Activity

WEHI-539, has high affinity (subnanomolar) and selectivity for BCL-XL and potently kills cells by selectively antagonizing its prosurvival activity. WEHI-539 has a high affinity for BCL-XL (IC50 = 1.1 nM).
Targets	BCL-XL
IC50	1.1 nM

Quality Control

Purity = 95.06%

WEHI-539 [1431866-33-9]

Cat# A3935-5mg

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Brand : APExBIO Technology