A8193-50mg | ABT-737 [852808-04-9] Clinisciences

Background

ABT-737 is a novel and potent inhibitor of B-cell lymphoma 2 (BCL-2) family proteins, which are critical for cell survival and overexpressed in many tumor cells, with high affinity towards BCL-X_L, BCL-2, and BCL-w but no affinity towards less homologous proteins, such as BCL-B, MCL-1, and A1. ABT-737 has shown single-agent activity against lymphoma and small-cell lung cancer as well as substantial antimyeloma activity both in vitro and in vivo. In recent studies, acute myeloid leukemia blast, origenitor, and stem cells are effectively killed by ABT-737 with normal hematopoietic cells intact. The disruption of the BCL-2/BAX complex and BAK-dependent but BIM-independent activation of the intrinsic apoptotic pathway could also be induced by ABT-737.

Reference

Marina Konopleva, Rooha Contractor, Twee Tsao, Ismael Samudio, Peter P. Ruvolo, Shinichi Kitada, Xingming Deng, Dayong Zhai, Yue-Xi Shi, Thomas Sneed, Monique Verhaegen, Maria Soengas, Vivian R. Ruvolo, Teresa McQueen, Wendy D. Schober, Julie C. Watt, Tilahun Jiffar, Xiaoyang Ling, Frank C. Marini, David Harris, Martin Dietrich, Zeev Estrov, James McCubrey, W. Stratford May, John C. Reed, and Michael Andreeff. Mechanisms of apoptosis sensitivity and resistance to the BH3 mimetic ABT-737 in acute myeloid leukemia. Cancer Cell 2006: 10; 375-388

Suzanne Trudel, A. Keith Stewart, Zhihua Li, Yanjun Shu, Sheng-Ben Liang, Young Trieu, Donna Reece, Josh Paterson, Dingyan Wang, and Xiao-Yan Wen. The Bcl-2 family protein inhibitor,ABT-737, has substantial antimyeloma activity and shows synergistic effect with dexamethasone and melphalan. Clin Cancer Res 2007; 13 (2) 621-629

Product Citation

1. Sarah V Schweighofer, Daniel C Jans, et al. "Endogenous BAX and BAK form mosaic rings of variable size and composition on apoptotic mitochondria." Cell Death Differ. 2024 Apr;31(4):469-478. PMID: 38503846
2. Esmee Vringer, Rosalie Heilig, et al. "Mitochondrial outer membrane integrity regulates a ubiquitin-dependent NF-κB inflammatory response." EMBO J. 2024 Mar;43(6):904-930. PMID: 38337057
3. Esther A Guzmán, Tara A Peterson, et al. "The Marine Natural Compound Dragmacidin D Selectively Induces Apoptosis in Triple-Negative Breast Cancer Spheroids." Mar Drugs. 2023 Dec 15;21(12):642. PMID: 38132962
4. Qilian Ma, Jiaqi Xin, et al. "UBQLN2 and HSP70 participate in Parkin‐mediated mitophagy by facilitating outer mitochondrial membrane rupture." EMBO Rep. 2023 Sep 6;24(9):e55859. PMID: 37501540
5. Bianca A. Romo. "Estrogen Receptor (ER) Alpha Regulatory Mechanisms and Therapeutic Strategies in ER+ Breast Cancer." Dartmouth College. October 09, 2023.
6. Schwartz, Hannah, et al. "In vitro Methods to Better Evaluate Drug Responses in Cancer." UMass Chan Medical School. September 8, 2022.
7. Anna L. Koessinger, Catherine Cloix, et al. "Increased apoptotic sensitivity of glioblastoma enables therapeutic targeting by BH3-mimetics." Cell Death Differ. 2022 Oct;29(10):2089-2104. PMID: 35473984
8. Hector Flores-Romero, Lisa Hohorst, et al. "BCL‐2‐family protein tBID can act as a BAX‐like effector of apoptosis." EMBO J. 2021 Dec 21;e108690. PMID: 34931711
9. Florian J Bock, Egor Sedov, et al. "Apoptotic stress-induced FGF signalling promotes non-cell autonomous resistance to cell death." Nat Commun. 2021 Nov 12;12(1):6572. PMID: 34772930
10. 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
11. Alexander-Floyd J, Haroon S, et al. "Unexpected cell type-dependent effects of autophagy on polyglutamine aggregation revealed by natural genetic variation in C. elegans." BMC Biol. 2020;18(1):18. Published 2020 Feb 24. doi:10.1186/s12915-020-0750-5. PMID: 32093691
12. Lee B, Min JA, et al. "A novel mechanism of irinotecan targeting MDM2 and Bcl-xL." Biochem Biophys Res Commun. 2019 Jun 25;514(2):518-523. PMID: 31056264
13. Thompson PJ, Shah A, et al. "Targeted Elimination of Senescent Beta Cells Prevents Type 1 Diabetes." Cell Metab. 2019 Feb 14. pii: S1550-4131(19)30021-X. PMID: 30799288
8. Sheridan J.S. Carrington. "Differential Glycosylation of the Inwardly Rectifying Potassium Channel Kir7.1 by G protein-coupled Receptors." Vanderbilt University. 2019.
15. Yochum ZA, Cades J, et al. "Targeting the EMT transcription factor TWIST1 overcomes resistance to EGFR inhibitors in EGFR-mutant non-small-cell lung cancer." Oncogene. 2018 Aug 31. PMID: 30171258
16. Jeong HJ, Ryu KJ, et al. "Anticancer agent ABT-737 possesses anti-atopic dermatitis activity via blockade of caspase-1 in atopic dermatitis in vitro and in vivo models." Immunopharmacol Immunotoxicol. 2018 Jun 29:1-8. PMID: 29957081
17. Kim HY, Jeong HJ, et al. "Anti-allergic and anti-inflammatory effects of the Bcl-2 inhibitor ABT-737 on experimental allergic rhinitis models." Eur J Pharmacol. 2018 May 30;833:34-43. PMID: 29856968
18. Cao Y, Chen M, et al. "The proton pump inhibitor pantoprazole disrupts protein degradation systems and sensitizes cancer cells to death under various stresses."Cell Death Dis. 2018 May 22;9(6):604. PMID: 29789637
19. Giampazolias E, Zunino B, et al. "Mitochondrial permeabilization engages NF-κB-dependent anti-tumour activity under caspase deficiency." Nat Cell Biol. 2017 Sep;19(9):1116-1129. PMID: 28846096
20. 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
21. Joel Riley, Giovanni Quarato, et al. "Activated BAX/BAK enable mitochondrial inner membrane permeabilisation and mtDNA release during cell death."bioRxiv. 2018 February 26.
22. Frevert, Marie Louise. "24 drugs as potential SKP2 Inhibitors: a novel approach to finding new antidepressants. Dissertation, LMU München: Medizinische Fakultät." d-nb.info. 2017.
23. Xiang XY, Kang JS, et al. "SIRT3 participates in glucose metabolism interruption and apoptosis induced by BH3 mimetic S1 in ovarian cancer cells." Int J Oncol. 2016 Aug;49(2):773-84. PMID: 27277143
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26. 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	813.43
Cas No.	852808-04-9
Formula	C₄₂H₄₅ClN₆O₅S₂
Synonyms	ABT 737, ABT737
Solubility	≥40.67 mg/mL in DMSO; insoluble in EtOH; insoluble in H2O
Chemical Name	4-[4-[[2-(4-chlorophenyl)phenyl]methyl]piperazin-1-yl]-N-[4-[[(2R)-4-(dimethylamino)-1-phenylsulfanylbutan-2-yl]amino]-3-nitrophenyl]sulfonylbenzamide
SDF	Download SDF
Canonical SMILES	CN(C)CCC(CSC1=CC=CC=C1)NC2=C(C=C(C=C2)S(=O)(=O)NC(=O)C3=CC=C(C=C3)N4CCN(CC4)CC5=CC=CC=C5C6=CC=C(C=C6)Cl)[N+](=O)[O-]
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:
Cell lines	Small-cell lung cancer (SCLC) cell (NCI-H889, NCI-H1963, NCI-H1417, NCI-H146, NCI-187, DMS79, NCI-1048, NCI-H82, NCI-H196, H69AR, and DMS114) lines.
Preparation method	The solubility of this compound in DMSO is >10 mM. General tips for obtaining a higher concentration: Please warm the tube at 37 °C for 10 minutes and/or shake it in the ultrasonic bath for a while.Stock solution can be stored below -20°C for several months.
Reaction Conditions	48 h; 10 μM
Applications	The ability of ABT-737 to inhibit cell proliferation with single-agent activity was evaluated against a panel of 11 kinds of SCLC cell lines. Ac-DEVD-AMC, a substrate for activated caspase 3, was used to treatment of H146 cells for 24 h. A dose-dependent increase in apoptosis coincided with a dose-dependent decrease in cell viability following ABT-737 treatment suggesting that ABT-737 inhibits cell proliferation through the induction of apoptosis.
Animal experiment:
Animal models	Lymphoma-prone Eμ- myc transgenic mice
Dosage form	75 mg/kg body weight; the tail injection.
Applications	All B-lymphoid subsets in the ABT-737-treatment (75 mg/kg) cohort were significantly decreased, compared with the vehicle-treated animals, in both the bone marrow and the spleen. Eμ- myc animals treated with ABT-737 contained significantly (**P
Other notes	Please test the solubility of all compounds indoor, and the actual solubility may slightly differ with the theoretical value. This is caused by an experimental system error and it is normal.
References: [1] Tahir S K, Yang X, Anderson M G, et al. Influence of Bcl-2 family members on the cellular response of small-cell lung cancer cell lines to ABT-737[J]. Cancer research, 2007, 67(3): 1176-1183. [2] Kelly P N, Grabow S, Delbridge A R D, et al. Prophylactic treatment with the BH3 mimetic ABT-737 impedes Myc-driven lymphomagenesis in mice[J]. Cell Death & Differentiation, 2012, 20(1): 57-63.

Biological Activity

ABT-737 is a BH3 mimetic inhibitor of Bcl-xL, Bcl-2 and Bcl-w with EC50 of 78.7 nM, 30.3 nM and 197.8 nM, respectively; no inhibition observed against Mcl-1, Bcl-B or Bfl-1.
Targets	Bcl-xL	Bcl-2	Bcl-w
IC50	78.7 nM (EC50)	30.3 nM (EC50)	197.8 nM (EC50)

ABT-737 [852808-04-9]

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