Name: S63845
Price: 244.00 USD

- Overview
  - Please contact us at for specific academic pricing.
    
    Background
    
    S63845 is a small molecule MCL1 inhibitor with Ki < 1.2 nM [1].
    Myeloid cell leukemia 1 (MCL1) is a pro-survival protein and belongs to BCL-2 family proteins. BCL-2 family proteins are key regulators of the mitochondrial apoptotic pathway. MCL1 is overexpressed in many cancers, so inhibitors targeting this protein may kills MCL1-dependent cancer cells [1].
    S63845 is a highly selective and potent MCL1 inhibitor. S63845 bound human MCL1 with KD value of 0.19 nM. S63845 was approximately 1,000-fold more potent in killing MCL1-dependent H929 multiple myeloma cells than MCL1 inhibitor A-1210477. S63845 also induced caspase-dependent phosphatidyl-serine exposure, PARP cleavage and cytochrome c release from mitochondria. In HeLa cells, S63845 disrupted binding of BAK and BAX to MCL1. S63845 killed cancer cells through activation of the BAX/BAK-dependent mitochondrial apoptotic pathway by direct inhibition of MCL1 [1].
    In immunocompromised mice with human multiple myeloma (H929 and AMO1) xenografts, intravenously injected (i.v.) S63845 showed dose-dependent anti-tumour activity with maximal tumour growth inhibition (TGImax) of 103% and 114% in the H929 and AMO1 model, respectively [1].
- Properties
  - Alternative Name
    
    (S)-2-(((S)-5-(3-chloro-2-methyl-4-(2-(4-methylpiperazin-1-yl)ethoxy)phenyl)-6-(5-fluorofuran-2-yl)thieno[2,3-d]pyrimidin-4-yl)oxy)-3-(2-((1-(2,2,2-trifluoroethyl)-1H-pyrazol-5-yl)methoxy)phenyl)propanoic acid
    
    CAS Number
    
    1799633-27-4
    
    Molecular Formula
    
    C39H37ClF4N6O6S
    
    Molecular Weight
    
    829.26
    
    Purity
    
    98.00%
    
    Solubility
    
    insoluble in H2O; ≥20 mg/mL in MeOH; ≥41.45 mg/mL in DMSO
    
    Storage
    
    Store at -20°C
    
    * For Research Use Only
- Reference
  - 1. Daniel Thomalla, Laura Beckmann, et al. "Deregulation and epigenetic modification of BCL2-family genes cause resistance to venetoclax in hematologic malignancies." Blood. 2022 Jun 15;blood.2021014304. PMID: 35704690
    2. Collins Waguia Kontchou, Ian E. Gentle, et al. "Chlamydia trachomatis inhibits apoptosis in infected cells by targeting the pro-apoptotic proteins Bax and Bak." Cell Death Differ. 2022 Apr 9. PMID: 35397654
    3. Vinzenz Särchen, Senthan Shanmugalingam, et al. "Pediatric multicellular tumor spheroid models illustrate a therapeutic potential by combining BH3 mimetics with Natural Killer (NK) cell-based immunotherapy." Cell Death Discov. 2022 Jan 10;8(1):11. PMID: 35013156
    4. Christine Greil, Julia Felthaus, et al. "Targeting mitotic exit in solid tumors." Am J Cancer Res. 2021 Jul 15;11(7):3698-3710. eCollection 2021. PMID: 34354869
    5. Chiara Boccellato, Emily Kolbe, et al. "Marizomib sensitizes primary glioma cells to apoptosis induced by a latest-generation TRAIL receptor agonist." Cell Death Dis. 2021 Jun 24;12(7):647. PMID: 34168123
    6. 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
    7. Adam Z Spitz, Emmanouil Zacharioudakis, et al. "Eltrombopag directly inhibits BAX and prevents cell death." Nat Commun. 2021 Feb 18;12(1):1134. PMID: 33602934
    8. Corinna König, Laura K. Hillert-Richter, et al. "Pharmacological targeting of c-FLIP L and Bcl-2 family members promotes apoptosis in CD95L-resistant cells." Sci Rep. 2020 Nov 30;10(1):20823. PMID: 33257694
    9. Lei Chen, Peimin Feng, et al. "Protective effects of isoquercitrin on streptozotocin‐induced neurotoxicity." J Cell Mol Med. 2020 Sep;24(18):10458-10467. PMID: 32738031
    10. Shahbandi A, Rao SG, et al. "BH3 mimetics selectively eliminate chemotherapy-induced senescent cells and improve response in TP53 wild-type breast cancer." Cell Death Differ. 2020;10.1038/s41418-020-0564-6. PMID: 32457483
    11. Kehr S, Haydn T, et al. "Targeting BCL-2 proteins in pediatric cancer: Dual inhibition of BCL-XL and MCL-1 leads to rapid induction of intrinsic apoptosis." Cancer Lett. 2020;482:19-32. PMID: 32145345
    12. Rohner L, Reinhart R, et al. "Impact of BH3-mimetics on Human and Mouse Blood Leukocytes: A Comparative Study." Sci Rep. 2020;10(1):222. PMID: 31937836
    13. Mattes K, Gerritsen M, et al. "CD34+ acute myeloid leukemia cells with low levels of reactive oxygen species show increased expression of stemness-genes and can be targeted by the BCL2 inhibitor Venetoclax." Haematologica. 2019 Nov 14. pii: haematol.2019.229997. PMID: 31727766
    14. Smith VM, Dietz A, et al. "Specific interactions of BCL-2 family proteins mediate sensitivity to BH3-mimetics in diffuse large B-cell lymphoma." Haematologica. 2019 Oct 10. pii: haematol.2019.220525. PMID: 31601689
    15. Zhao X, Ren Y, et al. "BCL2 Amplicon Loss and Transcriptional Remodeling Drives ABT-199 Resistance in B Cell Lymphoma Models." Cancer Cell. 2019 May 13;35(5):752-766.e9. PMID: 31085176
    16. Liang H, Chen Z, et al. "Inhibition of cyclin E1 overcomes temozolomide resistance in glioblastoma by Mcl-1 degradation." Mol Carcinog. 2019 Aug;58(8):1502-1511. PMID: 31045274
    17. Brokatzky D, Dörflinger B, et al. "A non-death function of the mitochondrial apoptosis apparatus in immunity." EMBO J. 2019 Jun 3;38(11). pii:e100907. PMID: 30979778
    18. Annunziato S, de Ruiter JR, et al. "Comparative oncogenomics identifies combinations of driver genes and drug targets in BRCA1-mutated breast cancer." Nat Commun. 2019 Jan 23;10(1):397. PMID: 30674894
    19. Uchida A, Isobe Y, et al. "Targeting BCL2 with venetoclax is a promising therapeutic strategy for "double-protein-expression" lymphoma with MYC and BCL2 rearrangements."Haematologica. 2018 Dec 6. pii: haematol.2018.204958. PMID: 30523053
    20. Chauhan D, Bartok E, et al. "BAX/BAK-Induced Apoptosis Results in Caspase-8-Dependent IL-1β Maturation in Macrophages." Cell Rep. 2018 Nov 27;25(9):2354-2368.e5. PMID: 30485805
    21. Bojarczuk K, Wienand K, et al. "Targeted inhibition of PI3Kα/δ is synergistic with BCL-2 blockade in genetically defined subtypes of DLBCL." Blood. 2018 Oct 15. pii: blood-2018-08-872465. PMID: 30322870
    22. Manzano M, Patil A, et al. "Gene essentiality landscape and druggable oncogenic dependencies in herpesviral primary effusion lymphoma." Nat Commun. 2018 Aug 15;9(1):3263. PMID: 30111820
    23. TReinhart R, Kaufmann T. "IL-4 enhances survival of in vitro-differentiated mouse basophils through transcription-independent signaling downstream of PI3K."Cell Death Dis. 2018 Jun 18;9(7):713. PMID: 29915306
    24. Wilson Xuan Mai."Comprehensive Characterization of the Apoptotic Machinery in Glioblastoma Identifies New Therapeutic Strategies." UNIVERSITY OF CALIFORNIA.2018-01-01.
    25. 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
    26. Campbell KJ, Dhayade S, et al. "MCL-1 is a prognostic indicator and drug target in breast cancer." Cell Death Dis. 2018 Jan 16;9(2):19. PMID: 29339815
    27. Lagares D, Santos A, et al. "Targeted apoptosis of myofibroblasts with the BH3 mimetic ABT-263 reverses established fibrosis." Sci Transl Med. 2017 Dec 13;9(420). pii:eaal3765. PMID: 29237758

S63845

S63845

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