A8737-25mg | S63845 [1799633-27-4] Biotrend

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].

Reference:

1.Kotschy A, Szlavik Z, Murray J, et al. The MCL1 inhibitor S63845 is tolerable and effective in diverse cancer models. Nature. 2016 Oct 19;538(7626):477-482.

1. Romo, Bianca A, et al. "Estrogen Receptor (ER) Alpha Regulatory Mechanisms and Therapeutic Strategies in ER+ Breast Cancer" (2024). Dartmouth College Ph.D Dissertations. 182.
2. Liu B, Zhou Y, et al. "EVA1A regulates hematopoietic stem cell regeneration via ER-mitochondria mediated apoptosis." Cell Death Dis 2023 Jan 30;14(1) PMID: 36717548
3. Lankes, Katharina, et al. "Synthetic lethalities to target a MYC-driven PDAC subtype" Technische Universität München. 2023.
4. Boccellato, Chiara, et al. "Overcoming glioblastoma intractability: pre-clinical characterisation of TRAIL sensitisation by marizomib and novel treatment perspectives." Universität Stuttgart. 2022.
5. 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
6. 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
7. 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
8. , 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
9. 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
10. 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
11. 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
12. 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
13. 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
14. 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
15. 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
16. 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
17. 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
18. 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
19. 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
20. 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
21. 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
22. 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
23. 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
24. 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
25. 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
26. 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
27. 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
28. 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
29. Wilson Xuan Mai."Comprehensive Characterization of the Apoptotic Machinery in Glioblastoma Identifies New Therapeutic Strategies." UNIVERSITY OF CALIFORNIA.2018-01-01.
30. 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
31. 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
32. 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

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Storage	Store at -20°C
M.Wt	829.26
Cas No.	1799633-27-4
Formula	C₃₉H₃₇ClF₄N₆O₆S
Solubility	insoluble in H2O; ≥20 mg/mL in MeOH; ≥41.45 mg/mL in DMSO
Chemical 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
SDF	Download SDF
Canonical SMILES	OC([C@@H](OC1=NC=NC2=C1[C@]([C@]3=C(C)C(Cl)=C(C=C3)OCCN4CCN(C)CC4)=C(C5=CC=C(F)O5)S2)CC6=CC=CC=C6OCC7=CC=NN7CC(F)(F)F)=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.

Cell experiment [1]:
Cell lines	Haematological cancer-derived cell lines, Myeloma cell lines, Human lymphomas and chronic myeloid leukaemia cell lines
Preparation method	This compound is soluble in DMSO. 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.
Reacting condition	1-10 μM, 48 h, 37°C
Applications	S63845 is a small molecule MCL1 inhibitor with Ki <1.2 nM. S63845 is effective against haematological cancer-derived cell lines. S63845 potently killed MCL1-dependent H929 multiple myeloma cells. S63845 disrupted binding of BAK and BAX to MCL1 in HeLa cells. Treatment with S63845 increased MCL1 protein levels in the HCT-116 colon carcinoma cell line. In the tested myeloma cell lines, some were highly sensitive to S63845 (IC50 <0.1 μM), six lines were moderately sensitive (0.1 μM <IC50 <1 μM) and two lines were insensitive (IC50 >1 μM). In a panel of human lymphomas and chronic myeloid leukaemia 11 cell lines: five lines were highly sensitive to S63845 (IC50 <0.1 μM), three were moderately sensitive (0.1 μM <IC50 <1 μM) and three were insensitive to S63845 (IC50 >1 μM). In a panel of eight AML cell lines: all lines were sensitive to S63845 (IC50 4–233 nM) [1].
Animal experiment [1]:
Animal models	Human multiple myeloma (H929 and AMO1) xenografted mice
Dosage form	Intravenously injected (i.v.), 25 mg/kg
Application	Intravenously injected (i.v.) S63845 exerted dose-dependent anti-tumour activity in human multiple myeloma (H929 and AMO1) xenografts in immunocompromised mice, with maximal tumour growth inhibition (TGImax) of 114% in the AMO1 model and 103% in the H929 model. S63845 (25 mg/kg) induced complete regression in 7 out of 8 of the mice at 100 days after treatment in the AMO1 model. S63845 (i.v., 25 mg/kg, 5 days) cured 70% of immuno-competent C57BL/6 mice bearing Eμ-Myc mouse lymphomas, with no side-effects evident in normal tissues. S63845 (12.5 mg/kg) showed potent activity in the MV4-11 human AML xenograft model, with a TGImax of 86%. S63845 (25 mg/kg) resulted in completeremission in 6 out of 8 mice after 80 days.
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]. Kotschy A, Szlavik Z, Murray J, et al. The MCL1 inhibitor S63845 is tolerable and effective in diverse cancer models. Nature. 2016 Oct 19;538(7626):477-482.

Purity = 98.96%

S63845 [1799633-27-4]

Katalog-Nummer A8737-25mg

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