S63845 | S-63845 | CAS#1799633-27-4 | MCL1 inhibitor

MedKoo Cat#: 406849 | Name: S63845

Description:

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

S63845 is a potent and selective MCL1 inhibitor (Ki (MCL1, FP) < 1.2 nM; Kd (MCL1, SPR) = 0.19 nM; Ki (BCL2, FP) > 10.000 1.2 nM; Ki (BCL-XL, FP) > 10.000 1.2 nM). S63845 specifically binds with high affinity to the BH3-binding groove of MCL1. S63845 potently kills MCL1-dependent cancer cells, including multiple myeloma, leukaemia and lymphoma cells, by activating the BAX/BAK-dependent mitochondrial apoptotic pathway. In vivo, S63845 shows potent anti-tumour activity with an acceptable safety margin as a single agent in several cancers. Moreover, MCL1 inhibition, either alone or in combination with other anti-cancer drugs, proved effective against several solid cancer-derived cell lines. These results point towards MCL1 as a target for the treatment of a wide range of tumours.

Chemical Structure

S63845

CAS#1799633-27-4

Theoretical Analysis

MedKoo Cat#: 406849

Name: S63845

CAS#: 1799633-27-4

Chemical Formula: C39H37ClF4N6O6S

Exact Mass: 828.2120

Molecular Weight: 829.26

Elemental Analysis: C, 56.49; H, 4.50; Cl, 4.27; F, 9.16; N, 10.13; O, 11.58; S, 3.87

Price and Availability

Size	Price	Availability
1mg	USD 90.00	Ready to ship
5mg	USD 300.00	Ready to ship
10mg	USD 550.00	Ready to ship

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Related CAS #

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Synonym

S63845; S-63845; S 63845.

IUPAC/Chemical Name

(R)-2-((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

InChi Key

ZFBHXVOCZBPADE-SSEXGKCCSA-N

InChi Code

InChI=1S/C39H37ClF4N6O6S/c1-23-26(7-8-28(34(23)40)53-18-17-49-15-13-48(2)14-16-49)32-33-36(45-22-46-37(33)57-35(32)29-9-10-31(41)55-29)56-30(38(51)52)19-24-5-3-4-6-27(24)54-20-25-11-12-47-50(25)21-39(42,43)44/h3-12,22,30H,13-21H2,1-2H3,(H,51,52)/t30-/m1/s1

SMILES Code

O=C(O)[C@@H](CC1=C(OCC2=CC=NN2CC(F)(F)F)C=CC=C1)OC3=C4C(SC(C5=CC=C(F)O5)=[C@@]4[C@@]6=C(C)C(Cl)=C(OCCN7CCN(C)CC7)C=C6)=NC=N3

Appearance

White to off-white 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

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#A9T06K05

QC Data

View QC data: current batch, Lot#A9T06K05

Safety Data Sheet (SDS)

View Safety Data Sheet (SDS)

Instruction

View handling instruction

Biological target:

S63845 is a potent and selective MCL1 inhibitor (Ki (MCL1, FP) < 1.2 nM; Kd (MCL1, SPR) = 0.19 nM; Ki (BCL2, FP) > 10.000 1.2 nM; Ki (BCL-XL, FP) > 10.000 1.2 nM). S63845 binds with high affinity to the BH3-binding groove of MCL1. S63845 potently kills MCL1-dependent cancer cells, including multiple myeloma, leukaemia and lymphoma cells, by activating the BAX/BAK-dependent mitochondrial apoptotic pathway.

In vitro activity:

This study investigated the effects of S63845 on several cutaneous T-cell lymphoma (CTCL) cell lines. S63845 induced significant apoptosis, reduced cell viability, disrupted mitochondrial function, and activated caspases in two CTCL cell lines (HH and HuT-78). However, two other cell lines (MyLa and SeAx) remained completely resistant to S63845. Cells resistant to S63845 were sensitive to inhibitors of Bcl-2, Bcl-xL, and Bcl-w, such as ABT-263 and ABT-737. Reference: Int J Mol Sci. 2022 Oct 18;23(20):12471. https://pubmed.ncbi.nlm.nih.gov/36293331/

In vivo activity:

In a mouse model of hematopoietic injury, S63845 affected the hematopoiesis of various lineages in the early stage of action, causing extramedullary compensatory hematopoiesis in the myeloid and megakaryocytic lineages. The maturation of the erythroid lineage in the intramedullary and extramedullary segments was blocked to varying degrees, and both the intramedullary and extramedullary lymphoid lineages were inhibited. Reference: Pharmaceutics. 2023 Mar 28;15(4):1085. https://pubmed.ncbi.nlm.nih.gov/37111571/

	Solvent	mg/mL	mM
Solubility
	DMF	30.0	36.18
	DMSO	54.4	65.65
	Ethanol	65.0	78.38
	Ethanol:PBS (pH 7.2) (1:7)	0.1	0.15

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 829.26 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. Sumarni U, Zhu J, Sinnberg T, Eberle J. Sensitivity of Cutaneous T-Cell Lymphoma Cells to the Mcl-1 Inhibitor S63845 Correlates with the Lack of Bcl-w Expression. Int J Mol Sci. 2022 Oct 18;23(20):12471. doi: 10.3390/ijms232012471. PMID: 36293331; PMCID: PMC9604298. 2. Kotschy A, Szlavik Z, Murray J, Davidson J, Maragno AL, Le Toumelin-Braizat G, Chanrion M, Kelly GL, Gong JN, Moujalled DM, Bruno A, Csekei M, Paczal A, Szabo ZB, Sipos S, Radics G, Proszenyak A, Balint B, Ondi L, Blasko G, Robertson A, Surgenor A, Dokurno P, Chen I, Matassova N, Smith J, Pedder C, Graham C, Studeny A, Lysiak-Auvity G, Girard AM, Gravé F, Segal D, Riffkin CD, Pomilio G, Galbraith LC, Aubrey BJ, Brennan MS, Herold MJ, Chang C, Guasconi G, Cauquil N, Melchiore F, Guigal-Stephan N, Lockhart B, Colland F, Hickman JA, Roberts AW, Huang DC, Wei AH, Strasser A, Lessene G, Geneste O. The MCL1 inhibitor S63845 is tolerable and effective in diverse cancer models. Nature. 2016 Oct 27;538(7626):477-482. doi: 10.1038/nature19830. Epub 2016 Oct 19. PMID: 27760111. 3. Zhang H, Li F, Yang M, Zhang W, He M, Xu H, Wang C, Zhang Y, Wang W, Gao Y, Du X, Li Y. MCL-1 Inhibitor S63845 Distinctively Affects Intramedullary and Extramedullary Hematopoiesis. Pharmaceutics. 2023 Mar 28;15(4):1085. doi: 10.3390/pharmaceutics15041085. PMID: 37111571; PMCID: PMC10144179. 4. Azad AI, Krishnan A, Troop L, Li Y, Katsumi T, Pavelko K, Kostallari E, Guicciardi ME, Gores GJ. Targeted Apoptosis of Ductular Reactive Cells Reduces Hepatic Fibrosis in a Mouse Model of Cholestasis. Hepatology. 2020 Sep;72(3):1013-1028. doi: 10.1002/hep.31211. PMID: 32128842; PMCID: PMC7774262.

In vitro protocol:

In vivo protocol:

1. Zhang H, Li F, Yang M, Zhang W, He M, Xu H, Wang C, Zhang Y, Wang W, Gao Y, Du X, Li Y. MCL-1 Inhibitor S63845 Distinctively Affects Intramedullary and Extramedullary Hematopoiesis. Pharmaceutics. 2023 Mar 28;15(4):1085. doi: 10.3390/pharmaceutics15041085. PMID: 37111571; PMCID: PMC10144179. 2. Azad AI, Krishnan A, Troop L, Li Y, Katsumi T, Pavelko K, Kostallari E, Guicciardi ME, Gores GJ. Targeted Apoptosis of Ductular Reactive Cells Reduces Hepatic Fibrosis in a Mouse Model of Cholestasis. Hepatology. 2020 Sep;72(3):1013-1028. doi: 10.1002/hep.31211. PMID: 32128842; PMCID: PMC7774262.

1: Su Y, Huo T, Wang Y, Li J. Construction and clinical significance of prognostic risk markers based on cancer driver genes in lung adenocarcinoma. Clin Transl Oncol. 2024 Sep 18. doi: 10.1007/s12094-024-03703-1. Epub ahead of print. PMID: 39292390. 2: Krastinaite I, Charkavliuk S, Navakauskiene R, Borutinskaite VV. Metformin as an Enhancer for the Treatment of Chemoresistant CD34+ Acute Myeloid Leukemia Cells. Genes (Basel). 2024 May 20;15(5):648. doi: 10.3390/genes15050648. PMID: 38790277; PMCID: PMC11121461. 3: Seipel K, Mandhair H, Bacher U, Pabst T. FLT3 and IRAK4 Inhibitor Emavusertib in Combination with BH3-Mimetics in the Treatment of Acute Myeloid Leukemia. Curr Issues Mol Biol. 2024 Mar 29;46(4):2946-2960. doi: 10.3390/cimb46040184. PMID: 38666914; PMCID: PMC11049208. 4: Galas-Filipowicz D, Chavda SJ, Gong JN, Huang DCS, Khwaja A, Yong K. Co- operation of MCL-1 and BCL-XL anti-apoptotic proteins in stromal protection of MM cells from carfilzomib mediated cytotoxicity. Front Oncol. 2024 Apr 8;14:1394393. doi: 10.3389/fonc.2024.1394393. PMID: 38651147; PMCID: PMC11033393. 5: Peng Z, Gillissen B, Richter A, Sinnberg T, Schlaak MS, Eberle J. Effective Targeting of Melanoma Cells by Combination of Mcl-1 and Bcl-2/Bcl-xL/Bcl-w Inhibitors. Int J Mol Sci. 2024 Mar 19;25(6):3453. doi: 10.3390/ijms25063453. PMID: 38542429; PMCID: PMC10970841. 6: Jia J, Ji W, Saliba AN, Csizmar CM, Ye K, Hu L, Peterson KL, Schneider PA, Meng XW, Venkatachalam A, Patnaik MM, Webster JA, Smith BD, Ghiaur G, Wu X, Zhong J, Pandey A, Flatten KS, Deng Q, Wang H, Kaufmann SH, Dai H. AMPK inhibition sensitizes acute leukemia cells to BH3 mimetic-induced cell death. Cell Death Differ. 2024 Apr;31(4):405-416. doi: 10.1038/s41418-024-01283-9. Epub 2024 Mar 27. PMID: 38538744; PMCID: PMC11043078. 7: Durand R, Descamps G, Bellanger C, Dousset C, Maïga S, Alberge JB, Derrien J, Cruard J, Minvielle S, Lilli NL, Godon C, Le Bris Y, Tessoulin B, Amiot M, Gomez-Bougie P, Touzeau C, Moreau P, Chiron D, Moreau-Aubry A, Pellat-Deceunynck C. A p53 score derived from TP53 CRISPR/Cas9 HMCLs predicts survival and reveals a major role of BAX in the response to BH3 mimetics. Blood. 2024 Mar 28;143(13):1242-1258. doi: 10.1182/blood.2023021581. PMID: 38096363. 8: Juarez D, Buono R, Matulis SM, Gupta VA, Duong M, Yudiono J, Paul M, Mallya S, Diep G, Hsin P, Lu A, Suh SM, Dong VM, Roberts AW, Leverson JD, Jalaluddin M, Liu Z, Bueno OF, Boise LH, Fruman DA. Statin-induced Mitochondrial Priming Sensitizes Multiple Myeloma Cells to BCL2 and MCL-1 Inhibitors. Cancer Res Commun. 2023 Dec 8;3(12):2497-2509. doi: 10.1158/2767-9764.CRC-23-0350. PMID: 37956312; PMCID: PMC10704957. 9: Hartman ML, Koziej P, Kluszczyńska K, Czyz M. Pro-Apoptotic Activity of MCL-1 Inhibitor in Trametinib-Resistant Melanoma Cells Depends on Their Phenotypes and Is Modulated by Reversible Alterations Induced by Trametinib Withdrawal. Cancers (Basel). 2023 Sep 29;15(19):4799. doi: 10.3390/cancers15194799. PMID: 37835493; PMCID: PMC10571954. 10: Acton A, Placzek WJ. Myeloid Cell Leukemia 1 Small Molecule Inhibitor S63845 Synergizes with Cisplatin in Triple-Negative Breast Cancer. Cancers (Basel). 2023 Sep 8;15(18):4481. doi: 10.3390/cancers15184481. PMID: 37760451; PMCID: PMC10526511. 11: Seipel K, Kohler S, Bacher U, Pabst T. HSP90 Inhibitor PU-H71 in Combination with BH3-Mimetics in the Treatment of Acute Myeloid Leukemia. Curr Issues Mol Biol. 2023 Aug 23;45(9):7011-7026. doi: 10.3390/cimb45090443. PMID: 37754227; PMCID: PMC10529370. 12: Jacob M, Wiedemann S, Brücher D, Pieper NM, Birkhold M, Särchen V, Jeroch J, Demes MC, Gretser S, Braun Y, Gradhand E, Rothweiler F, Michaelis M, Cinatl J Jr, Vogler M. Increased MCL1 dependency leads to new applications of BH3-mimetics in drug-resistant neuroblastoma. Br J Cancer. 2023 Nov;129(10):1667-1678. doi: 10.1038/s41416-023-02430-8. Epub 2023 Sep 19. PMID: 37723317; PMCID: PMC10646009. 13: Mishra A, Kumar A, Naik L, Patel S, Das M, Behura A, Nayak DK, Mishra A, Bhutia SK, Singh R, Dhiman R. Soybean lectin-triggered IL-6 secretion induces autophagy to kill intracellular mycobacteria through P2RX7 dependent activation of the JAK2/STAT3/Mcl-1 pathway. Cytokine. 2023 Nov;171:156366. doi: 10.1016/j.cyto.2023.156366. Epub 2023 Sep 18. PMID: 37716189. 14: Sneyers F, Kerkhofs M, Speelman-Rooms F, Welkenhuyzen K, La Rovere R, Shemy A, Voet A, Eelen G, Dewerchin M, Tait SWG, Ghesquière B, Bootman MD, Bultynck G. Intracellular BAPTA directly inhibits PFKFB3, thereby impeding mTORC1-driven Mcl-1 translation and killing MCL-1-addicted cancer cells. Cell Death Dis. 2023 Sep 8;14(9):600. doi: 10.1038/s41419-023-06120-4. PMID: 37684238; PMCID: PMC10491774. 15: Asai-Nishishita A, Kawahara M, Tatsumi G, Iwasa M, Fujishiro A, Nishimura R, Minamiguchi H, Kito K, Murata M, Andoh A. FUS-ERG induces late-onset azacitidine resistance in acute myeloid leukaemia cells. Sci Rep. 2023 Sep 2;13(1):14454. doi: 10.1038/s41598-023-41230-1. PMID: 37660196; PMCID: PMC10475016. 16: Arandjelovic P, Kim Y, Cooney JP, Preston SP, Doerflinger M, McMahon JH, Garner SE, Zerbato JM, Roche M, Tumpach C, Ong J, Sheerin D, Smyth GK, Anderson JL, Allison CC, Lewin SR, Pellegrini M. Venetoclax, alone and in combination with the BH3 mimetic S63845, depletes HIV-1 latently infected cells and delays rebound in humanized mice. Cell Rep Med. 2023 Sep 19;4(9):101178. doi: 10.1016/j.xcrm.2023.101178. Epub 2023 Aug 30. PMID: 37652018; PMCID: PMC10518630. 17: Li Y, Du L, Ye K, Sun X, Hu L, Gao S, Dai H. AKT inhibition sensitizes acute leukemia cells to S63845-induced apoptosis. Hematology. 2023 Dec;28(1):2214465. doi: 10.1080/16078454.2023.2214465. PMID: 37222135. 18: Pan P, Ge W, Lei Z, Luo W, Liu Y, Guan Z, Chen L, Yu Z, Shen M, Hu D, Xiang Q, Wang W, Wan P, Tian M, Yu Y, Luo Z, Chen X, Xiao H, Zhang Q, Liang X, Chen X, Li Y, Wu J. SARS-CoV-2 N protein enhances the anti-apoptotic activity of MCL-1 to promote viral replication. Signal Transduct Target Ther. 2023 May 9;8(1):194. doi: 10.1038/s41392-023-01459-8. PMID: 37160897; PMCID: PMC10169150. 19: Zhang H, Li F, Yang M, Zhang W, He M, Xu H, Wang C, Zhang Y, Wang W, Gao Y, Du X, Li Y. MCL-1 Inhibitor S63845 Distinctively Affects Intramedullary and Extramedullary Hematopoiesis. Pharmaceutics. 2023 Mar 28;15(4):1085. doi: 10.3390/pharmaceutics15041085. PMID: 37111571; PMCID: PMC10144179. 20: Opydo M, Mlyczyńska A, Mlyczyńska E, Rak A, Kolaczkowska E. Synergistic Action of MCL-1 Inhibitor with BCL-2/BCL-XL or MAPK Pathway Inhibitors Enhances Acute Myeloid Leukemia Cell Apoptosis and Differentiation. Int J Mol Sci. 2023 Apr 13;24(8):7180. doi: 10.3390/ijms24087180. PMID: 37108344; PMCID: PMC10138770.

1. Srivastava S, Sekar G, Ojoawo A, Aggarwal A, Ferreira E, Uchikawa E, Yang M, Grace CR, Dey R, Lin YL, Guibao CD, Jayaraman S, Mukherjee S, Kossiakoff AA, Dong B, Myasnikov A, Moldoveanu T. Structural basis of BAK sequestration by MCL-1 in apoptosis. Mol Cell. 2025 Apr 17;85(8):1606-1623.e10. doi: 10.1016/j.molcel.2025.03.013. Epub 2025 Apr 4. PMID: 40187349; PMCID: PMC12086701.