S63845
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MedKoo CAT#: 406849

CAS#: 1799633-27-4

Description: 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

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S63845
CAS# 1799633-27-4

Theoretical Analysis

MedKoo Cat#: 406849
Name: S63845
CAS#: 1799633-27-4
Chemical Formula: C39H37ClF4N6O6S
Exact Mass: 828.21
Molecular Weight: 829.265
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 Quantity
1mg USD 90 Ready to ship
5mg USD 300 Ready to ship
10mg USD 550 Ready to ship
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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:

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/

Solubility Data

Solvent Max Conc. mg/mL Max Conc. 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

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.

Recalculate based on batch purity %
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: 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.
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.

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1: 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 19;538(7626):477-482. doi: 10.1038/nature19830. [Epub ahead of print] PubMed PMID: 27760111.

2: Nagai Y, Ueno S, Saeki Y, Soga F, Yanagihara T. Expression of the D3 dopamine receptor gene and a novel variant transcript generated by alternative splicing inhuman peripheral blood lymphocytes. Biochem Biophys Res Commun. 1993 Jul 15;194(1):368-74. PubMed PMID: 7916609.