Synonym
MS1943; MS 1943; MS-1943
IUPAC/Chemical Name
6-(6-(4-(2-(2-((3r,5r,7r)-adamantan-1-yl)acetamido)ethyl)piperazin-1-yl)pyridin-3-yl)-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-1-isopropyl-1H-indazole-4-carboxamide
InChi Key
WQIQJFXBAJJKNT-SIAAHZTCSA-N
InChi Code
InChI=1S/C42H54N8O3/c1-26(2)50-37-18-33(17-34(36(37)25-46-50)40(52)45-24-35-27(3)13-28(4)47-41(35)53)32-5-6-38(44-23-32)49-11-9-48(10-12-49)8-7-43-39(51)22-42-19-29-14-30(20-42)16-31(15-29)21-42/h5-6,13,17-18,23,25-26,29-31H,7-12,14-16,19-22,24H2,1-4H3,(H,43,51)(H,45,52)(H,47,53)/t29-,30+,31-,42?
SMILES Code
CC(C)N(N=C1)C2=C1C(C(NCC3=C(C)C=C(C)NC3=O)=O)=CC(C4=CC=C(N=C4)N(CC5)CCN5CCNC(CC67C[C@H]8C[C@H](C[C@H](C8)C7)C6)=O)=C2
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
>3 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
Biological target:
MS1943 is an EZH2 selective degrader with an IC50 value of 120 nM.
In vitro activity:
To gain mechanistic insights into how MS1943 induces cell death, MDA-MB-468 cells were treated with MS1943 or DMSO control and changes of gene expression were assessed using RNA-seq experiments. Interestingly, MS1943-treated cells were characterized by a unique set of deregulated genes that could readily separate them from control cells (Fig. 6a). It was identified that several PRC2 target gene programs, including Wnt/ß-catenin signaling (c-Myc, cyclin D1 and Axin2), RUNX3, CK5 and CK6, were significantly altered in MS1943-treated cells with a false discovery rate (FDR) at 5%, as when EZH2 is degraded. It was confirmed through quantitative real-time PCR that Xbp1 and its downstream effectors Chop and Bip were upregulated in response to treatment with MS1943 in MDA-MB-468 cells starting at 4 h of treatment and that induction was sustained for at least two days (Supplementary Fig. 14). Of note, the processed/spliced Xbp1 transcript (Xbp1–207) that can result in active XBP139 was the only transcript that was significantly upregulated after treatment with the degrader as evidenced by our RNA-seq data (Fig. 6c). Taken together, these data suggest that EZH2 degradation could result in sustained overactivation of the UPR pathway in MS1943-sensitive cells due to prolonged ER stress, which in turn could be deleterious and lead to apoptosis. To test this hypothesis, MDA-MB-468 cells (which are sensitive to MS1943) and MDA-MB-231 cells (which are insensitive to MS1943) were treated with the ER-stress inducer tunicamycin and found that it effectively induced cell death in MDA-MB-468 cells but not in MDA-MB-231 cells (Fig. 6d and Supplementary Fig. 15). These results suggest hat MS1943 mediates its cytotoxic effects through ER stress and UPR induction in cells that are dependent for their growth on EZH2.
Nat Chem Biol. 2020 Feb; 16(2): 214–222. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6982609/
In vivo activity:
It was decided to evaluate the in vivo antitumor activity of MS1943 by treating mice bearing MDA-MB-468 tumor xenografts with 150 mg per kg body weight once daily i.p. injection of MS1943. Importantly, tumor growth was completely suppressed by MS1943, in comparison to the vehicle group (Fig. 4b). At this dose, MS1943 was well tolerated by the test mice, which did not exhibit any weight loss or other overt toxicities (Fig. 4c). To further investigate the effects of MS1943 in vivo, tumor samples were analyzed at the endpoint of the experiment using immunohistochemistry. Consistent with the in vitro data, a significant reduction of both EZH2 protein levels and H3K27me3 mark were observed in the tumors from mice treated with MS1943 (Fig. 5a,b). The antitumoral effect of MS1943 was due to increased apoptosis, as measured by cleaved caspase-3 levels, as well as decreased proliferation, as measured by staining with Ki-67 (Fig. 5a,b). Thus, a PK/PD relationship has been established for MS1943 in this tumor xenograft model. Overall, MS1943 was efficacious in vivo and well tolerated in mice at the efficacious dose.
Nat Chem Biol. 2020 Feb; 16(2): 214–222. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6982609/
|
Solvent |
mg/mL |
mM |
| Solubility |
| Soluble in DMSO |
100.0 |
139.10 |
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
718.95
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. Ma A, Stratikopoulos E, Park KS, Wei J, Martin TC, Yang X, Schwarz M, Leshchenko V, Rialdi A, Dale B, Lagana A, Guccione E, Parekh S, Parsons R, Jin J. Discovery of a first-in-class EZH2 selective degrader. Nat Chem Biol. 2020 Feb;16(2):214-222. doi: 10.1038/s41589-019-0421-4. Epub 2019 Dec 9. PMID: 31819273; PMCID: PMC6982609.
In vitro protocol:
1. Ma A, Stratikopoulos E, Park KS, Wei J, Martin TC, Yang X, Schwarz M, Leshchenko V, Rialdi A, Dale B, Lagana A, Guccione E, Parekh S, Parsons R, Jin J. Discovery of a first-in-class EZH2 selective degrader. Nat Chem Biol. 2020 Feb;16(2):214-222. doi: 10.1038/s41589-019-0421-4. Epub 2019 Dec 9. PMID: 31819273; PMCID: PMC6982609.
In vivo protocol:
1. Ma A, Stratikopoulos E, Park KS, Wei J, Martin TC, Yang X, Schwarz M, Leshchenko V, Rialdi A, Dale B, Lagana A, Guccione E, Parekh S, Parsons R, Jin J. Discovery of a first-in-class EZH2 selective degrader. Nat Chem Biol. 2020 Feb;16(2):214-222. doi: 10.1038/s41589-019-0421-4. Epub 2019 Dec 9. PMID: 31819273; PMCID: PMC6982609.
1: Ma A, Stratikopoulos E, Park KS, Wei J, Martin TC, Yang X, Schwarz M,
Leshchenko V, Rialdi A, Dale B, Lagana A, Guccione E, Parekh S, Parsons R, Jin
J. Discovery of a first-in-class EZH2 selective degrader. Nat Chem Biol. 2020
Feb;16(2):214-222. doi: 10.1038/s41589-019-0421-4. Epub 2019 Dec 9. PMID:
31819273; PMCID: PMC6982609.
2: Jeong Y, Kim SB, Yang CE, Yu MS, Choi WS, Jeon Y, Lim JY. Overcoming the
therapeutic limitations of EZH2 inhibitors in Burkitt's lymphoma: a
comprehensive study on the combined effects of MS1943 and Ibrutinib. Front
Oncol. 2023 Sep 11;13:1252658. doi: 10.3389/fonc.2023.1252658. PMID: 37752998;
PMCID: PMC10518396.
3: Kuser-Abali G, Zhang Y, Szeto P, Zhao P, Masoumi-Moghaddam S, Fedele CG,
Leece I, Huang C, Cheung JG, Ameratunga M, Noguchi F, Andrews MC, Wong NC,
Schittenhelm RB, Shackleton M. UHRF1/UBE2L6/UBR4-mediated ubiquitination
regulates EZH2 abundance and thereby melanocytic differentiation phenotypes in
melanoma. Oncogene. 2023 Apr;42(17):1360-1373. doi: 10.1038/s41388-023-02631-8.
Epub 2023 Mar 11. PMID: 36906655; PMCID: PMC10121471.
4: Kim SB, Yang CE, Jeong Y, Yu M, Choi WS, Lim JY, Jeon Y. Dual Targeting of
EZH2 Degradation and EGFR/HER2 Inhibition for Enhanced Efficacy against
Burkitt's Lymphoma. Cancers (Basel). 2023 Sep 8;15(18):4472. doi:
10.3390/cancers15184472. PMID: 37760442; PMCID: PMC10526300.
