Synonym
EPZ031686; EPZ-031686; EPZ 031686; NSC804862; NSC 804862; NSC-804862;
IUPAC/Chemical Name
6-chloro-2-oxo-N-((1R,3r,5S)-8-(((1-(4,4,4-trifluorobutyl)piperidin-4-yl)methyl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)indoline-5-carboxamide
InChi Key
OTEIUEJPHNOGBG-ACDBMABISA-N
InChi Code
InChI=1S/C26H34ClF3N4O4S/c27-22-14-23-17(11-24(35)32-23)10-21(22)25(36)31-18-12-19-2-3-20(13-18)34(19)39(37,38)15-16-4-8-33(9-5-16)7-1-6-26(28,29)30/h10,14,16,18-20H,1-9,11-13,15H2,(H,31,36)(H,32,35)/t18-,19+,20-
SMILES Code
O=C(C1=CC2=C(NC(C2)=O)C=C1Cl)N[C@H]3C[C@@](N4S(=O)(CC5CCN(CCCC(F)(F)F)CC5)=O)([H])CC[C@@]4([H])C3
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
SET and MYND domain containing-3 (SMYD3) is a member of the lysine methyltransferase family of proteins, and plays an important role in the methylation of various histone and non-histone targets. Proper functioning of SMYD3 is very important for the target molecules to determine their different roles in chromatin remodeling, signal transduction and cell cycle control. Due to the abnormal expression of SMYD3 in tumors, it is projected as a prognostic marker in various solid cancers.
Biological target:
EPZ031686 is an orally available SMYD3 inhibitor with an IC50 of 3 nM in cell-free assay.
In vitro activity:
EPZ030456 was slightly less stable than EPZ031686 (24 mL/min/kg). EPZ030456 also had a lower apical-to-basolateral apparent permeability (Papp= 0.34 ± 0.22 × 10–6 cm/s) in Caco-2 cells than EPZ031686 (Papp= 0.64 ± 0.20 × 10–6 cm/s). Both compounds were subject to active efflux in the Caco-2 cells, with efflux ratio values of 104 and 41, respectively. EPZ030456 and EPZ031686 had a free fraction of 0.32 ± 0.035 and 0.53 ± 0.12 in mouse plasma, respectively.
Reference: ACS Med Chem Lett. 2016 Feb 11; 7(2): 134–138. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4753551/
In vivo activity:
Male mice administered a single dose of EPZ031686 at 1 mg/kg by i.v. bolus showed a moderate clearance (CL) of 27 ± 3.9 mL/min/kg, in very good agreement with the mouse microsomal data, with a volume of distribution at steady state (Vss) of 2.3 ± 0.29 L/kg, translating to a mean terminal half-life (t1/2) of 1.7 ± 0.13 h. Approximately 20% of the administered dose was excreted unchanged in urine after 24 h, equivalent to a renal clearance (CLr) of 5.3 ± 1.6 mL/min/kg. Following 5 and 50 mg/kg p.o. dosing, both Cmax and AUC0-last increased in a slightly higher than dose-proportional manner, while t1/2 remained unchanged, suggesting a possible saturation of intestinal efflux. Bioavailability (F) of 48 ± 5.4% and 69 ± 8.2% was observed at 5 and 50 mg/kg, respectively, leading to EPZ031686 unbound blood concentration remaining above the SMYD3 ICW IC50 value for more than 12 h after a 50 mg/kg p.o. administration. In contrast, EPZ030456 solubility was not sufficient to be formulated for oral dosing at >30 mg/mL using a vehicle amenable to repeat dosing.
Reference: ACS Med Chem Lett. 2016 Feb 11; 7(2): 134–138. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4753551/
|
Solvent |
mg/mL |
mM |
| Solubility |
| DMSO |
5.9 |
9.98 |
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
591.09
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. Mitchell LH, Boriack-Sjodin PA, Smith S, Thomenius M, Rioux N, Munchhof M, Mills JE, Klaus C, Totman J, Riera TV, Raimondi A, Jacques SL, West K, Foley M, Waters NJ, Kuntz KW, Wigle TJ, Scott MP, Copeland RA, Smith JJ, Chesworth R. Novel Oxindole Sulfonamides and Sulfamides: EPZ031686, the First Orally Bioavailable Small Molecule SMYD3 Inhibitor. ACS Med Chem Lett. 2015 Aug 27;7(2):134-8. doi: 10.1021/acsmedchemlett.5b00272. PMID: 26985287; PMCID: PMC4753551.
In vitro protocol:
1. Mitchell LH, Boriack-Sjodin PA, Smith S, Thomenius M, Rioux N, Munchhof M, Mills JE, Klaus C, Totman J, Riera TV, Raimondi A, Jacques SL, West K, Foley M, Waters NJ, Kuntz KW, Wigle TJ, Scott MP, Copeland RA, Smith JJ, Chesworth R. Novel Oxindole Sulfonamides and Sulfamides: EPZ031686, the First Orally Bioavailable Small Molecule SMYD3 Inhibitor. ACS Med Chem Lett. 2015 Aug 27;7(2):134-8. doi: 10.1021/acsmedchemlett.5b00272. PMID: 26985287; PMCID: PMC4753551.
In vivo protocol:
1. Mitchell LH, Boriack-Sjodin PA, Smith S, Thomenius M, Rioux N, Munchhof M, Mills JE, Klaus C, Totman J, Riera TV, Raimondi A, Jacques SL, West K, Foley M, Waters NJ, Kuntz KW, Wigle TJ, Scott MP, Copeland RA, Smith JJ, Chesworth R. Novel Oxindole Sulfonamides and Sulfamides: EPZ031686, the First Orally Bioavailable Small Molecule SMYD3 Inhibitor. ACS Med Chem Lett. 2015 Aug 27;7(2):134-8. doi: 10.1021/acsmedchemlett.5b00272. PMID: 26985287; PMCID: PMC4753551.
1: Rajajeyabalachandran G, Kumar S, Murugesan T, Ekambaram S, Padmavathy R,
Jegatheesan SK, Mullangi R, Rajagopal S. Therapeutical potential of deregulated
lysine methyltransferase SMYD3 as a safe target for novel anticancer agents.
Expert Opin Ther Targets. 2017 Feb;21(2):145-157. doi:
10.1080/14728222.2017.1272580. Epub 2016 Dec 26. PubMed PMID: 28019723.
2: Mitchell LH, Boriack-Sjodin PA, Smith S, Thomenius M, Rioux N, Munchhof M,
Mills JE, Klaus C, Totman J, Riera TV, Raimondi A, Jacques SL, West K, Foley M,
Waters NJ, Kuntz KW, Wigle TJ, Scott MP, Copeland RA, Smith JJ, Chesworth R.
Novel Oxindole Sulfonamides and Sulfamides: EPZ031686, the First Orally
Bioavailable Small Molecule SMYD3 Inhibitor. ACS Med Chem Lett. 2015 Aug
27;7(2):134-8. doi: 10.1021/acsmedchemlett.5b00272. eCollection 2016 Feb 11.
PubMed PMID: 26985287; PubMed Central PMCID: PMC4753551.
