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MedKoo Cat#: 407278 | Name: BAY-598
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Description:

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

BAY-598 is a potent, peptide-competitive chemical probe for SMYD2. BAY-598 has a unique chemotype relative to the current SMYD2 chemical probe LLY-507. BAY-598 inhibits in vitro methylation of p53K370 with IC50 = 27 nM and has more than 100-fold selectivity over other histone methyltransferases and other non-epigenetic targets. BAY-598 inhibits the methylation of p53K370 in cells with IC50 < 1 µM. (Further to this, BAY-598 has properties that are compatible with in vivo experiments.) A control compound, BAY-369, has also been developed. BAY-369 inhibits the in vitro methylation of p53K370 with IC50 > 70 micromolar.

Chemical Structure

BAY-598
BAY-598
CAS#1906919-67-2 (S-isomer)

Theoretical Analysis

MedKoo Cat#: 407278

Name: BAY-598

CAS#: 1906919-67-2 (S-isomer)

Chemical Formula: C22H20Cl2F2N6O3

Exact Mass: 524.0942

Molecular Weight: 525.34

Elemental Analysis: C, 50.30; H, 3.84; Cl, 13.50; F, 7.23; N, 16.00; O, 9.14

Price and Availability

Size Price Availability Quantity
5mg USD 90.00 Ready to Ship
10mg USD 150.00 Ready to Ship
25mg USD 250.00 Ready to Ship
50mg USD 450.00 Ready to Ship
100mg USD 750.00 Ready to Ship
200mg USD 1,350.00 Ready to Ship
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Related CAS #
1906919-67-2 (S-isomer) 1906920-28-2 (BAY598 R-isomer) 1906920-07-7 (BAY598 recamic mixture)
Synonym
BAY-598; BAY 598; BAY598.
IUPAC/Chemical Name
(S,E)-N-(1-(N'-cyano-N-(3-(difluoromethoxy)phenyl)carbamimidoyl)-3-(3,4-dichlorophenyl)-4,5-dihydro-1H-pyrazol-4-yl)-N-ethyl-2-hydroxyacetamide
InChi Key
OTTJIRVZJJGFTK-SFHVURJKSA-N
InChi Code
InChI=1S/C22H20Cl2F2N6O3/c1-2-31(19(34)11-33)18-10-32(30-20(18)13-6-7-16(23)17(24)8-13)22(28-12-27)29-14-4-3-5-15(9-14)35-21(25)26/h3-9,18,21,33H,2,10-11H2,1H3,(H,28,29)/t18-/m0/s1
SMILES Code
CCN(C(CO)=O)[C@H]1CN(/C(NC2=CC=CC(OC(F)F)=C2)=N/C#N)N=C1C3=CC(Cl)=C(Cl)C=C3
Appearance
Beige 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, not in water
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 protein 2 (SMYD2) is a member of the SMYD family of protein methyltransferases. All five members of this family (SMYD1–5) contain a conserved catalytic SET domain and a zinc-finger MYND motif. SMYD2 methylates both histone and non-histone proteins, including p53/TP53 and RB1 [1-3]. It specifically methylates histone H3 'Lys-4' (H3K4me) and dimethylates histone H3 'Lys-36' (H3K36me2) [1]. It has relatively higher methyltransferase activity on p53/TP53 and monomethylates 'Lys-370' of p53/TP53, leading to decreased DNA-binding activity and subsequent transcriptional regulation activity of p53/TP53. SMYD2 is over-expressed in esophageal squamous primary carcinomas and that over-expression correlates with poor patient survival [2]. (http://www.thesgc.org/chemical-probes/BAY-598)
Biological target:
BAY-598 is selective small molecule inhibitor of SMYD2 with an IC50 of 27 nM.
In vitro activity:
Endogenous methylation of p53 protein was characterized by treatment of KYSE-150 esophageal cancer cells with increasing concentrations of (S)-4 (BAY-598) for 5 days. The KYSE-150 cell line model was selected based on a described SMYD2 (SET and MYND domain containing protein 2) gene amplification and a heterozygous R248Q mutation in p53 (COSMIC), leading to p53 protein accumulation without a stress stimulus. After treatment with (S)-4, a significant reduction of methylation was detected confirming that p53 is a cellular target of SMYD2-dependent methylation (Figure 6B). Nevertheless overall endogenous detection of p53 protein methylation led to weak signals, hence this method was not useful for the determination of a cellular IC50. Therefore, an established system with a transient FLAG-tagged SMYD2 and FLAG-tagged p53 overexpression in HEK293T cells as benchmark assay was employed. This assay has been used previously to characterize the structurally unrelated SMYD2 inhibitor. As shown in Figure 6C, (S)-4 showed a concentration-dependent decrease in p53 methylation without affecting p53 total protein levels. A cellular IC50 of 58 nM was determined (Figure 6D), which confirms that (S)-4 is the most potent cellular-active SMYD2 inhibitor known to date (Figure 1). Reference: J Med Chem. 2016 May 26; 59(10): 4578–4600. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4917279/
In vivo activity:
To this end, mice bearing subcutaneous tumor xenografts (tumor tissue derived from the SMYD2-overexpressing KYSE-150 cell line) were treated orally with 10, 30, 70, or 100 mg/kg (S)-4, or vehicle (PEG 400/water 8:2), once daily for 3 days. (S)-4 significantly reduced the methylation with doses starting from 30 mg/kg, with most significant effects in the 100 mg/kg treated group (P < 0.001, Student’s t test) (Figure 9A). Treatment with 10 mg/kg (S)-4 resulted in no significant effect on the methylation level. Then the KYSE-150 esophageal xenograft model was used to evaluate if the observed improved apoptosis induction in the in vitro setting after treatment with doxorubicin (Figure 8B) could translate to antitumor efficacy in vivo. Four groups of tumor-bearing mice were treated as follows: Group 1 (control group) was only treated with vehicle (Solutol/ethanol/water 1:1:8) iv qd and once at day 4 with the vehicle used for doxorubicin (saline) iv; group 2 was treated with (S)-4 at 500 mg/kg po qd; group 3 was treated with 10 mg/kg doxorubicin iv once at day 4; group 4 was treated with a combination of (S)-4 and doxorubicin. There was a slight reduction in area (Figure 9B) and weight (Figure 9C) of tumors from mice treated with the combination of (S)-4 and doxorubicin relative to tumors from the control group. Therefore, combination of a SMYD2 inhibitor with a chemotherapeutic agent resulted in reduced cancer cell growth in vivo. In comparison, the monotherapy groups treated with only doxorubicin or (S)-4 showed no significant antitumor efficacy relative to the vehicle control group. Reference: J Med Chem. 2016 May 26; 59(10): 4578–4600. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4917279/
Solvent mg/mL mM
Solubility
DMSO 69.2 131.69
DMF 30.0 57.11
Ethanol 30.0 57.11
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 525.34 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. Eggert E, Hillig RC, Koehr S, Stöckigt D, Weiske J, Barak N, Mowat J, Brumby T, Christ CD, Ter Laak A, Lang T, Fernandez-Montalvan AE, Badock V, Weinmann H, Hartung IV, Barsyte-Lovejoy D, Szewczyk M, Kennedy S, Li F, Vedadi M, Brown PJ, Santhakumar V, Arrowsmith CH, Stellfeld T, Stresemann C. Discovery and Characterization of a Highly Potent and Selective Aminopyrazoline-Based in Vivo Probe (BAY-598) for the Protein Lysine Methyltransferase SMYD2. J Med Chem. 2016 May 26;59(10):4578-600. doi: 10.1021/acs.jmedchem.5b01890. Epub 2016 May 3. PMID: 27075367; PMCID: PMC4917279.
In vitro protocol:
1. Eggert E, Hillig RC, Koehr S, Stöckigt D, Weiske J, Barak N, Mowat J, Brumby T, Christ CD, Ter Laak A, Lang T, Fernandez-Montalvan AE, Badock V, Weinmann H, Hartung IV, Barsyte-Lovejoy D, Szewczyk M, Kennedy S, Li F, Vedadi M, Brown PJ, Santhakumar V, Arrowsmith CH, Stellfeld T, Stresemann C. Discovery and Characterization of a Highly Potent and Selective Aminopyrazoline-Based in Vivo Probe (BAY-598) for the Protein Lysine Methyltransferase SMYD2. J Med Chem. 2016 May 26;59(10):4578-600. doi: 10.1021/acs.jmedchem.5b01890. Epub 2016 May 3. PMID: 27075367; PMCID: PMC4917279.
In vivo protocol:
1. Eggert E, Hillig RC, Koehr S, Stöckigt D, Weiske J, Barak N, Mowat J, Brumby T, Christ CD, Ter Laak A, Lang T, Fernandez-Montalvan AE, Badock V, Weinmann H, Hartung IV, Barsyte-Lovejoy D, Szewczyk M, Kennedy S, Li F, Vedadi M, Brown PJ, Santhakumar V, Arrowsmith CH, Stellfeld T, Stresemann C. Discovery and Characterization of a Highly Potent and Selective Aminopyrazoline-Based in Vivo Probe (BAY-598) for the Protein Lysine Methyltransferase SMYD2. J Med Chem. 2016 May 26;59(10):4578-600. doi: 10.1021/acs.jmedchem.5b01890. Epub 2016 May 3. PMID: 27075367; PMCID: PMC4917279.
1: Eggert E, Hillig RC, Koehr S, Stöckigt D, Weiske J, Barak N, Mowat J, Brumby T, Christ CD, Ter Laak A, Lang T, Fernandez-Montalvan AE, Badock V, Weinmann H, Hartung IV, Barsyte-Lovejoy D, Szewczyk M, Kennedy S, Li F, Vedadi M, Brown PJ, Santhakumar V, Arrowsmith CH, Stellfeld T, Stresemann C. Discovery and Characterization of a Highly Potent and Selective Aminopyrazoline-Based in Vivo Probe (BAY-598) for the Protein Lysine Methyltransferase SMYD2. J Med Chem. 2016 May 26;59(10):4578-600. doi: 10.1021/acs.jmedchem.5b01890. PubMed PMID: 27075367; PubMed Central PMCID: PMC4917279. 2: Ahmed H, Duan S, Arrowsmith CH, Barsyte-Lovejoy D, Schapira M. An Integrative Proteomic Approach Identifies Novel Cellular SMYD2 Substrates. J Proteome Res. 2016 Jun 3;15(6):2052-9. doi: 10.1021/acs.jproteome.6b00220. PubMed PMID: 27163177.