BAY-958 1335490-39-5_Others_Signaling Pathways_Products

BAY-958 is a lead compound for Atuveciclib (formerly known as BAY-1143572) which is novel, potent, oral and highly selective PTEFb/CDK9 inhibitor. It inhibits CDK9/CycT1 with an IC50 of 13 nM and is more than 100-fold more selective for CDK9 over CDK2. It also inhibits GSK3 kinase with IC50 values of 45 nM and 87 nM for GSK3α and GSK3β respectively. Atuveciclib is currently in Phase I clinical trial. Selective inhibition of exclusively transcription-regulating PTEFb/CDK9 is a promising new approach in cancer therapy. Starting from lead compound BAY-958, lead optimization efforts strictly focusing on kinase selectivity, physicochemical and DMPK properties finally led to the identification of the orally available clinical candidate atuveciclib (BAY 1143572). Structurally characterized by an unusual benzyl sulfoximine group, BAY 1143572 exhibited the best overall profile in vitro and in vivo, including high efficacy and good tolerability in xenograft models in mice and rats. BAY 1143572 is the first potent and highly selective PTEFb/CDK9 inhibitor to enter clinical trials for the treatment of cancer.

Physicochemical Properties

Molecular Formula

C17H16FN5O3S

Molecular Weight

389.40404510498

Exact Mass

389.095

CAS #

1335490-39-5

Related CAS #

1335490-39-5(BAY-958);

PubChem CID

53491924

Appearance

Typically exists as solid at room temperature

LogP

2.1

Hydrogen Bond Donor Count

Hydrogen Bond Acceptor Count

Rotatable Bond Count

Heavy Atom Count

Complexity

575

Defined Atom Stereocenter Count

InChi Key

MGCPJSMHKDVTGW-UHFFFAOYSA-N

InChi Code

InChI=1S/C17H16FN5O3S/c1-26-15-8-12(18)5-6-14(15)16-20-10-21-17(23-16)22-13-4-2-3-11(7-13)9-27(19,24)25/h2-8,10H,9H2,1H3,(H2,19,24,25)(H,20,21,22,23)

Chemical Name

(3-((4-(4-Fluoro-2-methoxyphenyl)-1,3,5-triazin-2-yl)amino)phenyl)methanesulfonamide

Synonyms

BAY-958; BAY 958; BAY958

HS Tariff Code

2934.99.9001

Storage

Powder-20°C 3 years

4°C 2 years

In solvent -80°C 6 months

-20°C 1 month

Shipping Condition

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

Biological Activity

ln Vitro

In vitro activity: BAY-958 is a lead compound for Atuveciclib (formerly known as BAY-1143572) which is novel, potent, oral and highly selective PTEFb/CDK9 inhibitor. It inhibits CDK9/CycT1 with an IC50 of 13 nM and is more than 100-fold more selective for CDK9 over CDK2. It also inhibits GSK3 kinase with IC50 values of 45 nM and 87 nM for GSK3α and GSK3β respectively. Atuveciclib is currently in Phase I clinical trial. Selective inhibition of exclusively transcription-regulating PTEFb/CDK9 is a promising new approach in cancer therapy. Starting from lead compound BAY-958, lead optimization efforts strictly focusing on kinase selectivity, physicochemical and DMPK properties finally led to the identification of the orally available clinical candidate atuveciclib (BAY 1143572). Structurally characterized by an unusual benzyl sulfoximine group, BAY 1143572 exhibited the best overall profile in vitro and in vivo, including high efficacy and good tolerability in xenograft models in mice and rats. BAY 1143572 is the first potent and highly selective PTEFb/CDK9 inhibitor to enter clinical trials for the treatment of cancer.

Kinase Assay: Merck Millipore CDK assays: Assays were performed according to the Merck Millipore KinaseProfilerTM standard protocols, with an ATP concentration of 10 μm..

Cell Assay: HeLa human cervical tumor cells (CCL‐2) were obtained from the American Type Culture Collection (Manassas, USA) and MOLM‐13 human acute myeloid leukemia cells (ACC 554) were obtained from the German Collection of Microorganisms and Cell Cultures (Braunschweig, Germany). Authentication of cell lines was conducted at the German Collection of Microorganisms and Cell Cultures via PCR‐based DNA profiling of polymorphic short tandem repeats. Cells were propagated under the suggested growth conditions in a humidified 37 °C incubator. Proliferation assays were conducted in 96‐well plates at densities of 3000 (HeLa) and 5000 (MOLM‐13) cells per well in the growth medium containing 10 % fetal calf serum (FCS). Cells were treated in quadruplicate with serial dilutions of test compounds for 96 h. Relative cell numbers were quantified by crystal violet staining (HeLa) or CellTitre‐Glo Luminescent Cell Viability Assay (Promega) (MOLM‐13). IC50 values (inhibitory concentration at 50 % of maximal effect) were determined by means of a four‐parameter fit on measurement data which were normalized to vehicle (DMSO) treated cells (=100 %) and measurement readings taken immediately before compound exposure (=0 %).

ln Vivo

In an in vivo pharmacokinetic study in rats, BAY 1143572 showed low blood clearance (CLb 1.1 L/h/kg). The volumes of distribution (V ss) of BAY 1143572 is 1.0 L/kg. BAY 1143572 shows significantly improved oral bioavailability of 54 %. The blood/plasma ratios is about 1. It does not show significant inhibition of cytochrome P450 activity, with IC50 values >20 μM. The administration of BAY 1143572 in immunocompromized NOD/Shi-scid/IL-2Rγ null (NOG) mice xenografted with patient-derived ATL cells greatly reduced the infiltration of ATL cells into organs, such as liver and bone marrow. Decreased human soluble IL2R levels in serum were also observed, which indicated a reduction of ATL tumor burden.

Animal Protocol

Immunocompromized NOD/Shi-scid/IL-2Rγ null (NOG) mice xenografted with patient-derived ATL cells and in vivo pharmacokinetic in rats

References

ChemMedChem. 2017 Nov 8;12(21):1776-1793.;Molecules. 2018, 23(5). pii: E1057.

Solubility Data

Solubility (In Vitro)

DMSO: >10mM

Water:<1mg/mL

Ethanol:<1mg/mL

Solubility (In Vivo)

Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.

Injection Formulations
(e.g. IP/IV/IM/SC) Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)
*Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution.
Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)
Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil)
Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals).
Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)]
*Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.
Injection Formulation 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (i.e. 500 μL 2-Hydroxypropyl-β-cyclodextrin → 500 μL Saline)
Injection Formulation 6: DMSO : PEG300 : castor oil : Saline = 5 : 10 : 20 : 65 (i.e. 50 μL DMSO → 100 μLPEG300 → 200 μL castor oil → 650 μL Saline)
Injection Formulation 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (i.e. 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline)
Injection Formulation 8: Dissolve in Cremophor/Ethanol (50 : 50), then diluted by Saline
Injection Formulation 9: EtOH : Corn oil = 10 : 90 (i.e. 100 μL EtOH → 900 μL Corn oil)
Injection Formulation 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL EtOH → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)

Oral Formulations Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium)
Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose
Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals).
Oral Formulation 3: Dissolved in PEG400
Oral Formulation 4: Suspend in 0.2% Carboxymethyl cellulose
Oral Formulation 5: Dissolve in 0.25% Tween 80 and 0.5% Carboxymethyl cellulose
Oral Formulation 6: Mixing with food powders

Note: Please be aware that the above formulations are for reference only. InvivoChem strongly recommends customers to read literature methods/protocols carefully before determining which formulation you should use for in vivo studies, as different compounds have different solubility properties and have to be formulated differently.

(Please use freshly prepared in vivo formulations for optimal results.)

Preparing Stock Solutions		1 mg	5 mg	10 mg
	1 mM	2.5681 mL	12.8403 mL	25.6805 mL
	5 mM	0.5136 mL	2.5681 mL	5.1361 mL
	10 mM	0.2568 mL	1.2840 mL	2.5681 mL

*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.

PeptideDB

BAY-958 1335490-39-5

CAS No.: 1335490-39-5

Physicochemical Properties

Biological Activity

Solubility Data