SB1317

CDK,JAK and FLT inhibitor CAS# 937270-47-8

SB1317

Catalog No. BCC1925----Order now to get a substantial discount!

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Quality Control of SB1317

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Chemical structure

SB1317

3D structure

Chemical Properties of SB1317

Cas No. 937270-47-8 SDF Download SDF
PubChem ID 16739650 Appearance Powder
Formula C23H24N4O M.Wt 372.46
Type of Compound N/A Storage Desiccate at -20°C
Synonyms TG02
Solubility DMSO : 26.5 mg/mL (71.15 mM; Need ultrasonic and warming)
SMILES CN1CC=CCCOC2=CC=CC(=C2)C3=NC(=NC=C3)NC4=CC=CC(=C4)C1
Standard InChIKey VXBAJLGYBMTJCY-NSCUHMNNSA-N
Standard InChI InChI=1S/C23H24N4O/c1-27-13-3-2-4-14-28-21-10-6-8-19(16-21)22-11-12-24-23(26-22)25-20-9-5-7-18(15-20)17-27/h2-3,5-12,15-16H,4,13-14,17H2,1H3,(H,24,25,26)/b3-2+
General tips For obtaining a higher solubility , please warm the tube at 37 ℃ and shake it in the ultrasonic bath for a while.Stock solution can be stored below -20℃ for several months.
We recommend that you prepare and use the solution on the same day. However, if the test schedule requires, the stock solutions can be prepared in advance, and the stock solution must be sealed and stored below -20℃. In general, the stock solution can be kept for several months.
Before use, we recommend that you leave the vial at room temperature for at least an hour before opening it.
About Packaging 1. The packaging of the product may be reversed during transportation, cause the high purity compounds to adhere to the neck or cap of the vial.Take the vail out of its packaging and shake gently until the compounds fall to the bottom of the vial.
2. For liquid products, please centrifuge at 500xg to gather the liquid to the bottom of the vial.
3. Try to avoid loss or contamination during the experiment.
Shipping Condition Packaging according to customer requirements(5mg, 10mg, 20mg and more). Ship via FedEx, DHL, UPS, EMS or other couriers with RT, or blue ice upon request.

Biological Activity of SB1317

DescriptionSB1317 is a potent inhibitor of CDK2, JAK2, and FLT3 for the treatment of cancer, with IC50 of 13, 73, and 56 nM for CDK2, JAK2 and FLT3, respectively.In Vitro:SB1317 has a highly novel kinase inhibitory spectrum inhibiting 17 kinases from a panel of 63, 11 of which are CDK/JAK/FLT family members. The others, Lck, Fyn, Fms, TYRO3, ERK5, and p38δ, are implicated in inflammatory and proliferative processes. Human CYP1A2, 3A4, 2C9, and 2C19 isoforms are not inhibited by SB1317 at the highest tested concentration of 25 μM, but SB1317 inhibits CYP2D6 with IC50=0.95 μM, approximately at the plasma Cmax observed at the maximum tolerated dose. SB1317 inhibits cell proliferation concentrations in HCT-116 (IC50=0.079 μM) and HL-60 (IC50=0.059 μM)[1]. SB1317 is a novel small molecule potent CDK/JAK2/FLT3 inhibitor. SB1317 is mainly metabolized by CYP3A4 and CY1A2 in vitro. SB1317 does not inhibit any of the major human CYPs in vitro except CYP2D6 (IC50=1 μM). SB1317 does not significantly induce CYP1A and CYP3A4 in human hepatocytes in vitro[2].In Vivo:Treatment with SB1317 at 75 mg/kg po q.d. 3×/week significantly inhibits the growth of tumors with a mean TGI of 82%, while the lower dose of 50 mg/kg po 3×/week is marginally effective. Treatment with SB1317 using either regime significantly inhibits the growth of tumors with mean TGIs of 42% and 63% for the oral and ip delivery methods, respectively[1]. In pharmacokinetic studies SB1317 shows moderate to high systemic clearance (relative to liver blood flow), high volume of distribution (>0.6 L/kg), oral bioavailability of 24%, ~4 and 37% in mice, rats and dogs, respectively; and extensive tissue distribution in mice[2].

References:
[1]. William AD, et al. Discovery of kinase spectrum selective macrocycle (16E)-14-methyl-20-oxa-5,7,14,26-tetraazatetracyclo[19.3.1.1(2,6).1(8,12)]heptacosa-1(25),2(26),3,5,8(27),9,11,16,21,23-decaene (SB1317/TG02), a potent inhibitor of cyclin dependent kina [2]. Pasha MK, et al. Preclinical metabolism and pharmacokinetics of SB1317 (TG02), a potent CDK/JAK2/FLT3 inhibitor. Drug Metab Lett. 2012 Mar;6(1):33-42.

Protocol

Kinase Assay [1]
The recombinant enzymes (CDK2/cyclin A, JAK2, and FLT3) are used. All assays are carried out in 384-well white microtiter plates using the PKLight assay system. This assay platform is a luminometric assay for the detection of ATP in the reaction using a luciferase-coupled reaction. The compounds are tested at eight concentrations prepared from 3- or 4-fold serial dilution starting at 10 μM. For CDK2/cyclin A assay, the reaction mixture consisted of the following components in 25 μL of assay buffer (50 mM Hepes, pH 7.5, 10 mM MgCl2, 5 mM MnCl2, 5 mM BGP, 1 mM DTT, 0.1 mM sodium orthovanadate), 1.4 μg/mL of CDK2/cyclin A complex, 0.5 μM RbING substrate, and 0.5 μM ATP. The mixture is incubated at room temperature for 2 h. Then 13 μL of PKLight ATP detection reagent is added and the mixture is incubated for 10 min. Luminescence signals are detected on a multilabel plate reader. The analytical software Prism 5.0 is used to generate IC50 values from the data[1].

Cell Assay [1]
All cell lines are obtained from the American Type Culture Collection and cultured. For proliferation assays in 96-well plates, 20 000 cells are seeded in 100 μL of medium and treated the following day with compounds (e.g., SB1317 ) (in triplicate) at concentrations up to 10 μM for 48 h. Cell viability is monitored using the CellTiter-96 Aqueous One solution cell proliferation assay. Dose-response curves are plotted to determine IC50 values for the compounds using the XL-fit software[1].

Animal Administration [1]
Mice and Rats[1] Male BALB/c mice (aged ~10-12 weeks and weighing 17-22 g), male Beagle dogs (~6-7 months of age, weighing 10-14 kg), and male Wistar rats (aged 6-8 weeks, weighing 239-249 g) are used in this study. The oral doses for mice, dogs, and rats are 75, 10, and 10 mg/kg, respectively. The doses are administered by gavage as suspensions (0.5% methylcellulose and 0.1% Tween 80) to mice and rats, and as gelatin capsules (12 Torpac) to dogs. Following oral dosing serial blood samples are collected (cardiac puncture in mice, jugular vein in dogs, and superior vena cava in rats) at different time points (0-24 h) in tubes containing K3EDTA as anticoagulant, centrifuged, and plasma is separated and stored at -70°C until analysis. Plasma samples are processed and analyzed by LC-MS/MS. Pharmacokinetic parameters are estimated by noncompartmental methods using WinNonlin.

References:
[1]. William AD, et al. Discovery of kinase spectrum selective macrocycle (16E)-14-methyl-20-oxa-5,7,14,26-tetraazatetracyclo[19.3.1.1(2,6).1(8,12)]heptacosa-1(25),2(26),3,5,8(27),9,11,16,21,23-decaene (SB1317/TG02), a potent inhibitor of cyclin dependent kina [2]. Pasha MK, et al. Preclinical metabolism and pharmacokinetics of SB1317 (TG02), a potent CDK/JAK2/FLT3 inhibitor. Drug Metab Lett. 2012 Mar;6(1):33-42.

SB1317 Dilution Calculator

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SB1317 Molarity Calculator

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Preparing Stock Solutions of SB1317

1 mg 5 mg 10 mg 20 mg 25 mg
1 mM 2.6849 mL 13.4243 mL 26.8485 mL 53.697 mL 67.1213 mL
5 mM 0.537 mL 2.6849 mL 5.3697 mL 10.7394 mL 13.4243 mL
10 mM 0.2685 mL 1.3424 mL 2.6849 mL 5.3697 mL 6.7121 mL
50 mM 0.0537 mL 0.2685 mL 0.537 mL 1.0739 mL 1.3424 mL
100 mM 0.0268 mL 0.1342 mL 0.2685 mL 0.537 mL 0.6712 mL
* Note: If you are in the process of experiment, it's necessary to make the dilution ratios of the samples. The dilution data above is only for reference. Normally, it's can get a better solubility within lower of Concentrations.

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Background on SB1317

SB1317 is a potent inhibitor of Cyclin dependent kinases (CDKs), FMS-like tyrosine kinase-3 (FLT3) and Janus kinase 2 (JAK2) with IC50 values of 13nM, 56nM and 73nM for CDK2, JAK2 and FLT3, respectively [1].
CDKs are serine-threonine kinases that regulating the cell cycle. JAK2 is a nonreciprocal intracellular tyrosine kinase that transduces cytokine-mediated signals via the JAK-STAT pathway. FLT3 is a cytokine receptor and plays an important role in the normal development of haematopoietic stem cells [1].
In luciferase-expressing MM1S cells, SB1317 overcame the proliferative/protective advantage conferred by IL-6. In MM1S cells, SB1317 increased the percentage of cells in G2/M phases and decreased cells in the S phase. Also, SB1317 increased the amount of cells in the subG0 region [2].
In CB17-SCID mice bearing human multiple myeloma plasmacytoma xenograft models (the bortezomib-sensitive MM1S model and the more bortezomib-resistant OPM2 model), SB1317 significantly inhibited tumor growth [2]. In a subcutaneous AML model, treatment mice with SB1317 dosed 10, 20 or 40 mg/kg daily for 21 days reduced the average tumor volume by 53%, 61% and 113%, respectively [3].
References:
[1]. William AD, Lee AC, Goh KC, et al. Discovery of kinase spectrum selective macrocycle (16E)-14-methyl-20-oxa-5,7,14,26-tetraazatetracyclo[19.3.1.1(2,6).1(8,12)]heptacosa-1(25),2(26),3,5,8(27),9,11,16,21,23-decaene (SB1317/TG02), a potent inhibitor of cyclin dependent kinases (CDKs), Janus kinase 2 (JAK2), and fms-like tyrosine kinase-3 (FLT3) for the treatment of cancer. J Med Chem, 2012, 55(1): 169-196.
[2]. Álvarez-Fernández S, Ortiz-Ruiz MJ, Parrott T, et al. Potent antimyeloma activity of a novel ERK5/CDK inhibitor. Clin Cancer Res, 2013, 19(10): 2677-2687.
[3]. Goh KC, Novotny-Diermayr V, Hart S, et al. TG02, a novel oral multi-kinase inhibitor of CDKs, JAK2 and FLT3 with potent anti-leukemic properties. Leukemia, 2012, 26(2): 236-243.

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References on SB1317

Discovery of kinase spectrum selective macrocycle (16E)-14-methyl-20-oxa-5,7,14,26-tetraazatetracyclo[19.3.1.1(2,6).1(8,12)]heptaco sa-1(25),2(26),3,5,8(27),9,11,16,21,23-decaene (SB1317/TG02), a potent inhibitor of cyclin dependent kinases (CDKs), Janus kinase 2 (JAK2), and fms-like tyrosine kinase-3 (FLT3) for the treatment of cancer.[Pubmed:22148278]

J Med Chem. 2012 Jan 12;55(1):169-96.

Herein, we describe the design, synthesis, and SAR of a series of unique small molecule macrocycles that show spectrum selective kinase inhibition of CDKs, JAK2, and FLT3. The most promising leads were assessed in vitro for their inhibition of cancer cell proliferation, solubility, CYP450 inhibition, and microsomal stability. This screening cascade revealed 26 h as a preferred compound with target IC(50) of 13, 73, and 56 nM for CDK2, JAK2 and FLT3, respectively. Pharmacokinetic (PK) studies of 26 h in preclinical species showed good oral exposures. Oral efficacy was observed in colon (HCT-116) and lymphoma (Ramos) xenograft studies, in line with the observed PK/PD correlation. 26h (SB1317/TG02) was progressed into development in 2010 and is currently undergoing phase 1 clinical trials in advanced leukemias and multiple myeloma.

Preclinical metabolism and pharmacokinetics of SB1317 (TG02), a potent CDK/JAK2/FLT3 inhibitor.[Pubmed:22372550]

Drug Metab Lett. 2012 Mar;6(1):33-42.

SB1317 (TG02) is a novel small molecule potent CDK/JAK2/FLT3 inhibitor. To evaluate full potential of this development candidate, we conducted drug metabolism and pharmacokinetic studies of this novel anti-cancer agent. SB1317 was soluble, highly permeable in Caco-2 cells, and showed > 99% binding to plasma from mice, dog and humans. It was metabolically stable in human and dog liver microsomes relative to mouse and rat. SB1317 was mainly metabolized by CYP3A4 and CY1A2 in vitro. SB1317 did not inhibit any of the major human CYPs in vitro except CYP2D6 (IC50=1 muM). SB1317 did not significantly induce CYP1A and CYP3A4 in human hepatocytes in vitro. The metabolic profiles in liver microsomes from preclinical species were qualitatively similar to humans. In pharmacokinetic studies SB1317 showed moderate to high systemic clearance (relative to liver blood flow), high volume of distribution ( > 0.6 L/kg), oral bioavailability of 24%, approximately 4 and 37% in mice, rats and dogs, respectively; and extensive tissue distribution in mice. The favorable ADME of SB1317 supported its preclinical development as an oral drug candidate.

Structure-based design of nitrogen-linked macrocyclic kinase inhibitors leading to the clinical candidate SB1317/TG02, a potent inhibitor of cyclin dependant kinases (CDKs), Janus kinase 2 (JAK2), and Fms-like tyrosine kinase-3 (FLT3).[Pubmed:22820730]

J Mol Model. 2013 Jan;19(1):119-30.

A high-throughput screen against Aurora A kinase revealed several promising submicromolar pyrimidine-aniline leads. The bioactive conformation found by docking these leads into the Aurora A ATP-binding site had a semicircular shape. Macrocycle formation was proposed to achieve novelty and selectivity via ring-closing metathesis of a diene precursor. The nature of the optimal linker and its size was directed by docking. In a kinase panel screen, selected macrocycles were active on other kinase targets, mainly FLT3, JAK2, and CDKs. These compounds then became leads in a CDK/FLT3/JAK2 inhibitor project. Macrocycles with a basic nitrogen in the linker form a salt bridge with Asp86 in CDK2 and Asp698 in FLT3. Interaction with this residue explains the observed selectivity. The Asp86 residue is conserved in most CDKs, resulting in potent pan-CDK inhibition by these compounds. Optimized macrocycles generally have good DMPK properties, and are efficacious in mouse models of cancer. Compound 5 (SB1317/TG02), a pan-CDK/FLT3/JAK2 inhibitor, was selected for preclinical development, and is now in phase 1 clinical trials.

Description

SB1317 is a potent inhibitor of CDK2, JAK2, and FLT3 for the treatment of cancer, with IC50 of 13, 73, and 56 nM for CDK2, JAK2 and FLT3, respectively.

Keywords:

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