LFM-A13BTK-specific tyrosine kinase inhibitor CAS# 244240-24-2 |
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| Cas No. | 244240-24-2 | SDF | Download SDF |
| PubChem ID | 54676905 | Appearance | Powder |
| Formula | C11H8Br2N2O2 | M.Wt | 360 |
| Type of Compound | N/A | Storage | Desiccate at -20°C |
| Solubility | DMSO : ≥ 42 mg/mL (116.67 mM) H2O : < 0.1 mg/mL (insoluble) *"≥" means soluble, but saturation unknown. | ||
| Chemical Name | (Z)-2-cyano-N-(2,5-dibromophenyl)-3-hydroxybut-2-enamide | ||
| SMILES | CC(=C(C#N)C(=O)NC1=C(C=CC(=C1)Br)Br)O | ||
| Standard InChIKey | UVSVTDVJQAJIFG-VURMDHGXSA-N | ||
| Standard InChI | InChI=1S/C11H8Br2N2O2/c1-6(16)8(5-14)11(17)15-10-4-7(12)2-3-9(10)13/h2-4,16H,1H3,(H,15,17)/b8-6- | ||
| 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. |
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| 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. |
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| 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. | ||
| Description | LFM-A13 is a potent BTK, JAK2, PLK inhibitor, inhibits recombinant BTK, Plx1 and PLK3 with IC50s of 2.5 μM, 10 μM and 61 μM LFM-A13 shows no effects on JAK1 and JAK3, Src family kinase HCK, EGFR and IRK.In Vitro:LFM-A13 significantly inhibits BTK activity with an IC50 of 6.2 ± 0.3 μg/mL (= 17.2 ± 0.8 μM). The calculated Kis of LFM-A13 for BTK, JAK1, JAK3, IRK, EGFR and HCK are 1.4, 110, 148, 31.6, 166 and 214 μM. LFM-A13 (200 μM) markedly increases the chemosensitivity of ALL-1 cells to ceramide-induced apoptosis[1]. LFM-A13 (100 μM) suppresses Epo-induced phosphorylation of EpoR, Jak2, Btk, Stat5 and Erk1/2 in R10 cells. LFM-A13 (100 μM) inhibits auto-phosphorylation of Jak2, Tec and Btk rather than Lyn kinase auto-phosphorylation in COS cells[2]. LFM-A13 potently inhibits Plx1 with IC50 of 10 μM also inhibits BRK, BMX, FYN and with IC50s of 267, 281, 240 and 215 μM[4].In Vivo:LFM-A13 (25, 50 and 100 mg/kg) shows no apparent toxicity to rats. LFM-A13 (50 mg/kg, three times a week, i.p.) attenuates DMBA-induced mammary tumorigenesis in mice. LFM-A13 alone or in combination with paclitaxel shows marked effect on the DMBA-induced breast tumor incidence, mean tumor numbers, average tumor weight, and size in BALB/c mice. LFM-A13 (50 mg/kg, three times a week, i.p.) significantly decreases PLK1, cyclin D1, CDK-4, P53 and Bcl-2 expression, but increases the expression of p21, IκB, Bax and caspase 3 expression in mice[3]. LFM-A13 (200 mg/kg) does not cause hematologic toxicity in rats. LFM-A13 (10 or 50 mg/kg, i.p.) exhibits anti-tumor effects dose dependently in the MMTV/Neu transgenic mouse model of breast cancer[4]. References: | |||||
LFM-A13 Dilution Calculator
LFM-A13 Molarity Calculator
| 1 mg | 5 mg | 10 mg | 20 mg | 25 mg | |
| 1 mM | 2.7778 mL | 13.8889 mL | 27.7778 mL | 55.5556 mL | 69.4444 mL |
| 5 mM | 0.5556 mL | 2.7778 mL | 5.5556 mL | 11.1111 mL | 13.8889 mL |
| 10 mM | 0.2778 mL | 1.3889 mL | 2.7778 mL | 5.5556 mL | 6.9444 mL |
| 50 mM | 0.0556 mL | 0.2778 mL | 0.5556 mL | 1.1111 mL | 1.3889 mL |
| 100 mM | 0.0278 mL | 0.1389 mL | 0.2778 mL | 0.5556 mL | 0.6944 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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Description:
IC50: 17.2 μM
Bruton’s tyrosine kinase (BTK), a member of the BTK/Tec family of protein tyrosine kinases, is a cytoplasmic PTK involved in signal transduction pathways regulating growth and differentiation of B-lineage lymphoid cells. BTK participates in signal transduction pathways initiated by the binding of a variety of extracellular ligands to their cell-surface receptors. LFM-A13 is a BTK-specific tyrosine kinase inhibitor.
In vitro: LFM-A13 inhibited recombinant BTK expressed in a baculovirus expression vector system. Besides its remarkable potency in BTK kinase assays, LFM-A13 was also found to be a highly specific inhibitor of BTK. Even at very high concentrations, LFM-A13 did not affect the activity of other protein tyrosine kinases [1].
In vivo: LFM-A13 exhibited a favorable pharmacokinetic behavior which was not adversely affected by the standard chemotherapy drugs and significantly improved the chemotherapy response and survival outcome of BCL-1 leukemia cells challenged mice. While only 14% of mice treated with the standard triple-drug combination treatment became long-term survivors, 41% of mice treated with this combination plus LFM-A13 survived long-term [2].
Clinical trial: Up to now, LFM-A13 is still in the preclinical development stage.
Reference:
[1] Mahajan S, Ghosh S, Sudbeck EA, Zheng Y, Downs S, Hupke M, Uckun FM. Rational design and synthesis of a novel anti-leukemic agent targeting Bruton's tyrosine kinase (BTK), LFM-A13 [alpha-cyano-beta-hydroxy-beta-methyl-N-(2, 5-dibromophenyl)propenamide]. J Biol Chem. 1999 Apr 2;274(14):9587-99.
[2] Uckun FM, Zheng Y, Cetkovic-Cvrlje M, Vassilev A, Lisowski E, Waurzyniak B, Chen H, Carpenter R, Chen CL. In vivo pharmacokinetic features, toxicity profile, and chemosensitizing activity of alpha-cyano-beta-hydroxy-beta- methyl-N-(2,5-dibromophenyl)propenamide (LFM-A13), a novel antileukemic agent targeting Bruton's tyrosine kinase. Clin Cancer Res. 2002 May;8(5):1224-33.
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In vitro and in vivo chemosensitizing activity of LFM-A13, a dual-function inhibitor of Bruton's tyrosine kinase and polo-like kinases, against human leukemic B-cell precursors.[Pubmed:21650085]
Arzneimittelforschung. 2011;61(4):252-9.
The present study documents the chemosensitizing anti-leukemic activity of the leflunomide metabolite (LFM) analog, LFM-A13, a dual-function inhibitor of Bruton's tyrosine kinase (BTK) and Polo-like kinases (PLK), against human leukemic B-cell precursors. The results in 135 xenografted NOD/SCID mice regarding the anti-leukemic activity of GMP-grade LFM-A13, obtained with only 4-days of LFM-A13 therapy at nontoxic dose levels corresponding to 1-20% of its NOAEL (no observable advserse effect level), alone or in combination with the standard chemotherapy drug vincristine, demonstrate the potential of LFM-A13 as a new anti-leukemic drug candidate. All 82 LFM-A13-treated mice, including those receiving a combination of vincristine + LFM-A13 at the highest dose level of LFM-A13, tolerated their treatments well without weight loss, diarrhea, lethargy/ paralysis, other signs of morbidity, or mortality. The present study provides preclinical proof-of-principle for the development of LFM-A13 as a new chemosensitizing and apoptosis-promoting anti-leukemic agent and lends support to the hypothesis that the chemoresistance of relapsed B-cell precursor acute lymphoblastic leukemia (BCP-ALL) can be overcome by using LFM-A13 in combination with chemotherapy. Also presented are the results of a comprehensive meta-analysis of the overexpression of genes for LFM-A13 targeted kinases and their downstream effector molecules in B-lineage lymphoid malignancies utilizing the Oncomine database.
Preclinical toxicity and pharmacokinetics of the Bruton's tyrosine kinase-targeting anti-leukemic drug candidate, alpha-cyano-beta-hydroxy-beta-methyl-N- (2,5-dibromophenyl) propenamide (LFM-A13).[Pubmed:17341007]
Arzneimittelforschung. 2007;57(1):31-46.
The leflunomide (CAS 75706-12-6) metabolite (LFM) analog alpha-cyano-beta-hydroxy-beta-methyl-N-(2,5-dibromophenyl)-propenamide (LFM-A13, DDE-28, CAS 244240-24-2) is a rationally-designed specific inhibitor of the TEC family protein tyrosine kinase, Bruton's tyrosine kinase (BTK). LFM-A13 exhibited favorable pharmacokinetics in CD-1 mice, BALB/c mice, rats, and dogs. The intraperitoneal bioavailability was estimated to be -100%, while the oral bioavailability was -30%. LFM-A13 enters, but does not bind to multiple tissues followed by a rapid elimination from most of the tissues. Limited distribution of LFM-A13 to extravascular tissues and its corresponding low volume of distribution could be attributed to its plasma protein binding. LFM-A13 was not toxic to mice, rats, or dogs at daily dose levels as high as 100 mg/kg. LFM-A13 formulated as a suspension and hard gelatin capsules for oral administration showed a rapid absorption and favorable pharmacokinetic features. These preclinical research studies provide the basis for future pre-IND studies and clinicaldevelopment of LFM-A13 as an intravenously or orally administered new anti-leukemia agent targeting BTK.
Large-scale synthesis of GMP grade alpha-cyano-beta-hydroxy-beta-methyl-N-(2,5-dibromophenyl) propenamide (LFM-A13), a new anti-cancer drug candidate.[Pubmed:17469650]
Arzneimittelforschung. 2007;57(3):155-63.
The leflunomide (CAS 75706-12-6) metabolite (LFM) analog alpha-cyano-beta-hydroxy-beta-methyl-N-(2,5-dibromophenyl)-propenamide (LFM-A13, DDE-28, CAS 244240-24-2), is a rationally designed inhibitor of the anti-apoptotic enzyme Bruton's tyrosine kinase (BTK). LFM-A13 is being developed as a novel dual-function anticancer drug with apoptosis-promoting and anti-thrombotic properties. LFM-A13 was prepared under current Good Manufacturing Practice (cGMP) conditions on the scale of kilograms.
Chemosensitizing anti-cancer activity of LFM-A13, a leflunomide metabolite analog targeting polo-like kinases.[Pubmed:18073537]
Cell Cycle. 2007 Dec 15;6(24):3021-6.
LFM-A13 (alpha-cyano-beta-hydroxy-beta-methyl-N-(2,5-dibromophenyl)propenamide) has recently been identified as an inhibitor of Polo-like kinases (Plk). LFM-A13 does not inhibit other serine/threonine kinases including CDK, CHK, RAF, DAPK, IKK, IRAK, JNK, MAPK, PKC and SAPK. LFM-A13-treated human cancer cells develop abnormal mitotic spindles and G(2)/M-arrest during cell cycle progression. LFM-A13 was not toxic to rodents or dogs at daily dose levels as high as 100 mg/kg. Notably, at a low dose level of 10 mg/kg, which does not result in delayed tumor progression in the MMTV/neu transgenic mouse model of HER2 positive breast cancer, LFM-A13 markedly enhanced the anti-cancer activity of the mitotic spindle poison paclitaxel. These results indicate that LFM-A13 may be useful in the treatment of cancer patients.
