LFM-A13 is a potent and selective inhibitor of Bruton's tyrosine kinase (BTK). LFM-A13 may be useful as a new class of chemosensitizing and apoptosis-promoting antileukemic agents for treatment of patients with chemotherapy-resistant B-lineage leukemias or lymphomas.
CAS Number: 244240-24-2
Molecular Weight: 360.00
Chemical Name: Cyano-N-(2,5-dibromophenyl)-3-hydroxy-2-butenamide
Appearance: Solid Power
Purity: ≥98% (or refer to the Certificate of Analysis)
Solubility: Soluble in DMSO, not in water
Shipping Condition: Shipped under ambient temperature as non-hazardous chemical or refer to Certificate of Analysis
Storage Condition: Dry, dark and -20 oC for 1 year or refer to the Certificate of Analysis.
Shelf Life: ≥12 months if stored properly.
Stock Solution Storage: 0 - 4 oC for 1 month or refer to the Certificate of Analysis.
Drug Formulation: To be determined.
HS Tariff Code: 382200
How to use
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. 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. 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.
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. 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.
- Uckun F, Dibirdik I, Sarkissian A, Qazi S. 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. Arzneimittelforschung. 2011;61(4):252-9. doi: 10.1055/s-0031-1296196. PubMed PMID: 21650085.
- Uckun FM. Chemosensitizing anti-cancer activity of LFM-A13, a leflunomide metabolite analog targeting polo-like kinases. Cell Cycle. 2007 Dec 15;6(24):3021-6. Epub 2007 Sep 26. PubMed PMID: 18073537.
- DuMez D, Venkatachalam TK, Uckun FM. 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. Arzneimittelforschung. 2007;57(3):155-63. PubMed PMID: 17469650.
- Uckun FM, Tibbles H, Venkatachalam T, DuMez D, Erbeck D. 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). Arzneimittelforschung. 2007;57(1):31-46. PubMed PMID: 17341007.
- Uckun FM, Dibirdik I, Qazi S, Vassilev A, Ma H, Mao C, Benyumov A, Emami KH. Anti-breast cancer activity of LFM-A13, a potent inhibitor of Polo-like kinase (PLK). Bioorg Med Chem. 2007 Jan 15;15(2):800-14. Epub 2006 Oct 26. PubMed PMID: 17098432.
- Tibbles HE, Samuel P, Erbeck D, Mahajan S, Uckun FM. In vivo toxicity and antithrombotic profile of the oral formulation of the antileukemic agent, LFM-A13-F. Arzneimittelforschung. 2004;54(6):330-9. PubMed PMID: 15281619.
- van den Akker E, van Dijk TB, Schmidt U, Felida L, Beug H, LÃ¶wenberg B, von Lindern M. The Btk inhibitor LFM-A13 is a potent inhibitor of Jak2 kinase activity. Biol Chem. 2004 May;385(5):409-13. PubMed PMID: 15196000.
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