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KW-2449 CAS: 1000669-72-6

Category: Inhibitors
Product Name: KW-2449
Cat No: I000066
CAS No: 1000669-72-6
Synonyms: [4-[(E)-2-(1H-indazol-3-yl)ethenyl]phenyl]-piperazin-1-ylmethanone
Molecular Formula: C20H20N4O
Molecular Weight: 332.4
SMILES: O=C(C1=CC=C(/C=C/C2=NNC3=C2C=CC=C3)C=C1)N4CCNCC4
InChI: InChI=1S/C20H20N4O/c25-20(24-13-11-21-12-14-24)16-8-5-15(6-9-16)7-10-19-17-3-1-2-4-18(17)22-23-19/h1-10,21H,11-14H2,(H,22,23)/b10-7+
InChIKey: YYLKKYCXAOBSRM-JXMROGBWSA-N
Solubility: DMSO ≥63mg/mL Water <1.2mg/mL Ethanol ≥63mg/mL
Target: FLT3
IC50: 6.6 nM [1]
Storage: powder
CAS 1000669-72-6,KW-2449
  • Description

KW-2449 is a multiple-targeted inhibitor, mostly for Flt3 with IC50 of 6.6 nM, modestly potent to FGFR1, Bcr-Abl and Aurora A; little effect on PDGFRβ, IGF-1R, EGFR.
IC50 value: 6.6 nM [1]
Target: Flt3
in vitro: Phosphorylation levels of FLT3 and STAT5 are decreased by KW-2449 in a dose-dependent manner. In addition, it potently inhibits ABL-T315I, which is associated with IM resistance, with IC50 of 4 nM. On the other hand, KW-2449 has little effect on PDGFRβ, IGF-1R, EGFR, and various serine/threonine kinases even at a concentration of 1 μM. KW-2449 has the potent growth inhibitory activities against not only FLT3/ITD-expressing leukemia cells but also FLT3/KDM-activated and wild-type FLT3-overexpressing leukemia cells [1]. KW-2449 is rapidly absorbed and converted to a major metabolite M1.Preclinical studies reveal that KW-2449 is converted by monoamine oxidase-B (MAO-B) and aldehyde oxidase into its major metabolite M1.KW-2449 mediates cytotoxicity thru inhibition of FLT3/ITD.KW-2449 is a direct inhibitor of FLT3 and induces inhibition of its downstream target STAT5 [2]. KW2449 interacts synergistically with HDACIs to induce apoptosis in Ph+ CML cells in a time- and concentration-dependent manner. KW2449 synergistically enhances the lethality of vorinostat/SNDX275 in CML cells.KW-2449 regimens are active against additional IM-resistant Bcr/Abl+ leukemia cells. KW2449 moderately reduces phosphorylation of histone H3, an indicator of Aurora B activity, in nocodozole-treated K562 cells [3].
in vivo: In the MOLM-13 tumor xenograft model, oral administration of KW-2449 for 14 days shows a potent and significant antitumor effect in a dose-dependent manner [1].

  • Spec

Appearance:Solid powder
Purity: > 98%

  • References


1:HDAC inhibitors potentiate the activity of the BCR/ABL kinase inhibitor KW-2449 in imatinib-sensitive or -resistant BCR/ABL+ leukemia cells in vitro and in vivo. Nguyen T, Dai Y, Attkisson E, Kramer L, Jordan N, Nguyen N, Kolluri N, Muschen M, Grant S.Clin Cancer Res. 2011 May 15;17(10):3219-32. doi: 10.1158/1078-0432.CCR-11-0234. Epub 2011 Apr 7. PMID: 21474579 Free PMC Article
2:KW-2449, a novel multikinase inhibitor, suppresses the growth of leukemia cells with FLT3 mutations or T315I-mutated BCR/ABL translocation. Shiotsu Y, Kiyoi H, Ishikawa Y, Tanizaki R, Shimizu M, Umehara H, Ishii K, Mori Y, Ozeki K, Minami Y, Abe A, Maeda H, Akiyama T, Kanda Y, Sato Y, Akinaga S, Naoe T.Blood. 2009 Aug 20;114(8):1607-17. doi: 10.1182/blood-2009-01-199307. Epub 2009 Jun 18. PMID: 19541823 Free Article
3:A pharmacodynamic study of the FLT3 inhibitor KW-2449 yields insight into the basis for clinical response. Pratz KW, Cortes J, Roboz GJ, Rao N, Arowojolu O, Stine A, Shiotsu Y, Shudo A, Akinaga S, Small D, Karp JE, Levis M.Blood. 2009 Apr 23;113(17):3938-46. doi: 10.1182/blood-2008-09-177030. Epub 2008 Nov 24. PMID: 19029442 Free PMC Article
4:[New therapeutic option for leukemia patients, with FLT3/Aurora kinase inhibitor, KW-2449: strategy and comparison with other kinase inhibitors]. Shiotsu Y.Rinsho Ketsueki. 2008 Aug;49(8):641-9. Review. Japanese. No abstract available. PMID: 18800614


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