WARNING: This product is for research use only, not for human or veterinary use.
MedKoo CAT#: 206213
CAS#: 1000669-72-6
Description: KW-2449 is a novel multikinase inhibitor, which suppresses the growth of leukemia cells with FLT3 mutations or T315I-mutated BCR/ABL translocation. Recent research showed that HDACIs increase KW-2449 lethality in Bcr/Abl(+) cells in association with inhibition of Bcr/Abl, generation of ROS, and induction of DNA damage. This strategy preferentially targets primary Bcr/Abl(+) hematopoietic cells and exhibits enhanced in vivo activity. Combining KW-2449 with HDACIs warrants attention in IM-resistant Bcr/Abl(+) leukemias. (source: Clin Cancer Res. 2011 May 15;17(10):3219-32. Epub 2011 Apr 7.).
MedKoo Cat#: 206213
Name: KW-2449
CAS#: 1000669-72-6
Chemical Formula: C20H20N4O
Exact Mass: 332.16371
Molecular Weight: 332.4
Elemental Analysis: C, 72.27; H, 6.06; N, 16.86; O, 4.81
Synonym: KW2449; KW-2449; KW 2449.
IUPAC/Chemical Name: (E)-(4-(2-(1H-indazol-3-yl)vinyl)phenyl)(piperazin-1-yl)methanone
InChi Key: YYLKKYCXAOBSRM-JXMROGBWSA-N
InChi Code: 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+
SMILES Code: O=C(C1=CC=C(/C=C/C2=NNC3=C2C=CC=C3)C=C1)N4CCNCC4
Appearance: Solid powder
Purity: >98% (or refer to the Certificate of Analysis)
Shipping Condition: Shipped under ambient temperature as non-hazardous chemical. This product is stable enough for a few weeks during ordinary shipping and time spent in Customs.
Storage Condition: Dry, dark and at 0 - 4 C for short term (days to weeks) or -20 C for long term (months to years).
Solubility: soluble in DMSO, not soluble in water.
Shelf Life: >5 years if stored properly
Drug Formulation: This drug may be formulated in DMSO
Stock Solution Storage: 0 - 4 C for short term (days to weeks), or -20 C for long term (months).
HS Tariff Code: 2934.99.9001
| Biological target: | KW-2449 is a multi-targeted kinase inhibitor of FLT3, ABL, ABLT315I and Aurora kinase with IC50s of 6.6, 14, 4 and 48 nM, respectively. |
| In vitro activity: | KW-2449 inhibited the growth of human ALL cell line RS4;11, which expresses unphosphorylated wt-FLT3, with the GI50 value of 0.23 μM (Table 2). Because KW-2449 shows potent Aurora A and Aurora B kinase inhibition, it was evaluated whether the growth inhibitory effect on RS4;11 was induced by Aurora kinase inhibition. When the cell cycle was arrested in the M-phase by nocodazole, phosphorylated histone-H3 (P-HH3) was clearly observed in RS4;11, but it was decreased by the treatment with KW-2449 in a dosedependent manner (Figure 6A). Cell cycle distribution analysis indicated that KW-2449 (0.60 μM) induced G2/M arrest and apparent increase of sub-G1 apoptotic cells after 24 hours and 48 hours of exposure, respectively (Figure 6B). Even at 0.30 μM, KW-2449 slightly decreased the population of S-phase cells from 49.0% to 40.6% after 72 hours (histogram data not shown). The increase of annexin V–positive (early apoptotic) cells was also observed at the GI50 value against RS4;11 cells (Figure 6C). These results suggested that KW-2449 has a growth inhibitory potency against leukemia cells even without activated FLT3 through the inhibition of Aurora kinase, although its potency was 5- to10-fold lower than that against those with activated FLT3 kinase. Reference: Blood. 2009 Aug 20;114(8):1607-17. https://pubmed.ncbi.nlm.nih.gov/19541823/ |
| In vivo activity: | In vivo antileukemia activities of KW-2449 were evaluated using MOLM-13, FLT3-ITD AML, xenograft model. First, the concentrations of KW-2449 in both plasma and tumor after oral administration were sequentially examined in SCID mice bearing the subcutaneous MOLM-13 tumor. The tumor/plasma concentration ratio of KW-2449 tended to increase along with the time after administration and reached approximately 400, 24 hours after dosing (Figure 3A). The levels of P-FLT3 and P-STAT5 in the tumor were completely reduced from 4 to 12 hours after the administration of KW-2449 (Figure 3B). In the MOLM-13 tumor xenograft model, oral administration of KW-2449 for 14 days showed a potent and significant antitumor effect in a dose-dependent manner (Figure 4A). KW-2449 treatment at 2.5 and 5.0 mg/kg twice a day showed growth inhibition of tumors with the ratio of tumor volume in the treated to control mice minimum values (T/Cmin) of 0.57 and 0.29, respectively (Figure 4B). Furthermore, KW-2449 treatment at 10 mg/kg twice a day showed tumor regression with T/Cmin of 0.010 and treatment at 20 mg/kg twice a day completely eradicated tumors in all mice (Figure 4C). Reference: Blood. 2009 Aug 20;114(8):1607-17. https://pubmed.ncbi.nlm.nih.gov/19541823 |
| Solvent | Max Conc. mg/mL | Max Conc. mM | |
|---|---|---|---|
| Solubility | |||
| DMSO | 49.0 | 147.41 |
The following data is based on the product molecular weight 332.4 Batch specific molecular weights may vary from batch to batch due to the degree of hydration, which will affect the solvent volumes required to prepare stock solutions.
| Concentration / Solvent Volume / Mass | 1 mg | 5 mg | 10 mg |
|---|---|---|---|
| 1 mM | 1.15 mL | 5.76 mL | 11.51 mL |
| 5 mM | 0.23 mL | 1.15 mL | 2.3 mL |
| 10 mM | 0.12 mL | 0.58 mL | 1.15 mL |
| 50 mM | 0.02 mL | 0.12 mL | 0.23 mL |
| Formulation protocol: | 1. 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. KW-2449, a novel multikinase inhibitor, suppresses the growth of leukemia cells with FLT3 mutations or T315I-mutated BCR/ABL translocation. Blood. 2009 Aug 20;114(8):1607-17. doi: 10.1182/blood-2009-01199307. Epub 2009 Jun 18. PMID: 19541823. 2. Nguyen T, Dai Y, Attkisson E, Kramer L, Jordan N, Nguyen N, Kolluri N, Muschen M, Grant S. 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. Clin Cancer Res. 2011 May 15;17(10):3219-32. doi: 10.1158/1078-0432.CCR-11-0234. Epub 2011 Apr 7. PMID: 21474579; PMCID: PMC3096723 |
| In vitro protocol: | 1. 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. KW-2449, a novel multikinase inhibitor, suppresses the growth of leukemia cells with FLT3 mutations or T315I-mutated BCR/ABL translocation. Blood. 2009 Aug 20;114(8):1607-17. doi: 10.1182/blood-2009-01199307. Epub 2009 Jun 18. PMID: 19541823. 2. Nguyen T, Dai Y, Attkisson E, Kramer L, Jordan N, Nguyen N, Kolluri N, Muschen M, Grant S. 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. Clin Cancer Res. 2011 May 15;17(10):3219-32. doi: 10.1158/1078-0432.CCR-11-0234. Epub 2011 Apr 7. PMID: 21474579; PMCID: PMC3096723 |
| In vivo protocol: | 1. 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. KW-2449, a novel multikinase inhibitor, suppresses the growth of leukemia cells with FLT3 mutations or T315I-mutated BCR/ABL translocation. Blood. 2009 Aug 20;114(8):1607-17. doi: 10.1182/blood-2009-01199307. Epub 2009 Jun 18. PMID: 19541823. 2. Nguyen T, Dai Y, Attkisson E, Kramer L, Jordan N, Nguyen N, Kolluri N, Muschen M, Grant S. 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. Clin Cancer Res. 2011 May 15;17(10):3219-32. doi: 10.1158/1078-0432.CCR-11-0234. Epub 2011 Apr 7. PMID: 21474579; PMCID: PMC3096723 |
1. Pratz, Keith W.; Sato, Takashi; Murphy, Kathleen M.; Stine, Adam; Rajkhowa, Trivikram; Levis, Mark. FLT3-mutant allelic burden and clinical status are predictive of response to FLT3 inhibitors in AML. Blood (2010), 115(7), 1425-1432. CODEN: BLOOAW ISSN:0006-4971. AN 2010:301893
2. Shiotsu, Yukimasa; Kiyoi, Hitoshi; Akinaga, Shiro; Naoe, Tomoki. Screening of molecular target therapy of cancer and generation of new kinase inhibitor, KW-2449. Saibo (2009), 41(9), 381-384. CODEN: SAIBC7 ISSN:1346-7557. AN 2009:1319160
3. Verma, Dushyant; Kantarjian, Hagop M.; Jones, Dan; Luthra, Rajyalakshmi; Borthakur, Gautam; Verstovsek, Srdan; Rios, Mary Beth; Cortes, Jorge. Chronic myeloid leukemia (CML) with P190BCR-ABL: analysis of characteristics, outcomes, and prognostic significance. Blood (2009), 114(11), 2232-2235. CODEN: BLOOAW ISSN:0006-4971. CAN 152:188988 AN 2009:1173490
4. Shiotsu, Yukimasa; Kiyoi, Hitoshi; Ishikawa, Yuichi; Tanizaki, Ryohei; Shimizu, Makiko; Umehara, Hiroshi; Ishii, Kenichi; Mori, Yumiko; Ozeki, Kazutaka; Minami, Yosuke; Abe, Akihiro; Maeda, Hiroshi; Akiyama, Tadakazu; Kanda, Yutaka; Sato, Yuko; Akinaga, Shiro; Naoe, Tomoki. KW-2449, a novel multikinase inhibitor, suppresses the growth of leukemia cells with FLT3 mutations or T315I-mutated BCR/ABL translocation. Blood (2009), 114(8), 1607-1617. CODEN: BLOOAW ISSN:0006-4971. CAN 151:462381 AN 2009:1081843
5. Pratz, Keith W.; Cortes, Jorge; Roboz, Gail J.; Rao, Niranjan; Arowojolu, Omotayo; Stine, Adam; Shiotsu, Yukimasa; Shudo, Aiko; Akinaga, Shiro; Small, Donald; Karp, Judith E.; Levis, Mark. A pharmacodynamic study of the FLT3 inhibitor KW-2449 yields insight into the basis for clinical response. Blood (2009), 113(17), 3938-3946. CODEN: BLOOAW ISSN:0006-4971. CAN 152:701 AN 2009:541826
6. Tomillero A; Moral M A Gateways to clinical trials. Methods and findings in experimental and clinical pharmacology (2009), 31(1), 47-57. Journal code: 7909595. ISSN:0379-0355. PubMed ID 19357798 AN 2009268576
7. Shiotsu Yukimasa New therapeutic option for leukemia patients, with FLT3/Aurora kinase inhibitor, KW-2449: strategy and comparison with other kinase inhibitors. [Rinsho ketsueki] The Japanese journal of clinical hematology (2008), 49(8), 641-9. Journal code: 2984782R. ISSN:0485-1439. PubMed ID 18800614 AN 2008612636
8. Bayes M; Rabasseda X Gateways to clinical trials. Methods and findings in experimental and clinical pharmacology (2008), 30(1), 67-99. Journal code: 7909595. ISSN:0379-0355. PubMed ID 18389098 AN 2008229509
KW-2449, a multikinase inhibitor of FLT3, ABL, ABL-T315I, and Aurora kinase, is under investigation to treat leukemia patients. KW-2449 showed the potent growth inhibitory effects on leukemia cells with FLT3 mutations by inhibition of the FLT3 kinase, resulting in the down-regulation of phosphorylated-FLT3/STAT5, G1 arrest, and apoptosis. Oral administration of KW-2449 showed dose-dependent and significant tumor growth inhibition in FLT3-mutated xenograft model with min. bone marrow suppression. In FLT3 wild-type human leukemia, it induced the redn. of phosphorylated histone H3, G2/M arrest, and apoptosis. In imatinib-resistant leukemia, KW-2449 contributed to release of the resistance by the simultaneous down-regulation of BCR/ABL and Aurora kinases. Furthermore, the antiproliferative activity of KW-2449 was confirmed in primary samples from AML and imatinib-resistant patients. The inhibitory activity of KW-2449 is not affected by the presence of human plasma protein, such as .alpha.1-acid glycoprotein. These results indicate KW-2449 has potent growth inhibitory activity against various types of leukemia by several mechanisms of action. KW-2449 has significant activity and warrants clin. study in leukemia patients with FLT3 mutations as well as imatinib-resistant mutations. See: Shiotsu, Yukimasa; Kiyoi, Hitoshi; Ishikawa, Yuichi; Tanizaki, Ryohei; Shimizu, Makiko; Umehara, Hiroshi; Ishii, Kenichi; Mori, Yumiko; Ozeki, Kazutaka; Minami, Yosuke; Abe, Akihiro; Maeda, Hiroshi; Akiyama, Tadakazu; Kanda, Yutaka; Sato, Yuko; Akinaga, Shiro; Naoe, Tomoki. Fuji Research Park, Kyowa Hakko Kirin, Shizuoka, Japan. Blood (2009), 114(8), 1607-1617.
