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MedKoo CAT#: 206213
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
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
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.
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