SKLB-677, an FLT3 and Wnt/β-catenin signaling inhibitor, displays potent activity in models of FLT3-driven AML.
FLT3 has been identified as a valid target for the treatment of acute myeloid leukemia (AML), and some FLT3 inhibitors have shown very good efficacy in treating AML in clinical trials. Nevertheless, recent studies indicated that relapse and drug resistance are still difficult to avoid, and leukemia stem cells (LSCs) are considered one of the most important contributors. Here, we report the characterization of SKLB-677, a new FLT3 inhibitor developed by us recently. SKLB-677 exhibits low nanomolar potency in biochemical and cellular assays. It is efficacious in animal models at doses as low as 1mg/kg when administrated orally once daily. In particular, SKLB-677 but not first-generation and second-generation FLT3 inhibitors in clinical trials has the ability to inhibit Wnt/β-catenin signaling; Wnt/β-catenin signaling is required for the development of LSCs, but not necessary for the development of adult hematopoietic stem cells (HSCs). This compound indeed showed considerable suppression effects on leukemia stem-like cells in in vitro functional assays, but had no influence on normal HSCs. Collectively, SKLB-677 is an interesting lead compound for the treatment of AML, and deserves further investigations.
State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University/Collaborative Innovation Center of Biotherapy, Chengdu, 610041, China.
Shuang
S
Ma
State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University/Collaborative Innovation Center of Biotherapy, Chengdu, 610041, China.
Ling-Ling
LL
Yang
State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University/Collaborative Innovation Center of Biotherapy, Chengdu, 610041, China.|Department of Hematology &Research Laboratory of Hematology, West China Hospital, Sichuan University, Chengdu, 610041, China.
Ting
T
Niu
State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University/Collaborative Innovation Center of Biotherapy, Chengdu, 610041, China.
Chuan
C
Cheng
State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University/Collaborative Innovation Center of Biotherapy, Chengdu, 610041, China.
Lei
L
Zhong
State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University/Collaborative Innovation Center of Biotherapy, Chengdu, 610041, China.
Ming-Wu
MW
Zheng
State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University/Collaborative Innovation Center of Biotherapy, Chengdu, 610041, China.
Yu
Y
Xiong
State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University/Collaborative Innovation Center of Biotherapy, Chengdu, 610041, China.
Lin-Li
LL
Li
Department of Clinical Medicine, School of Medicine, Nankai University, Tianjin, 300071, China.
Rong
R
Xiang
State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University/Collaborative Innovation Center of Biotherapy, Chengdu, 610041, China.
Li-Juan
LJ
Chen
State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University/Collaborative Innovation Center of Biotherapy, Chengdu, 610041, China.
Qiao
Q
Zhou
State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University/Collaborative Innovation Center of Biotherapy, Chengdu, 610041, China.
Yu-Quan
YQ
Wei
State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University/Collaborative Innovation Center of Biotherapy, Chengdu, 610041, China.
Sheng-Yong
SY
Yang
D000818:Animals; D030801:Animals, Genetically Modified; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D019008:Drug Resistance, Neoplasm; D005260:Female; D059585:G1 Phase Cell Cycle Checkpoints / Q000187:drug effects; D006801:Humans; D007555:Isoxazoles / Q000494:pharmacology*; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy*; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D010671:Phenylurea Compounds / Q000737:chemistry; D011720:Pyrazoles / Q000737:chemistry; D011743:Pyrimidines / Q000737:chemistry; D014508:Urea / Q000031:analogs & derivatives* / Q000494:pharmacology; D051153:Wnt Proteins / Q000037:antagonists & inhibitors*; D060449:Wnt Signaling Pathway / Q000187:drug effects*; D015027:Zebrafish; D051176:beta Catenin / Q000037:antagonists & inhibitors*; D051941:fms-Like Tyrosine Kinase 3 / Q000037:antagonists & inhibitors*
C000610642:1-(4-(1H-pyrazolo(3,4-d)pyrimidin-4-yloxy)-3-fluorophenyl)-3-(5-tert-butylisoxazol-3-yl)urea; C582543:1-(4-(1H-pyrazolo(3,4-d)pyrimidin-4-yloxy)phenyl)-3-(4-chloro-3-(trifluoromethyl)phenyl)urea; D000970:Antineoplastic Agents; D007555:Isoxazoles; D010671:Phenylurea Compounds; D011720:Pyrazoles; D011743:Pyrimidines; D051153:Wnt Proteins; D051176:beta Catenin; D014508:Urea; C497970:FLT3 protein, human; D051941:fms-Like Tyrosine Kinase 3