SKLB1028, a novel oral multikinase inhibitor of EGFR, FLT3 and Abl, displays exceptional activity in models of FLT3-driven AML and considerable potency in models of CML harboring Abl mutants

Zx, Cao; Liu, JJ; Zheng, Rong; Yang, Jianhong; Zhong, Lei; Xu, Yu; Lj, Wang; Zhang, Chun-Hui; Bl, Wang; Ma, Shumei; Zr, Wang; Hz, Xie; Yq, Wei; Sy, Yang

doi:10.1038/leu.2012.67

Cited by 14 publications

(6 citation statements)

References 15 publications

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“…SKLB-1028 is a multitarget inhibitor with FLT3 inhibitory activity. 112 A phase I trial (NCT02859948) was conducted to evaluate the safety, tolerability and pharmacokinetic characteristics of SKLB-1028 in FLT3 mutant AML subjects. 113 Moreover, it has been reported that SKLB-1028 also has inhibitory activity on FLT3 secondary mutations such as FLT3-D835Y and FLT3-F691L; therefore, it is considered a potential therapeutic drug for resistant AML patients harboring the corresponding mutations.…”

Section: Flt3 Inhibitorsmentioning

confidence: 99%

Small molecules in targeted cancer therapy: advances, challenges, and future perspectives

Zhong

Xiong

et al. 2021

Sig Transduct Target Ther

818

490

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Due to the advantages in efficacy and safety compared with traditional chemotherapy drugs, targeted therapeutic drugs have become mainstream cancer treatments. Since the first tyrosine kinase inhibitor imatinib was approved to enter the market by the US Food and Drug Administration (FDA) in 2001, an increasing number of small-molecule targeted drugs have been developed for the treatment of malignancies. By December 2020, 89 small-molecule targeted antitumor drugs have been approved by the US FDA and the National Medical Products Administration (NMPA) of China. Despite great progress, small-molecule targeted anti-cancer drugs still face many challenges, such as a low response rate and drug resistance. To better promote the development of targeted anti-cancer drugs, we conducted a comprehensive review of small-molecule targeted anti-cancer drugs according to the target classification. We present all the approved drugs as well as important drug candidates in clinical trials for each target, discuss the current challenges, and provide insights and perspectives for the research and development of anti-cancer drugs.

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Section: Flt3 Inhibitorsmentioning

confidence: 99%

Small molecules in targeted cancer therapy: advances, challenges, and future perspectives

Zhong

Xiong

et al. 2021

Sig Transduct Target Ther

818

490

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“…Compounds are likely better FLT3 inhibitors if they have high potency against MV4-11 cells but low or no activity against HeLa cells. To screen VEGFR2 kinase inhibitors, an in vivo live fluorescent transgenic zebrafish (FLK-1:EGFP) assay was adopted; VEGFR2 is one of the key regulators of angiogenesis, and the transgenic zebrafish assay has been utilized as a less costly and more rapid in vivo method for the screening of agents with antiangiogenic activity. − The combination of cell- and transgenic-zebrafish-based assays is an effective method for identifying dual inhibitors of FLT3 and VEGFR2. There are some advantages of performing SAR analysis with cell- and transgenic-zebrafish-based assays rather than enzymatic assays for hit/lead optimization.…”

Section: Results and Discussionmentioning

confidence: 99%

Structure–Activity Relationship Studies of Pyrazolo[3,4-d]pyrimidine Derivatives Leading to the Discovery of a Novel Multikinase Inhibitor That Potently Inhibits FLT3 and VEGFR2 and Evaluation of Its Activity against Acute Myeloid Leukemia in Vitro and in Vivo

Yang

et al. 2013

J. Med. Chem.

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We describe the structural optimization of a hit compound, 1-(4-(1H-pyrazolo[3,4-d]pyrimidin-4-ylamino)phenyl)-3-(3-methoxyphenyl)urea (1), which exhibits inhibitory activity but low potency against FLT3 and VEGFR2. A series of pyrazolo[3,4-d]pyrimidine derivatives were synthesized, and structure-activity relationship analysis using cell- and transgenic-zebrafish-based assays led to the discovery of a number of compounds that exhibited both high potency against FLT3-driven human acute myeloid leukemia (AML) MV4-11 cells and a considerable antiangiogenic effect in transgenic-zebrafish-based assays. The compound 1-(4-(1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)phenyl)-3-(4-chloro-3-(trifluoromethyl)phenyl)urea (33), which exhibited the highest activity in preliminary in vivo anti-AML assays, was chosen for further anti-AML studies. The results demonstrated that compound 33 is a multikinase inhibitor that potently inhibits FLT3 and VEGFR2. In an MV4-11 xenograft mouse model, a once-daily dose of compound 33 at 10 mg/kg for 18 days led to complete tumor regression without obvious toxicity. Western blot and immunohistochemical analyses were performed to determine the mechanism of action of compound 33.

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“…Solid tumors were removed and processed to immunohistochemical analysis when the mice were administrated after 12 days, half of the tumors were fixed in formalin followed by paraffin-embedded and the other were stored at -80˚C. To investigate the tumor proliferation inhibition potencies of SKLB-287, we examined the proliferous cells by immunostaining with Ki67 (Thermo Fisher Scientific), apoptosis cells by TUNEL (Promega Corporation), p-EGFR (Cell Signaling Technology) and p-ERK (Cell Signaling Technology) for MAPK signaling pathway in paraffin-embedded tumors as described previously [31]. To investigate whether SKLB-287 inhibited tumor growth by suppressing tumor angiogenesis, we examined the vessel density in tumor tissue as described previously [32].…”

Section: Methodsmentioning

confidence: 99%

SKLB-287, a novel oral multikinase inhibitor of EGFR and VEGFR2, exhibits potent antitumor activity in LoVo colorectal tumor model

Chen¹,

Y²,

Hw³

et al. 2014

neo

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Colorectal cancer (CRC) is the third common cancer and most of the chemotherapies of CRC currently used often suffer limited efficacy and large side effects. Targeted small-molecule by anti-tumor drugs are thought a promising strategy for improving the efficacy and reducing the side effects. In this investigation, we report a novel multikinase inhibitor, termed SKLB-287, which was discovered by us recently. SKLB-287 could efficiently inhibit the activation of endothelial growth factor receptor (EGFR) and vascular endothelial growth factor receptor 2 (VEGFR2). It displayed very good anti-proliferative activity against LoVo CRC cells and considerable antiangiogenic potency in transgenic zebrafish embryos. Oral administration of SKLB-287 resulted in dose-dependent suppression of tumor growth in LoVo xenograft mouse model. Immunohistochemistry was adopted to examine the in vivo anti-tumor mechanism of action of SKLB-287.

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SKLB1028, a novel oral multikinase inhibitor of EGFR, FLT3 and Abl, displays exceptional activity in models of FLT3-driven AML and considerable potency in models of CML harboring Abl mutants

Cited by 14 publications

References 15 publications

Small molecules in targeted cancer therapy: advances, challenges, and future perspectives

Small molecules in targeted cancer therapy: advances, challenges, and future perspectives

Structure–Activity Relationship Studies of Pyrazolo[3,4-d]pyrimidine Derivatives Leading to the Discovery of a Novel Multikinase Inhibitor That Potently Inhibits FLT3 and VEGFR2 and Evaluation of Its Activity against Acute Myeloid Leukemia in Vitro and in Vivo

SKLB-287, a novel oral multikinase inhibitor of EGFR and VEGFR2, exhibits potent antitumor activity in LoVo colorectal tumor model

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SKLB1028, a novel oral multikinase inhibitor of EGFR, FLT3 and Abl, displays exceptional activity in models of FLT3-driven AML and considerable potency in models of CML harboring Abl mutants

Cited by 14 publications

References 15 publications

Small molecules in targeted cancer therapy: advances, challenges, and future perspectives

Small molecules in targeted cancer therapy: advances, challenges, and future perspectives

Structure–Activity Relationship Studies of Pyrazolo[3,4-d]pyrimidine Derivatives Leading to the Discovery of a Novel Multikinase Inhibitor That Potently Inhibits FLT3 and VEGFR2 and Evaluation of Its Activity against Acute Myeloid Leukemia in Vitro and in Vivo

SKLB-287, a novel oral multikinase inhibitor of EGFR and VEGFR2, exhibits potent antitumor activity in LoVo colorectal tumor model

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Product

Resources

About

SKLB-287, a novel oral multikinase inhibitor of EGFR and VEGFR2, exhibits potent antitumor activity in LoVo colorectal tumor model