Structure–Activity Relationship Studies of Pyrazolo[3,4-<i>d</i>]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, Lingling; Li, Guobo; Ma, Shuang; Zou, Chan; Zhou, Shu; Sun, Qizheng; Cheng, Chuan; Chen, Xin; Wang, Lijiao; Feng, Shan; Li, Linli; Yang, Shengyong

doi:10.1021/jm301537p

Cited by 62 publications

(34 citation statements)

References 43 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…To determine whether the use of a combination treatment using IGF1R inhibitors and sorafenib is a viable clinical translational strategy to treat HCC, we examined whether ceritinib, an FDA‐approved dual ALK and IGF1R inhibitor for the treatment of non‐small cell lung cancer,17, 18 further sensitizes HCC cells to sorafenib treatment. To do so, we first examined the effect of ceritinib on HCC cell growth, which has not been reported.…”

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

Inhibition of insulin‐like growth factor 1 receptor enhances the efficacy of sorafenib in inhibiting hepatocellular carcinoma cell growth and survival

Wang

Bank

Malnassy

et al. 2018

Hepatology Communications

View full text Add to dashboard Cite

Hepatocellular carcinoma (HCC) is the fifth most common primary cancer and second largest cause of cancer‐related death worldwide. The first‐line oral chemotherapeutic agent sorafenib only increases survival in patients with advanced HCC by less than 3 months. Most patients with advanced HCC have shown limited response rates and survival benefits with sorafenib. Although sorafenib is an inhibitor of multiple kinases, including serine/threonine‐protein kinase c‐Raf, serine/threonine‐protein kinase B‐Raf, vascular endothelial growth factor receptor (VEGFR)‐1, VEGFR‐2, VEGFR‐3, and platelet‐derived growth factor receptor β, HCC cells are able to escape from sorafenib treatment using other pathways that the drug insufficiently inhibits. The aim of this study was to identify and target survival and proliferation pathways that enable HCC to escape the antitumor activity of sorafenib. We found that insulin‐like growth factor 1 receptor (IGF1R) remains activated in HCC cells treated with sorafenib. Knockdown of IGF1R sensitizes HCC cells to sorafenib treatment and decreases protein kinase B (AKT) activation. Overexpression of constitutively activated AKT reverses the effect of knockdown of IGF1R in sensitizing HCC cells to treatment with sorafenib. Further, we found that ceritinib, a drug approved by the U.S. Food and Drug Administration for treatment of non‐small cell lung cancer, effectively inhibits the IGF1R/AKT pathway and enhances the inhibitory efficacy of sorafenib in human HCC cell growth and survival in vitro, in a xenograft mouse model and in the c‐Met/β‐catenin‐driven HCC mouse model. Conclusion: Our study provides a biochemical basis for evaluation of a new combination treatment that includes IGF1R inhibitors, such as ceritinib and sorafenib, in patients with HCC. (Hepatology Communications 2018;2:732‐746)

show abstract

Section: Resultsmentioning

confidence: 99%

“…Although several IGF1R inhibitors have been tested in clinical trials,9, 15, 16 none have been approved by the U.S. Food and Drug Administration (FDA). Intriguingly, ceritinib (Zykadia), a potent anaplastic lymphoma kinase (ALK) inhibitor that is FDA approved for treatment of non‐small cell lung cancer,17 has been reported to effectively inhibit IGF1R 18…”

mentioning

confidence: 99%

Inhibition of insulin‐like growth factor 1 receptor enhances the efficacy of sorafenib in inhibiting hepatocellular carcinoma cell growth and survival

Wang

Bank

Malnassy

et al. 2018

Hepatology Communications

View full text Add to dashboard Cite

show abstract

“…Alkylation of [6] with benzylic-type bromides A-D (Fig. 3) in the presence of K 2 CO 3 yielded the corresponding bicyclic intermediates [7][8][9][10] that were regioselectively opened with a series of benzylic amines [a-h] and hydrazines [i-o] to furnish analogues [11][12][13][14].…”

Section: Rational Design Synthesis Characterization and Computationmentioning

confidence: 99%

“…8 Several groups have previously used endothelial-specific transgenic lines to screen for novel antiangiogenic compounds and developed automated methodologies to identify and quantify the antiangiogenic activity of compound libraries. [9][10][11][12][13][14] Previous work from our laboratories generated and characterized Tg(kdrl:gfp) s843 5 currently used extensively to study angiogenesis in vivo. In addition, based on the anthranilamide scaffold AAL993 (Fig.…”

Section: Introductionmentioning

confidence: 99%

A ZebrafishIn VivoPhenotypic Assay to Identify 3-Aminothiophene-2-Carboxylic Acid-Based Angiogenesis Inhibitors

Papakyriakou

Kefalos

Sarantis

et al. 2014

ASSAY and Drug Development Technologies

View full text Add to dashboard Cite

Small molecules that inhibit angiogenesis are attractive drug candidates for cancer, retinopathies, and age-related macular degeneration. In vivo, phenotypic screening in zebrafish (Danio rerio) emerges as a powerful methodology to identify and optimize novel compounds with pharmacological activity. Zebrafish provides several advantages for in vivo phenotypic screens especially for angiogenesis, since it develops rapidly, externally, and does not rely on a functional cardiovascular system to survive for several days during development. In this study, we utilize a transgenic line that allows the noninvasive monitoring of angiogenesis at a cellular level. The inhibition of angiogenesis can be observed under a fluorescent stereoscope and quantified. To exemplify the versatility and robustness of the zebrafish screen, we have employed a series of 60 novel compounds that were designed based on a potent VEGFR2 inhibitor. Herein, we report their structure-based design, synthesis, and in vivo zebrafish screening for optimal activity, toxicity, and off-target effects, which revealed six reversible inhibitors of angiogenesis.

show abstract

“…SC-535, 1-(4-(1H-pyrazolo[3,4-d] pyrimidin-4-yloxy)phenyl)-3-(4-chloro-3-(trifluoromethyl)phenyl)urea (Fig. 1A), is a multi-targeted kinase inhibitor discovered by us recently [22]. This compound can efficiently inhibit VEGFR2, BRAF V600E , wild-type BRAF (BRAF WT ), and CRAF, as well as other kinases, in which VEGFR2 is associated with angiogenesis, and BRAF V600E , BRAF WT , and CRAF are key components of the MAPK signaling pathway.…”

Section: Introductionmentioning

confidence: 99%

SC-535, a Novel Oral Multikinase Inhibitor, Showed Potent Antitumor Activity in Human Melanoma Models

Chen¹,

Ji²,

Yang³

et al. 2013

Cell Physiol Biochem

Self Cite

View full text Add to dashboard Cite

Background: Melanoma is considered as one of the most aggressive and deadliest cancers and current targeted therapies of melanoma often suffer limited efficacy or drug resistance. Discovery of novel multikinase inhibitors as anti-melanoma drug candidates is still needed. Methods: In this investigation, we assessed the in vitro and in vivo anti-melanoma activities of SC-535, which is a novel small molecule multikinase inhibitor discovered by us recently. We analyzed inhibitory effects of SC-535 on various melanoma cell lines and human umbilical vascular endothelial cells (HUVEC) in vitro. Tumor xenografts in athymic mice were used to examine the in vivo activity of SC-535. Results: SC-535 could efficiently inhibit vascular endothelial growth factor receptor (VEGFR) 1/2/3, B-RAF, and C-RAF kinases. It showed significant antiangiogenic potencies both in vitro and in vivo and considerable anti-proliferative ability against several melanoma cell lines. Oral administration of SC-535 resulted in dose-dependent suppression of tumor growth in WM2664 and C32 xenograft mouse models. Studies of mechanisms of action indicated that SC-535 suppressed the tumor angiogenesis and induced G2/M phase cell cycle arrest in human melanoma cells. SC-535 possesses favorable pharmacokinetic properties. Conclusion: All of these results support SC-535 as a potential candidate for clinical studies in patients with melanoma.

show abstract

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

Cited by 62 publications

References 43 publications

Inhibition of insulin‐like growth factor 1 receptor enhances the efficacy of sorafenib in inhibiting hepatocellular carcinoma cell growth and survival

Inhibition of insulin‐like growth factor 1 receptor enhances the efficacy of sorafenib in inhibiting hepatocellular carcinoma cell growth and survival

A ZebrafishIn VivoPhenotypic Assay to Identify 3-Aminothiophene-2-Carboxylic Acid-Based Angiogenesis Inhibitors

SC-535, a Novel Oral Multikinase Inhibitor, Showed Potent Antitumor Activity in Human Melanoma Models

Contact Info

Product

Resources

About