Development of novel inhibitors targeting HIF-1α towards anticancer drug discovery

Yewalkar, Nilambari; Deore, Vijaykumar; Padgaonkar, Amol; Manohar, Sonal M; Sahu, Bichismita; Kumar, Pramod; Jalota‐Badhwar, Archana; Joshi, Kalpana; Sharma, Somesh; Kumar, Sanjay

doi:10.1016/j.bmcl.2010.09.083

Cited by 17 publications

(11 citation statements)

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“…P3155 was identified by us as a potent HIF-1α inhibitor in the reporter gene based assay [11]. Specificity index (SI) was calculated, obtained by dividing the EC 50 in U251-pGL3 by the EC 50 in U251-HRE, which provides an indication of relative specificity towards inhibition of HIF-1 dependent transcription.…”

Section: Resultsmentioning

confidence: 99%

“…In our quest for finding potential therapeutics, we used pyridylpyrimidine as a basic scaffold; various molecules were designed, synthesized and characterized. Out of these molecules, P3155 and P2630 were identified as potent and specific HIF-1α inhibitors in the reporter gene-based assay [ref [11]- structure 7 and 4a respectively]. Herein, we report the anticancer activity and mechanism of action of P3155.…”

Section: Introductionmentioning

confidence: 99%

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A novel inhibitor of hypoxia-inducible factor-1α P3155 also modulates PI3K pathway and inhibits growth of prostate cancer cells

et al. 2011

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BackgroundHypoxia-inducible factor-1 (HIF-1) is a master regulator of the transcriptional response to hypoxia. It is essential for angiogenesis and is associated with tumor progression and overexpression of HIF-1α has been demonstrated in many common human cancers. Therefore, HIF-1α is one of the most compelling anticancer targets.MethodsTo identify HIF-1α inhibitors, luciferase reporter gene assay under hypoxia and normoxia was used. Detailed studies such as western blotting, RT-PCR, immunofluorescence were carried out to elucidate its mechanism of action. Antiangiogenic activity of P3155 was demonstrated by migration assay and tube formation assay. Efficacy study of P3155 was performed on PC-3 xenograft model.ResultsP3155 showed specific HIF-1α inhibition with IC50 of 1.4 μM under hypoxia. It suppressed HIF-1α expression as well as PI3K/Akt pathway and abrogated expression of HIF-1-inducible gene viz. vascular endothelial growth factor (VEGF). P3155 in combination with HIF-1α siRNA showed significant synergistic effect. In addition, it demonstrated significant in vivo efficacy and antiangiogenic potential in prostate cancer cell lines.ConclusionWe have identified a novel HIF-1α inhibitor P3155 that also modulates PI3K/Akt pathway, which may contribute to its significant in vitro and in vivo antitumor activity.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

A novel inhibitor of hypoxia-inducible factor-1α P3155 also modulates PI3K pathway and inhibits growth of prostate cancer cells

et al. 2011

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“…Pyridylpyrimidine analogs were reported by Yewalkar et al. as HIF‐1α inhibitors . These compounds exhibited moderate potency against HIF‐1α activity in reporter gene‐based assay under hypoxic conditions.…”

Section: Heterocyclesmentioning

confidence: 99%

Hypoxia‐inducible factor‐1 (HIF‐1) inhibitors from the last decade (2007 to 2016): A “structure–activity relationship” perspective

Bhattarai

Lee

2017

Medicinal Research Reviews

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Tumor hypoxia is a common feature in most solid tumors and is associated with overexpression of the hypoxia response pathway. Overexpression of the hypoxia-inducible factor (HIF-1) protein leads to angiogenesis, metastasis, apoptosis resistance, and many other pro-tumorigenic responses in cancer development. HIF-1 is a promising target in cancer drug development to increase the patient's response to chemotherapy and radiotherapy as well as the survival rate of cancer patients. Since up to 1% of genes are hypoxia-sensitive, a target-specific HIF-1 inhibitor may be a better clinical candidate in cancer drug discovery. Though no HIF-1 inhibitor is clinically available to date, a lot of effort has been applied during the last decade in search of potent HIF-1 inhibitors. In this review, we will summarize the structure-activity relationship of ten different chemotypes reported to be HIF-1 inhibitors in the last decade (2007-2016), their mechanisms of action for HIF-1 inhibition, progress in the way of target-specific inhibitors, and problems associated with current inhibitors. It is anticipated that the results of these research on the medicinal chemistry of HIF-1 inhibitors will provide decent information in the design and development of future inhibitors.

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“…38) Therefore, various HIF-1 inhibitors have been evaluated with respect to their effects on pathological angiogenesis and cancer. Of the many HIF-1 inhibitors identified, YC-1 [3-(5-hydroxymethyl-2-furyl)-1-benzylindazole 17) ], PX-12 [1-methylpropyl 2-imidazolyl disulfide 39) ], P2630 [pyridylpyrimidine 40) ], and other emerging compounds such as heteroaryls and thiazolidinone compounds [for review see ref. 41], have shown promising in vitro and in vivo antitumor activity.…”

Section: Discussionmentioning

confidence: 99%

Anti-tumor Activity of the Novel Hexahydrocannabinol Analog LYR-8 in Human Colorectal Tumor Xenograft Is Mediated through the Inhibition of Akt and Hypoxia-Inducible Factor-1α Activation

Thapa

Kang

Park

et al. 2012

Biological & Pharmaceutical Bulletin

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Cannabinoid compounds have been shown to exert anti-tumor effects by affecting angiogenesis, invasion, and metastasis. In the present study, we examined the action mechanism by which LYR-8, a novel hexahydrocannabinol analog, exerts anti-angiogenic and anti-tumor activity in human cancer xenografts. In the xenografted tumor tissues, LYR-8 significantly reduced the expression of hypoxia-inducible factor-1 alpha (HIF-1α), a transcription factor responsible for induction of angiogenesis-promoting factors, and its target genes, vascular endothelial growth factor (VEGF) and cyclooxygenase-2 (COX-2). In HT-29 human colon cancer cells treated with a hypoxia-inducing agent (CoCl(2)), LYR-8 dose-dependently suppressed the induction of HIF-1α and subsequently its targets, VEGF and COX-2. In addition, highly elevated prostaglandin E(2) (PGE(2)) concentrations in CoCl(2)-treated HT-29 cells were also significantly suppressed by LYR-8. However, LYR-8 alone in the absence of CoCl(2) did not alter the basal expression of VEGF and COX-2, or PGE(2) production. Furthermore, LYR-8 effectively suppressed Akt signaling, which corresponded to the suppression of CoCl(2)-induced HIF-1α accumulation. Taken together, LYR-8 exerts anti-tumor effects through the inhibition of Akt and HIF-1α activation, and subsequently suppressing factors regulating tumor microenvironment, such as VEGF and COX-2. These results indicate a novel function of cannabinoid-like compound LYR-8 as an anti-tumor agent with a HIF-1α inhibitory activity.

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Development of novel inhibitors targeting HIF-1α towards anticancer drug discovery

Cited by 17 publications

References 17 publications

A novel inhibitor of hypoxia-inducible factor-1α P3155 also modulates PI3K pathway and inhibits growth of prostate cancer cells

A novel inhibitor of hypoxia-inducible factor-1α P3155 also modulates PI3K pathway and inhibits growth of prostate cancer cells

Hypoxia‐inducible factor‐1 (HIF‐1) inhibitors from the last decade (2007 to 2016): A “structure–activity relationship” perspective

Anti-tumor Activity of the Novel Hexahydrocannabinol Analog LYR-8 in Human Colorectal Tumor Xenograft Is Mediated through the Inhibition of Akt and Hypoxia-Inducible Factor-1α Activation

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