Non-ATP competitive protein kinase inhibitors as anti-tumor therapeutics

Kirkland, Lindsay O.; McInnes, Campbell

doi:10.1016/j.bcp.2008.12.022

Cited by 51 publications

(32 citation statements)

References 62 publications

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“…114 Inhibitor design strategies The majority of small-molecule kinase inhibitors developed so far target the ATP binding site (i.e., acting as ATP competitors), although alternative approaches for inhibitor design in targeting sites other than the ATP cleft are being proposed. 115 Chemical scaffolds of the ATP competitive inhibitors usually consist of a planar heterocyclic system that acts as an ATP adenine mimetic. Due to highly conserved structure of the ATP binding domain of most kinases, these inhibitors may suffer from cross-reactivity with other kinases, resulting in poor safety and sometimes severe side effects.…”

Section: Compoundmentioning

confidence: 99%

Targeting CDK6 in cancer: State of the art and new insights

et al. 2015

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Cyclin-dependent kinase 6 (CDK6) plays a vital role in regulating the progression of the cell cycle. More recently, CDK6 has also been shown to have a transcriptional role in tumor angiogenesis. Up-regulated CDK6 activity is associated with the development of several types of cancers. While CDK6 is over-expressed in cancer cells, it has a low detectable level in non-cancerous cells and CDK6-null mice develop normally, suggesting a specific oncogenic role of CDK6, and that its inhibition may represent an ideal mechanism-based and low toxic therapeutic strategy in cancer treatment. Identification of selective small molecule inhibitors of CDK6 is thus needed for drug development. Herein, we review the latest understandings of the biological regulation and oncogenic roles of CDK6. The potential clinical relevance of CDK6 inhibition, the progress in the development of small-molecule CDK6 inhibitors and the rational design of potential selective CDK6 inhibitors are also discussed.

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Section: Compoundmentioning

confidence: 99%

Targeting CDK6 in cancer: State of the art and new insights

et al. 2015

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“…81 Recently, Merck has identified and optimized a series of thioquinazolinones that act as allosteric inhibitors of Chk1. 82 These compounds bind to Chk1 outside the ATP pocket, and while efficacious in vitro, their effectiveness as Chk1 inhibitors in cells has not yet been reported.…”

Section: Pharmacological Inhibitors Of Chk1mentioning

confidence: 99%

The G2 DNA damage checkpoint: Could this ancient regulator be the Achilles heel of cancer?

Kuntz

O’Connell²

2009

Cancer Biology & Therapy

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The maintenance of genomic integrity is important in normal cell growth and organism development, as well as in the prevention of cancer. Cell cycle checkpoints allow the cell time to complete replication and repair DNA damage before it can pass to the next cell cycle stage. These checkpoints ensure faithful segregation of one undamaged copy of the genome to each daughter cell. In humans, a DNA damage-based checkpoint signal in G(1) is propagated through activation of the tumor suppressor p53, which is mutated in many cancers. Chk1, a serine/threonine kinase, controls checkpoint responses in G(2). Chk1 is activated by the concerted action of many upstream proteins and prevents a cell from entering mitosis with damaged or incompletely replicated DNA. This checkpoint is conserved from the fission yeast, Schizosaccharomyces pombe through to humans. However, unlike p53, G(2) checkpoint genes are rarely if ever mutated in cancer cells. This suggests that these genes are essential for tumor cell viability and may represent valid anti-cancer drug targets. This review will describe the current understanding of the G(2) checkpoint including how the human biology has been informed by studies in fission yeast. It will also discuss the present status and future of potential cancer therapies aimed at inactivating this signaling pathway in tumor cells.

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“…To minimize the side effects of targeting FGFRs, non-ATP competitive FGFR1 inhibitor may have substantial benefits [14, 16]. Therefore, the exploration of novel inhibitors with better kinase selectivity has attracted extensive attention in recent years [13, 16, 31]. …”

Section: Discussionmentioning

confidence: 99%

Discovery of novel non-ATP competitive FGFR1 inhibitors and evaluation of their anti-tumor activity in non-small cell lung cancer in vitro and in vivo

Weng

et al. 2014

Oncotarget

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Accumulating evidence suggests that high expression of FGFR1 is closely related to the development of lung cancer especially in non-small cell lung cancers (NSCLC), to which non-ATP competitive inhibitors represent an effective therapeutical approach due to their good specificity. Herein, a series of NDGA analogues with the framework of bisaryl-1,4-dien-3-one as novel FGFR1 inhibitors have been designed and screened. Among them Aea4 and Aea25 showed strong FGFR1 ‵inhibition and high selectivity over other receptor kinases. The kinase inhibitory assay in different ATP concentrations and computer-assistant molecular docking showed that the FGFR1 inhibition mode of both Aea4 and Aea25 was non-ATP-competitive. The in vitro and in vivo study on anticancer efficacy of Aea4 and Aea25 against non-small cell lung cancer involves inhibition of cell proliferation, apoptosis induction and cell cycle arrest with no toxicity. Thus, these two novel non-ATP competitive inhibitors derived from NDGA may have a great therapeutic potential in the treatment of NSCLC. This work also provides a structural lead for the design of new non-ATP-competitive FGFR1 inhibitors.

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Non-ATP competitive protein kinase inhibitors as anti-tumor therapeutics

Cited by 51 publications

References 62 publications

Targeting CDK6 in cancer: State of the art and new insights

Targeting CDK6 in cancer: State of the art and new insights

The G2 DNA damage checkpoint: Could this ancient regulator be the Achilles heel of cancer?

Discovery of novel non-ATP competitive FGFR1 inhibitors and evaluation of their anti-tumor activity in non-small cell lung cancer in vitro and in vivo

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