Kinase Inhibitors: The Reality Behind the Success

Jeon, Jae Yoon; Sparreboom, Alex; Baker, Sharyn D.

doi:10.1002/cpt.815

Cited by 13 publications

(4 citation statements)

References 13 publications

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“…The limitation of such approaches to date has been the inability to achieve sufficient transfection in the target organ. A phase I study is currently recruiting to evaluate PR001A, a viral vector-based therapy to deliver GBA which rescues GCase activity and reduces α-synuclein levels in cell and mouse models [ 180 ], in patients with moderate to severe PD and GBA variants (NCT04127578). Preliminary results evaluation are expected in mid-2021.…”

Section: Therapeuticsmentioning

confidence: 99%

The Genetics of Parkinson’s Disease and Implications for Clinical Practice

Day

Mullin

2021

Genes

106

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The genetic landscape of Parkinson’s disease (PD) is characterised by rare high penetrance pathogenic variants causing familial disease, genetic risk factor variants driving PD risk in a significant minority in PD cases and high frequency, low penetrance variants, which contribute a small increase of the risk of developing sporadic PD. This knowledge has the potential to have a major impact in the clinical care of people with PD. We summarise these genetic influences and discuss the implications for therapeutics and clinical trial design.

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Section: Therapeuticsmentioning

confidence: 99%

The Genetics of Parkinson’s Disease and Implications for Clinical Practice

Day

Mullin

2021

Genes

106

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“…Scientists are working tirelessly to develop a drug that can effectively target the Src and its partner molecules, hoping to provide more targeted and effective treatments. This has led to the development and approval of Src and multi-kinase inhibitors such as dasatinib, bosutinib, and ponatinib [ 167 ]. A comprehensive list of completed and ongoing clinical trials with Src inhibitors is provided in Table 1 .…”

Section: Discussionmentioning

confidence: 99%

Role of c-Src in Carcinogenesis and Drug Resistance

Raji,

Tetteh,

Amin

2023

Cancers

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The aberrant transformation of normal cells into cancer cells, known as carcinogenesis, is a complex process involving numerous genetic and molecular alterations in response to innate and environmental stimuli. The Src family kinases (SFK) are key components of signaling pathways implicated in carcinogenesis, with c-Src and its oncogenic counterpart v-Src often playing a significant role. The discovery of c-Src represents a compelling narrative highlighting groundbreaking discoveries and valuable insights into the molecular mechanisms underlying carcinogenesis. Upon oncogenic activation, c-Src activates multiple downstream signaling pathways, including the PI3K-AKT pathway, the Ras-MAPK pathway, the JAK-STAT3 pathway, and the FAK/Paxillin pathway, which are important for cell proliferation, survival, migration, invasion, metastasis, and drug resistance. In this review, we delve into the discovery of c-Src and v-Src, the structure of c-Src, and the molecular mechanisms that activate c-Src. We also focus on the various signaling pathways that c-Src employs to promote oncogenesis and resistance to chemotherapy drugs as well as molecularly targeted agents.

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“…Nearly 2% of the human genome encodes protein kinases (http://kinase.com/kinbase/). Most of the kinase inhibitor drugs that are currently approved or in clinical trials, are intended for the treatment of cancers [12,13]. In our study, we employed a kinase inhibitor library that comprises 378 drugs containing a proportion of FDA approved agents, in addition to many in clinical trials at different phases.…”

Section: Introductionmentioning

confidence: 99%

Kinome inhibition reveals a role for polo‐like kinase 1 in targeting post‐transcriptional control in cancer

et al. 2021

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Dysfunctions in post-transcriptional control are observed in cancer and chronic inflammatory diseases. Here, we employed a kinome inhibitor library (n=378) in a reporter system selective for 3-untranslated region-AU-rich elements (ARE). Fifteen inhibitors reduced the ARE reporter activity; among the targets is the polo-like kinase 1 (PLK1). RNAseq experiments demonstrated that the PLK1 inhibitor, volasertib, reduces the expression of cytokine and cell growth ARE-mRNAs. PLK1 inhibition caused accelerated mRNA decay in cancer cells and was associated with reduced phosphorylation and stability of the mRNA decay-promoting protein, tristetraprolin (ZFP36/TTP). Ectopic expression of PLK1 increased abundance and stability of high molecular weight of ZFP36/TTP likely of the phosphorylated form. PLK1 effect was associated with the MAPK-MK2 pathway, a major regulator of ARE-mRNA stability, as evident from MK2 inhibition, in vitro phosphorylation, and knockout experiments. Mutational analysis demonstrates that TTP serine 186 is a target for PLK1 effect. Treatment of mice with the PLK1 inhibitor reduced both ZFP36/TTP phosphorylation in xenograft tumor tissues, and the tumor size. In cancer patients' tissues, PLK1/ARE-regulated gene cluster was overexpressed in solid tumors and associated with poor survival. The data showed that PLK1-mediated posttranscriptional aberration could be a therapeutic target.

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Kinase Inhibitors: The Reality Behind the Success

Cited by 13 publications

References 13 publications

The Genetics of Parkinson’s Disease and Implications for Clinical Practice

The Genetics of Parkinson’s Disease and Implications for Clinical Practice

Role of c-Src in Carcinogenesis and Drug Resistance

Kinome inhibition reveals a role for polo‐like kinase 1 in targeting post‐transcriptional control in cancer

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