Specific delivery of kinase inhibitors in nonmalignant and malignant diseases

Beuge, Marike Marjolijn van; Poelstra, Klaas; Prakash, Jai

doi:10.1517/17425247.2012.638625

Cited by 5 publications

(5 citation statements)

References 84 publications

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“…TYK2 pseudo-kinase inhibitors have shown that using human genetics with the analysis of rare coding variants enables both the identification and the design of novel drug targets 51 . Improving organ-specific (such as gut, lung or skin) 48 and/or cell-specific 261 delivery of kinase inhibitors should also improve therapeutic efficacy with reduced side effects.…”

Section: Future Directions and Conclusionmentioning

confidence: 99%

Kinase inhibition in autoimmunity and inflammation

Zarrin¹,

Bao²,

Lupardus³

et al. 2020

Nat Rev Drug Discov

265

210

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Despite recent advances in the treatment of autoimmune and inflammatory diseases, unmet medical needs in some areas still exist. One of the main therapeutic approaches to alleviate dysregulated inflammation has been to target the activity of kinases that regulate production of inflammatory mediators. Small-molecule kinase inhibitors have the potential for broad efficacy, convenience and tissue penetrance, and thus often offer important advantages over biologics. However, designing kinase inhibitors with target selectivity and minimal off-target effects can be challenging. Nevertheless, immense progress has been made in advancing kinase inhibitors with desirable drug-like properties into the clinic, including inhibitors of JAKs, IRAK4, RIPKs, BTK, SYK and TPL2. This Review will address the latest discoveries around kinase inhibitors with an emphasis on clinically validated autoimmunity and inflammatory pathways.

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Section: Future Directions and Conclusionmentioning

confidence: 99%

Kinase inhibition in autoimmunity and inflammation

Zarrin¹,

Bao²,

Lupardus³

et al. 2020

Nat Rev Drug Discov

265

210

View full text Add to dashboard Cite

show abstract

“…Use of small molecule protein kinase inhibitors for development of novel therapies for diseases other than cancer is gaining momentum due to the ease of modifying their chemical structure depending on the clinical needs, their adaptability to large scale production, and possible oral delivery . In this study, we identified H‐8 as a small molecule kinase inhibitor that targets hMSC, enhances their ex vivo OB differentiation and in vivo bone regeneration.…”

Section: Discussionmentioning

confidence: 99%

“…Small molecule protein kinase inhibitors have been developed as novel drugs for treatment of malignant and nonmalignant diseases . The USA food and drug administration has approved several kinase inhibitor drugs alleviating concerns about their safe use as therapeutic agents . Using small molecule protein kinase inhibitors for targeting human MSC and enhancing bone formation has not been previously explored.…”

Section: Introductionmentioning

confidence: 99%

Pharmacological Inhibition of Protein Kinase G1 Enhances Bone Formation by Human Skeletal Stem Cells Through Activation of RhoA-Akt Signaling

et al. 2015

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Development of novel approaches to enhance bone regeneration is needed for efficient treatment of bone defects. Protein kinases play a key role in regulation of intracellular signal transduction pathways, and pharmacological targeting of protein kinases has led to development of novel treatments for several malignant and nonmalignant conditions. We screened a library of kinase inhibitors to identify small molecules that enhance bone formation by human skeletal (stromal or mesenchymal) stem cells (hMSC). We identified H-8 (known to inhibit protein kinases A, C, and G) as a potent enhancer of ex vivo osteoblast (OB) differentiation of hMSC, in a stage-and cell type-specific manner, without affecting adipogenesis or osteoclastogenesis. Furthermore, we showed that systemic administration of H-8 enhances in vivo bone formation by hMSC, using a preclinical ectopic bone formation model in mice. Using functional screening of known H-8 targets, we demonstrated that inhibition of protein kinase G1 (PRKG1) and consequent activation of RhoA-Akt signaling is the main mechanism through which H-8 enhances osteogenesis. Our studies revealed PRKG1 as a novel negative regulator of OB differentiation and suggest that pharmacological inhibition of PRKG1 in hMSC implanted at the site of bone defect can enhance bone regeneration.

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“…PAP19 is an imatinib-like drug that inhibits the PDGFR-β. Gonzalo T et al have demonstrated that PAP19 reduce fibrotic markers in HSC and target HSC specifically in a rat model of hepatic fibrosis via the M6PHSA carrier [93]. …”

Section: Selective Delivery Of Tkis: a Potential Strategy For Reducinmentioning

confidence: 99%

Tyrosine kinase inhibitors: friends or foe in treatment of hepatic fibrosis?

Liu

Lin

et al. 2016

Oncotarget

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Aberrant activity of tyrosine kinases has been proved to be associated with multiple diseases including fibrotic diseases. Tyrosine kinases inhibitors (TKIs) might be a novel approach to transform the anti-fibrotic treatment. However, both beneficial and adverse effects are observed by researchers when using these TKIs in either preclinical animal models or patients with hepatic fibrosis. Since hepatotoxicity of TKIs is the leading cause for drug withdrawals thus limits its application in anti-fibrosis, not only efficacy but also safety of TKIs should be paid great concerns. It has been observed in a few studies that TKIs could induce relatively high rate of hepatic biochemical markers elevations and even result in liver failure. Fortunately, several strategies have been adopt to handle with the hepatotoxicity. Accumulating evidences suggest that hepatic stellate cells (HSC) play a pivotal role in hepatic fibrogenesis, so it might be a good option to develop selective TKIs specifically targeting HSCs. The present review will briefly summarize the anti-fibrotic mechanism of TKIs, adverse effects of TKIs as well as the novel developed selective delivery of TKIs.

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Specific delivery of kinase inhibitors in nonmalignant and malignant diseases

Cited by 5 publications

References 84 publications

Kinase inhibition in autoimmunity and inflammation

Kinase inhibition in autoimmunity and inflammation

Pharmacological Inhibition of Protein Kinase G1 Enhances Bone Formation by Human Skeletal Stem Cells Through Activation of RhoA-Akt Signaling

Tyrosine kinase inhibitors: friends or foe in treatment of hepatic fibrosis?

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