The potential of Src inhibitors

Elias, Daniel; Ditzel, Henrik J.

doi:10.18632/aging.100821

Cited by 19 publications

(10 citation statements)

References 8 publications

(10 reference statements)

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“…But roscovitine enhances the ATRA-induced increase of Lyn and Fgr in the nucleus and promotes ATRA-induced differentiation. This is paradoxical, however, as it is known that in a variety of cases SFK inhibitors can also act as activators, too [61], suggesting that context dependence may be a partial explanation. Certainly, off target effects of the drugs could have resulted in compensatory effects, too.…”

Section: Discussionmentioning

confidence: 99%

Roscovitine enhances all-trans retinoic acid (ATRA)-induced nuclear enrichment of an ensemble of activated signaling molecules and augments ATRA-induced myeloid cell differentiation

et al. 2020

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Although ATRA represents a successful differentiation therapy for APL, it is largely ineffective for non-APL AMLs. Hence combination therapies using an agent targeting ATRA-regulated molecules that drive cell differentiation/arrest are of interest. Using the HL-60 human non-APL AML model where ATRA causes nuclear enrichment of c-Raf that drives differentiation/G0-arrest, we now observe that roscovitine enhanced nuclear enrichment of certain traditionally cytoplasmic signaling molecules and enhanced differentiation and cell cycle arrest. Roscovitine upregulated ATRA-induced nuclear c-Raf phosphorylation at S259 and S289/296/301. Nuclear c-Raf interacted with RB protein and specifically with pS608RB, the hinge region phosphorylation controlling E2F binding and cell cycle progression. ATRA-induced loss of pS608RB with cell cycle arrest was associated with loss of RB-sequestered c-Raf, thereby coupling cell cycle arrest and increased availability of c-Raf to promote differentiation. Part of this mechanism reflects promoting cell cycle arrest via ATRAinduced upregulation of the p27 Kip1 CDKI. Roscovitine also enhanced the ATRAinduced nuclear enrichment of other signaling molecules traditionally perceived as cytoplasmic promoters of proliferation, but now known to promote differentiation; in particular: SFKs, Lyn, Fgr; adaptor proteins, c-Cbl, SLP-76; a guanine exchange factor, Vav1; and a transcription factor, IRF-1. Akin to c-Raf, Lyn bound to RB, specifically to pS608RB. Lyn-pS608RB association was greatly diminished by ATRA and essentially lost in ATRA plus roscovitine treated cells. Interestingly Lyn-KD enhanced such ATRAinduced nuclear signaling and differentiation and made roscovitine more effective. ATRA thus mobilized traditionally cytoplasmic signaling molecules to the nucleus where they drove differentiation which were further enhanced by roscovitine.

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Section: Discussionmentioning

confidence: 99%

Roscovitine enhances all-trans retinoic acid (ATRA)-induced nuclear enrichment of an ensemble of activated signaling molecules and augments ATRA-induced myeloid cell differentiation

et al. 2020

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“…Some do so by acting on the core Hippo kinase cascade, while others regulate YAP and TAZ independent of the Hippo pathway. Interestingly, FDA-approved drugs that target several of these pathways such as GPCRs, integrins, and Src already exist [ 216 , 217 , 218 , 219 , 220 , 221 , 222 ] and could be re-purposed for use in YAP/TAZ-dependent cancers. Below, we discuss several examples of regulators of YAP/TAZ that may be potential therapeutic targets for the treatment of metastatic disease.…”

Section: Therapeutic Potential Of Targeting Yap/taz-tead In Cancermentioning

confidence: 99%

YAP/TAZ Activation as a Target for Treating Metastatic Cancer

Lamar

Xiao

2018

Cancers

115

124

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Yes-Associated Protein (YAP) and Transcriptional Co-activator with PDZ-binding Motif (TAZ) have both emerged as important drivers of cancer progression and metastasis. YAP and TAZ are often upregulated or nuclear localized in aggressive human cancers. There is abundant experimental evidence demonstrating that YAP or TAZ activation promotes cancer formation, tumor progression, and metastasis. In this review we summarize the evidence linking YAP/TAZ activation to metastasis, and discuss the roles of YAP and TAZ during each step of the metastatic cascade. Collectively, this evidence strongly suggests that inappropriate YAP or TAZ activity plays a causal role in cancer, and that targeting aberrant YAP/TAZ activation is a promising strategy for the treatment of metastatic disease. To this end, we also discuss several potential strategies for inhibiting YAP/TAZ activation in cancer and the challenges each strategy poses.

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“…KX-01 is a small molecule dual inhibitor of SRC kinase and MT polymerization 147,153,154. There are a number of SRC inhibitors that failed to demonstrate clinical efficacy while undergoing breast cancer treatments 147,[155][156][157]. On the contrary, KX-01 has shown promising preclinical results, through a dual MOAs, in several breast cancer cell lines with the potential to overcome the therapeutic limitations of current SRC inhibitors [158][159][160].…”

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confidence: 99%

Current advances of tubulin inhibitors as dual acting small molecules for cancer therapy

et al. 2019

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Microtubule (MT)‐targeting agents are highly successful drugs as chemotherapeutic agents, and this is attributed to their ability to target MT dynamics and interfere with critical cellular functions, including, mitosis, cell signaling, intracellular trafficking, and angiogenesis. Because MT dynamics vary in the different stages of the cell cycle, these drugs tend to be the most effective against mitotic cells. While this class of drug has proven to be effective against many cancer types, significant hurdles still exist and include overcoming aspects such as dose limited toxicities and the development of resistance. Newer generations of developed drugs attack these problems and alternative approaches such as the development of dual tubulin and kinase inhibitors are being investigated. This approach offers the potential to show increased efficacy and lower toxicities. This review covers different categories of MT‐targeting agents, recent advances in dual inhibitors, and current challenges for this drug target.

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The potential of Src inhibitors

Cited by 19 publications

References 8 publications

Roscovitine enhances all-trans retinoic acid (ATRA)-induced nuclear enrichment of an ensemble of activated signaling molecules and augments ATRA-induced myeloid cell differentiation

Roscovitine enhances all-trans retinoic acid (ATRA)-induced nuclear enrichment of an ensemble of activated signaling molecules and augments ATRA-induced myeloid cell differentiation

YAP/TAZ Activation as a Target for Treating Metastatic Cancer

Current advances of tubulin inhibitors as dual acting small molecules for cancer therapy

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