A Potent and Selective ULK1 Inhibitor Suppresses Autophagy and Sensitizes Cancer Cells to Nutrient Stress

Martin, Katie R.; Celano, Stephanie L.; Solitro, Abigail R.; Günaydın, Hakan; Scott, M. Thompson; O’Hagan, Ronan; Shumway, Stuart D.; Fuller, Peter H.; MacKeigan, Jeffrey P.

doi:10.1016/j.isci.2018.09.012

Cited by 136 publications

(130 citation statements)

References 35 publications

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“…A recent structure-based study revealed that many compounds that would inhibit ULK1 would likely inhibit ULK2 and Aurora kinase as well (142). A more recently developed ULK1 inhibitor, ULK101, with increased specificity has been reported (143). The increasing number of tool compounds will allow for more specific interrogation of autophagy compared with LAP and other autophagy-related processes.…”

Section: Ulk1 Inhibitorsmentioning

confidence: 99%

Targeting Autophagy in Cancer: Recent Advances and Future Directions

2019

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Autophagy, a multistep lysosomal degradation pathway that supports nutrient recycling and metabolic adaptation, has been implicated as a process that regulates cancer. Although autophagy induction may limit the development of tumors, evidence in mouse models demonstrates that autophagy inhibition can limit the growth of established tumors and improve response to cancer therapeutics. Certain cancer genotypes may be especially prone to autophagy inhibition. Different strategies for autophagy modulation may be needed depending on the cancer context. Here, we review new advances in the molecular control of autophagy, the role of selective autophagy in cancer, and the role of autophagy within the tumor microenvironment and tumor immunity. We also highlight clinical efforts to repurpose lysosomal inhibitors, such as hydroxychloroquine, as anticancer agents that block autophagy, as well as the development of more potent and specifi c autophagy inhibitors for cancer treatment, and review future directions for autophagy research. Signifi cance: Autophagy plays a complex role in cancer, but autophagy inhibition may be an effective therapeutic strategy in advanced cancer. A deeper understanding of autophagy within the tumor microenvironment has enabled the development of novel inhibitors and clinical trial strategies. Challenges and opportunities remain to identify patients most likely to benefi t from this approach.

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Section: Ulk1 Inhibitorsmentioning

confidence: 99%

Targeting Autophagy in Cancer: Recent Advances and Future Directions

2019

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“…However, disruption of ULK1 and its associated protein complex lead to autophagy inhibition and cell death. As cancer cells generate energy and nutrients through autophagy mechanism and eventually help in cell survival and tumor progression, disruption of ULK1 function by developing small molecule inhibitors has become an attractive approach to treat cancer [75,76] . As a proof of concept, few ULK1 inhibitors have been reported in the literature [ Figure 9].…”

Section: Unc-51-like Kinases Inhibitorsmentioning

confidence: 99%

Targeting autophagy with small molecules for cancer therapy

Kondapuram¹,

Sarvagalla²,

Coumar³

2019

JCMT

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Autophagy is a conserved lysosomal-dependent catabolic process that maintains the cellular homeostasis by recycling misfolded proteins and damaged organelles. It involves a series of ordered events (initiation, nucleation, elongation, lysosomal fusion and degradation) that are tightly regulated/controlled by diverse cell signals and stress. It is like a double-edged sword that can play either a protective or destructive role in cancer, by pro-survival or apoptotic cues. Recently, modulating autophagy by pharmacological agents has become an attractive strategy to treat cancer. Currently, a number of small molecules that inhibit autophagy initiation (e.g., ULK kinase inhibitors), nucleation (e.g., Vps34 inhibitors), elongation (e.g., ATG4 inhibitors) and lysosome fusion (e.g., chloroquine, hydroxyl chloroquine, etc .) are reported in pre-clinical and clinical study. Also a number of small molecules reported to induce autophagy by targeting mammalian target of rapamycin (e.g., rapamycin analogs) or adenosine 5'-monophosphateactivated protein kinase (e.g., sulforaphane). The study results suggest that many potential "druggable" targets exist in the autophagy pathway that could be harnessed for developing new cancer therapeutics. In this review, we discuss the reported autophagy modulators (inhibitors and inducers), their molecular mode of action and their applications in cancer therapy.

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“…Although there are studies reporting autophagic cell death in mediating the anti-thyroid cancer effects of several small-molecular therapeutics (Lin et al 2010, Xiang et al 2018, future studies are still needed to validate such observations in thyroid cancers. When it comes to inhibiting autophagy for treating thyroid cancers, several promising inhibitors targeting the components of the autophagy pathway have been reported, including ULK1 inhibitors (Egan et al 2015, Martin et al 2018, Vps34 inhibitors (Liu et al 2011, Ronan et al 2014, Robke et al 2017, ATG4B inhibitor (Vezenkov et al 2015), lysosome inhibitors (McAfee et al 2012, Fu et al 2014, Kroemer & Galluzzi 2017, Rebecca et al 2017) and CQ/HCQ (Table 1). For clinical trials, HCQ is chosen over CQ because of its relatively less toxicity than CQ at peak concentrations (Barnard et al 2014, Manic et al 2014.…”

Section: Conclusion and Future Research Perspectivesmentioning

confidence: 99%

Targeting autophagy in thyroid cancers

Wei

Hardin

Luo

2019

Endocrine-Related Cancer

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Thyroid cancer is one of the most common endocrine malignancies. Although the prognosis for the majority of thyroid cancers is relatively good, patients with metastatic, radioiodine-refractory or anaplastic thyroid cancers have an unfavorable outcome. With the gradual understanding of the oncogenic events in thyroid cancers, molecularly targeted therapy using tyrosine kinase inhibitors (TKIs) is greatly changing the therapeutic landscape of radioiodine-refractory differentiated thyroid cancers (RR-DTCs), but intrinsic and acquired drug resistance, as well as adverse effects, may limit their clinical efficacy and use. In this setting, development of synergistic treatment options is of clinical significance, which may enhance the therapeutic effect of current TKIs and further overcome the resultant drug resistance. Autophagy is a critical cellular process involved not only in protecting cells and organisms from stressors but also in the maintenance and development of various kinds of cancers. Substantial studies have explored the complex role of autophagy in thyroid cancers. Specifically, autophagy plays important roles in mediating the drug resistance of small-molecular therapeutics, in regulating the dedifferentiation process of thyroid cancers and also in affecting the treatment outcome of radioiodine therapy. Exploring how autophagy intertwines in the development and dedifferentiation process of thyroid cancers is essential, which will enable a more profound understanding of the physiopathology of thyroid cancers. More importantly, these advances may fuel future development of autophagy-targeted therapeutic strategies for patients with thyroid cancers. Herein, we summarize the most recent evidence uncovering the role of autophagy in thyroid cancers and highlight future research perspectives in this regard. A novel ATG4B antagonist inhibits autophagy and has a negative impact on osteosarcoma tumors. Autophagy 10 2021-2035. (https://doi.

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A Potent and Selective ULK1 Inhibitor Suppresses Autophagy and Sensitizes Cancer Cells to Nutrient Stress

Cited by 136 publications

References 35 publications

Targeting Autophagy in Cancer: Recent Advances and Future Directions

Targeting Autophagy in Cancer: Recent Advances and Future Directions

Targeting autophagy with small molecules for cancer therapy

Targeting autophagy in thyroid cancers

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