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Roman ruins, ancient art and mouth-watering moussaka: 10 things to do in Cyprus! Lysosomotropic agents, as discussed in the previous section, inhibit the steps of autophagy involving the lysosome. The additional phases could be therapeutically targeted as well; however, since these earlier phases involve organelles lacking distinct characteristics such as a nonphysiological pH, it would be difficult to design compounds capable of inhibiting these structures. The only step that has been targeted, in addition to the lysosome's degradation of intracellular material, is the fusion of the autophagosome with the lysosome.
Bafilomycin A1 is characterized as a vacuolar-type proton pump inhibitor that is capable of increasing the lysosome's pH by preventing the influx of hydrogen ions. Studies have also shown that this compound inhibits autophagy at the fusion stage, however the mechanism remains to be elucidated [ 66 ]. The majority of the field has turned its focus to the development of inhibitors targeting key molecules associated with autophagy. As mentioned previously, there exist at least 30 ATG genes in yeast, all of which have homologues in mammalian systems.
These do not include the non- ATG genes known to encode proteins involved in this recycling process. The proteins that have been established as associated with, and in many cases essential for, the autophagy process include protein and lipid kinases i.
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Table 2 includes a list of proteins essential for autophagy and their suspected therapeutic potential. All autophagy-related ATG and autophagy-associated proteins currently known were scored for their potential to be therapeutically targeted.
Although efforts are only just beginning to identify and develop small molecule inhibitors of autophagy, several preliminary studies are worth reviewing. ULK1, the mammalian homologue of the yeast ATG1 protein, is the only known protein kinase essential for autophagy and consequently, is an ideal therapeutic target [ 67 ]. Only two studies investigating ULK1 inhibitors have been published thus far, however, several pharmaceutical companies are currently collaborating with academic laboratories to expand the biomedical research field's knowledge of autophagy and the subsequent development of small-molecule autophagy inhibitors.
One approach currently employed is to utilize high-throughput screening methods to evaluate existing kinase inhibitors for selectivity toward ULK1. The single published study in this realm illustrated nanomolar half maximal effective concentration EC 50 values of TBK1 inhibitors against ULK1 [ 68 ].
Although effects on autophagy as a whole were obvious and easily measured by LC3 protein levels, challenges arose in verifying ULK1 inhibition. Since the field's current knowledge of direct substrates of ULK1 is limited, and as antibodies for known substrates are few and far between, validating a bona-fide ULK1 marker will prove to be the biggest hurdle for those entering the ULK1 inhibitor race. Another approach is to develop novel kinase inhibitors selective for ULK1.
In the only study completed thus far, a small molecule inhibitor of ULK1 was developed using a highly cross-reactive FAK inhibitor as a chemical backbone [ 69 ]. Pyrimidine analogs were then screened for ULK1 inhibition, and structure—activity relationship analyses were then used to expand upon the pyrimidine scaffold. In addition, novel substrates of ULK1 were elucidated using phosphorylation site consensus mapping and were used to verify ULK1 selectivity with newly developed antibodies.
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Preliminary analyses in vitro showed low micromolar EC 50 values for the ULK1 inhibitor, as well as improved inhibition compared with chloroquine. Not only has this study established a benchmark for novel ULK1 inhibitors, but Shaw and colleagues have provided a working toolbox for the future validation of small molecule inhibitors of autophagy. As the only lipid kinase currently known in the autophagy pathway, VPS34 shows potential for therapeutic targeting equivalent to that of ULK1.
The few studies of VPS34 inhibitors have all employed high-throughput screening methods to evaluate existing compounds for VPS34 selectivity [ 73—77 ]. In vitro validation of lead compounds has illustrated effective autophagy inhibition; however, in vivo characterization and comparisons to lysosomotropic agents and other small molecule inhibitors of autophagy have yet to be performed. Although early in development, small molecule inhibitors of autophagy have shown promise in vitro and have excited the field Figure 4. When compared with lysosomotropic agents, targeted agents of the autophagy machinery will likely show efficacy at significantly lower doses.
The expectation is that this will translate into combination treatment strategies with limited toxicity to patients. In addition, targeting the autophagy pathway at the most upstream point is likely to prevent autophagosome formation and the potential for any intracellular degradation. Currently, the only foreseeable disadvantage of small-molecule autophagy inhibitors is the time to development. However, this acute inconvenience will undoubtedly be overshadowed by the clinical relevance of such compounds.
The primary molecular machinery involved in autophagy is illustrated. All current autophagy inhibitors are labeled in bold by their published name or, alternatively, the name of the first author of the associated publication. The early successes of both lysosomotropic agents and small molecule inhibitors of the autophagy pathway have poised the field for rapid growth and development.
Although few in number, clinical trials conducted thus far have clearly shown the safety and tolerability of lysosome-targeted compounds in cancer patients. In addition, the achievement of stable disease with hydroxychloroquine treatment has been observed in some cases. In response to these results, more potent lysosomotropic agents are being developed.
As preclinical validation of these compounds occurs over the next few years, it is likely that compounds such as Lys05, VATG and VATG will make their way to clinical trials. Small molecule enzymatic inhibitors of the autophagy pathway may provide a longer list of benefits than lysosomotropic agents, but such compounds will still have their place in anticancer therapy. As mentioned previously, further investigations into the dependencies of cancer cells have revealed the lysosome as a key survival node in certain oncogene-driven malignancies.
As processes like macropinocytosis are added to the list of a tumor's addictions, lysosomotropic agents will prove to be multifunctional. The advancement of lysosome-targeted autophagy inhibitors, though necessary and relevant, will likely be overshadowed by the novelty of small molecule inhibitors.
The newness of the autophagy field in general has spawned emotions of awe and wonder as key players within the pathway are discovered and further elucidated every month. The list of targetable molecules in Table 2 will continue to grow and be fine tuned. While the field develops, top prospects like ULK1 and VPS34 are expected to make headlines, assuming their continued success in the preclinical space.
Especially in the case of ULK1, as numerous collaborations are being born, the time to clinical relevance will be streamlined. Over the next decade, it is possible that an ULK1 inhibitor will make its way to a clinical trial. This is indeed an exciting time for the autophagy field. From the observation of the lysosome in the s by Christian de Duve, the biomedical research community's knowledge of autophagy and its involvement in human disease has grown exponentially. The serendipitous mechanism of action of antimalarial compounds accelerated investigations of autophagy inhibition in cancer patients.
With hydroxychloroquine leading the way, the field now has the privilege of watching more potent lysosomotropic agents and small molecule inhibitors hit the stage. As research and development continues over the next several years, autophagy inhibitors are expected to be the topic of numerous publications, scientific meetings and hallway conversations.
No matter the area of cancer research, autophagy inhibitors will make a significant impact. Autophagosome: A double-membrane vesicle capable of sequestering cytosolic material and delivering it to the lysosome for degradation. Lysosomotropic: The characteristic of being drawn to and trapped within the acidic lysosomal compartment. Autophagy dependence: The state of relying on autophagy for cell survival, as in oncogene addiction. Macropinocytosis: The process of engulfing extracellular material for digestion and recycling by the lysosome. Structure—activity relationship: A description of the common characteristics linking a molecule's physical state to its function.
Autophagy has emerged as a valid therapeutic target across multiple malignancies.
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Not only is autophagy employed as a chemoresistance mechanism, but numerous cancer types display a natural dependence upon this intracellular recycling process. The first autophagy inhibitors were born out of antimalarial research. When the lysosome-targeted mechanism of action for chloroquine and its derivative hydroxychloroquine was elucidated, the drugs became natural prospects for the inhibition of autophagy. The path to clinical trials for hydroxychloroquine was expedited due to its prior FDA approval and extensive characterization in the treatment of both malaria and inflammatory diseases.
Published results have thus far shown the safety, efficacy and tolerability of hydroxychloroquine in cancer patients, both as a single agent and in combination treatment strategies. In some cases, stable disease has even been achieved.