Novel Multitarget Therapies for Lung Cancer and Respiratory Disease

Yumura, Masako; Nagano, Tatsuya; Nishimura, Yoshihiro

doi:10.3390/molecules25173987

Cited by 15 publications

(12 citation statements)

References 66 publications

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“…[ 1 , 2 , 3 , 4 ] Among their several advantages, they offer the potential of higher efficacy due to synergistic effects, a minor insurgence of drug resistance, the lack of drug‐drug interactions and a better patient compliance. [1] Indeed, multi‐target drugs are recognized to be particularly important for the treatment of complex and multi‐factorial diseases, such as cancer and neurodegeneration,[ 5 , 6 , 7 , 8 ] in which complex networks of multiple and interconnected biological targets need to be simultaneously modulated. For this reason, the rational design of compounds with desired, ad hoc “polypharmacological” profiles has become increasingly important to discover better drug candidates.…”

Section: Introductionmentioning

confidence: 99%

Design and Synthesis of Hsp90 Inhibitors with B‐Raf and PDHK1 Multi‐Target Activity

et al. 2021

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The design of multi‐target ligands has become an innovative approach for the identification of effective therapeutic treatments against complex diseases, such as cancer. Recent studies have demonstrated that the combined inhibition of Hsp90 and B‐Raf provides synergistic effects against several types of cancers. Moreover, it has been reported that PDHK1, which presents an ATP‐binding pocket similar to that of Hsp90, plays an important role in tumor initiation, maintenance and progression, participating also to the senescence process induced by B‐Raf oncogenic proteins. Based on these premises, the simultaneous inhibition of these targets may provide several benefits for the treatment of cancer. In this work, we set up a design strategy including the assembly and integration of molecular fragments known to be important for binding to the Hsp90, PDHK1 and B‐Raf targets, aided by molecular docking for the selection of a set of compounds potentially able to exert Hsp90‐B‐Raf‐PDHK1 multi‐target activities. The designed compounds were synthesized and experimentally validated in vitro . According to the in vitro assays, compounds 4 a , 4 d and 4 e potently inhibited Hsp90 and moderately inhibited the PDHK1 kinase. Finally, molecular dynamics simulations were performed to provide further insights into the structural basis of their multi‐target activity.

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Section: Introductionmentioning

confidence: 99%

Design and Synthesis of Hsp90 Inhibitors with B‐Raf and PDHK1 Multi‐Target Activity

et al. 2021

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“…Therefore, they have therapeutic advantages over single-targeted inhibitors and have become a focus of antitumor drug research in recent years [ 95 , 96 ]. Recent reviews summarize the mechanisms of action of multitarget therapies and results of the latest clinical trials (e.g., [ 97 , 98 ]). On the other hand, these compounds may exhibit adverse events involving several biological systems due to their mechanism of multitargeted inhibition [ 99 ].…”

Section: Anticancer Activity Of Oximesmentioning

confidence: 99%

Oximes: Novel Therapeutics with Anticancer and Anti-Inflammatory Potential

et al. 2021

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Oximes have been studied for decades because of their significant roles as acetylcholinesterase reactivators. Over the last twenty years, a large number of oximes have been reported with useful pharmaceutical properties, including compounds with antibacterial, anticancer, anti-arthritis, and anti-stroke activities. Many oximes are kinase inhibitors and have been shown to inhibit over 40 different kinases, including AMP-activated protein kinase (AMPK), phosphatidylinositol 3-kinase (PI3K), cyclin-dependent kinase (CDK), serine/threonine kinases glycogen synthase kinase 3 α/β (GSK-3α/β), Aurora A, B-Raf, Chk1, death-associated protein-kinase-related 2 (DRAK2), phosphorylase kinase (PhK), serum and glucocorticoid-regulated kinase (SGK), Janus tyrosine kinase (JAK), and multiple receptor and non-receptor tyrosine kinases. Some oximes are inhibitors of lipoxygenase 5, human neutrophil elastase, and proteinase 3. The oxime group contains two H-bond acceptors (nitrogen and oxygen atoms) and one H-bond donor (OH group), versus only one H-bond acceptor present in carbonyl groups. This feature, together with the high polarity of oxime groups, may lead to a significantly different mode of interaction with receptor binding sites compared to corresponding carbonyl compounds, despite small changes in the total size and shape of the compound. In addition, oximes can generate nitric oxide. This review is focused on oximes as kinase inhibitors with anticancer and anti-inflammatory activities. Oximes with non-kinase targets or mechanisms of anti-inflammatory activity are also discussed.

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“…Thus, small molecules with multitarget activity are of increasing interest for interfering with derailed cellular signaling pathways or perturbed target networks implicated in complex multifactorial diseases such as COVID-19 [ 293 , 294 , 295 , 296 ]. In this situation, multi-target therapy could be used to provide a synergistic antiviral, immunomodulatory, and anti-inflammatory impact at the same time.…”

Section: Conclusion and Future Perspectivesmentioning

confidence: 99%

Problems of Pathogenesis and Pathogenetic Therapy of COVID-19 from the Perspective of the General Theory of Pathological Systems (General Pathological Processes)

Гусев

Sarapultsev

et al. 2021

IJMS

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The COVID-19 pandemic examines not only the state of actual health care but also the state of fundamental medicine in various countries. Pro-inflammatory processes extend far beyond the classical concepts of inflammation. They manifest themselves in a variety of ways, beginning with extreme physiology, then allostasis at low-grade inflammation, and finally the shockogenic phenomenon of “inflammatory systemic microcirculation”. The pathogenetic core of critical situations, including COVID-19, is this phenomenon. Microcirculatory abnormalities, on the other hand, lie at the heart of a specific type of general pathological process known as systemic inflammation (SI). Systemic inflammatory response, cytokine release, cytokine storm, and thrombo-inflammatory syndrome are all terms that refer to different aspects of SI. As a result, the metabolic syndrome model does not adequately reflect the pathophysiology of persistent low-grade systemic inflammation (ChSLGI). Diseases associated with ChSLGI, on the other hand, are risk factors for a severe COVID-19 course. The review examines the role of hypoxia, metabolic dysfunction, scavenger receptors, and pattern-recognition receptors, as well as the processes of the hemophagocytic syndrome, in the systemic alteration and development of SI in COVID-19.

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Novel Multitarget Therapies for Lung Cancer and Respiratory Disease

Cited by 15 publications

References 66 publications

Design and Synthesis of Hsp90 Inhibitors with B‐Raf and PDHK1 Multi‐Target Activity

Design and Synthesis of Hsp90 Inhibitors with B‐Raf and PDHK1 Multi‐Target Activity

Oximes: Novel Therapeutics with Anticancer and Anti-Inflammatory Potential

Problems of Pathogenesis and Pathogenetic Therapy of COVID-19 from the Perspective of the General Theory of Pathological Systems (General Pathological Processes)

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