Multi-target pharmacology: possibilities and limitations of the “skeleton key approach” from a medicinal chemist perspective

Talevi, Alan

doi:10.3389/fphar.2015.00205

Cited by 297 publications

(196 citation statements)

References 49 publications

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“…Current targeted therapeutics targeting a single key factor lead to the acquisition of drug resistance and relapse due to highly redundant and bypassable signaling pathways . Multitarget agents have attracted attention as potential therapeutic solutions to diseases of complex disorders and drug resistance . Natural products are a historically rich source of biologically active compounds for cancer treatment .…”

Section: Discussionmentioning

confidence: 99%

“…36 Multitarget agents have attracted attention as potential therapeutic solutions to diseases of complex disorders and drug resistance. 37,38 Natural products are a historically rich source of biologically active compounds for cancer treatment. 39 Therefore, the potential of natural products is discussed as a starting point for multitarget drug discovery.…”

Section: Discussionmentioning

confidence: 99%

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2′‐Hydroxycinnamaldehyde inhibits proliferation and induces apoptosis via signal transducer and activator of transcription 3 inactivation and reactive oxygen species generation

et al. 2018

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Inhibition of the signal transducer and activator of transcription 3 (STAT3) signaling pathway is a novel therapeutic strategy to treat human cancers with constitutively active STAT3. During the screening of natural products to find STAT3 inhibitors, we identified 2′‐hydroxycinnamaldehyde (HCA) as a STAT3 inhibitor, which was isolated from the stem bark of Cinnamomum cassia. In this study, we found that HCA inhibited constitutive and inducible STAT3 activation in STAT3‐activated DU145 prostate cancer cells. HCA selectively inhibited the STAT3 activity by direct binding to STAT3, which was confirmed by biochemical methods, including a pull‐down assay with biotin‐conjugated HCA, a drug affinity responsive target stability (DARTS) experiment and a cellular thermal shift assay (CETSA). HCA inhibited STAT3 phosphorylation at the tyrosine 705 residue, dimer formation, and nuclear translocation in DU145 cells, which led to a downregulation of STAT3 target genes. The downregulation of cell cycle progression and antiapoptosis‐related gene expression by HCA induced the accumulation of cells in the G0/G1 phase of the cell cycle and then induced apoptosis. We also found that reactive oxygen species (ROS) were involved in the HCA‐induced inhibition of STAT3 activation and cell proliferation because the suppressed p‐STAT3 level was rescued by glutathione or N‐acetyl‐L‐cysteine treatment, which are general ROS inhibitors. These results suggest that HCA could be a potent anticancer agent targeting STAT3‐activated tumor cells.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

2′‐Hydroxycinnamaldehyde inhibits proliferation and induces apoptosis via signal transducer and activator of transcription 3 inactivation and reactive oxygen species generation

et al. 2018

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“…Why is topiramate effective in migraine prophylaxis yet other voltage‐sensitive Na + channel blockers (eg, lamotrigine) are not? Drugs with multiple molecular targets may be more effective than highly selective single‐target agents in complex multifactorial disorders characterized by drug resistance . Topiramate's cumulative pharmacodynamic effects involving glutamate, GABA A , and voltage‐gated Ca 2+ channels may account for its benefits in migraine prophylaxis .…”

Section: Molecular Targets/mechanism(s) Of Actionmentioning

confidence: 99%

Topiramate in Migraine Prevention: A 2016 Perspective

Silberstein

2016

Headache

103

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Topiramate has activity at multiple molecular targets, which may account for why it is effective in migraine and most other, more specific, anticonvulsants are not. Based on randomized controlled trials, topiramate reduces migraine frequency and acute medication use, improves quality of life, and reduces disability in patients with episodic migraine and in those with chronic migraine with or without medication overuse headache. Its efficacy in chronic migraine is not improved by the addition of propranolol. Topiramate's ability to prevent progression from high-frequency episodic migraine to chronic migraine remains unclear. Consistent with clinicians' perceptions, migraineurs are more sensitive to topiramate-associated side effects than patients with epilepsy. Paresthesia is a common occurrence early in treatment but is rarely cause for terminating topiramate treatment. Cognitive problems occur much less frequently than paresthesia but are more troublesome in terms of treatment discontinuation. Cognitive complaints can often be managed by slowly increasing the topiramate dose in small increments to allow habituation. As with other carbonic anhydrase inhibitors, topiramate has metabolic effects that favor the development of metabolic acidosis and possibly renal stones. Because migraineurs have an increased risk of renal stones independent of topiramate exposure, clinicians should counsel all migraine patients to maintain hydration. Abrupt onset of blurring, other visual disturbances, and/or ocular pain following topiramate's initiation should be evaluated promptly since this may indicate rare but potentially sight-threatening idiosyncratic events. Postmarketing evidence has shown that first-trimester exposure to topiramate monotherapy is associated with increased occurrence of cleft lip with or without cleft palate (Pregnancy Category D). Even though topiramate's long half-life would seemingly support q.d. dosing, randomized controlled migraine trials used b.i.d. administration of immediate-release (IR) topiramate, which has more favorable plasma concentration-time profile (ie, lower peak concentrations and higher trough concentrations) than q.d. IR dosing. Given the sensitivity of migraineurs to topiramate-related adverse events, particularly cognitive effects, pharmacokinetic profiles should be considered when optimizing migraine outcomes. The extended-release (XR) formulations Qudexy XR (Upsher-Smith Laboratories) and Trokendi XR (Supernus Pharmaceuticals) were specifically designed to achieve the adherence benefits of q.d. dosing but with more favorable (ie, more constant) steady-state plasma concentrations over the 24-hour dosing interval vs IR topiramate b.i.d. Intriguing results from a study in healthy volunteers showed consistently less impairment in neuropsychometric tests of verbal fluency and mental processing speed with an XR topiramate formulation (Trokendi XR) vs IR topiramate b.i.d. These findings suggest a pharmacodynamic effect associated with significantly reducing plasma concentration fluctuatio...

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“…It is now recognized that many pharmaceuticals on the market for central nervous system (CNS) diseases, cancer and other conditions hit multiple targets [1–3]. The pharmacological spectrum of a given compound can contribute to its net biological benefit in a disease state or detract from it through undesired side-effects [4].…”

Section: Introductionmentioning

confidence: 99%

Polypharmacology of conformationally locked methanocarba nucleosides

Tosh

Toti

Ciancetta

2017

Drug Discovery Today

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A single molecular scaffold can be adapted to interact with diverse targets, either separately or simultaneously. Nucleosides and nucleotides in which ribose is substituted with bicyclo[3.1.0]hexane are an example of a versatile drug-like scaffold for increasing selectivity at their classical targets: kinases, polymerases, adenosine and P2 receptors. Also, by applying structure-based functional group manipulations, rigidified adenosine derivatives can be repurposed to satisfy pharmacophoric requirements of various GPCRs, ion channels, enzymes and transporters, initially detected as off-target activities. Recent examples include 5HT2B serotonin receptor antagonists and novel dopamine transporter allosteric modulators. This directable target diversity establishes rigid nucleosides as privileged scaffolds.

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Multi-target pharmacology: possibilities and limitations of the “skeleton key approach” from a medicinal chemist perspective

Cited by 297 publications

References 49 publications

2′‐Hydroxycinnamaldehyde inhibits proliferation and induces apoptosis via signal transducer and activator of transcription 3 inactivation and reactive oxygen species generation

2′‐Hydroxycinnamaldehyde inhibits proliferation and induces apoptosis via signal transducer and activator of transcription 3 inactivation and reactive oxygen species generation

Topiramate in Migraine Prevention: A 2016 Perspective

Polypharmacology of conformationally locked methanocarba nucleosides

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