Multi-Target Drugs: The Trend of Drug Research and Development

Lu, Jin‐Jian; Pan, Wei; Y, Hu; Wang, Yitao

doi:10.1371/journal.pone.0040262

Cited by 216 publications

(134 citation statements)

References 43 publications

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“…Some diseases, including BPH, are multifactorial (Roehrborn, 2008), most likely requiring multi-target strategies to improve therapeutic efficacy (Morphy et al, 2004;Lu et al, 2012). For the clinical management of BPH, we hypothesized that targeting of a 1D -adrenoceptors and 5-HT 1A receptors, in addition to a 1A -adrenoceptor antagonism, could be particularly interesting because both receptors stimulate prostate cell growth (Dizeyi et al, 2004;Kojima et al, 2009a), a 1D -adrenoceptors mRNA expression is increased in BPH (Kojima et al, 2009a), and nonprostatic a 1D -adrenoceptors may contribute to bladder overactivity (Malloy et al, 1998;Michel, 2010;Kurizaki et al, 2011).…”

Section: Discussionmentioning

confidence: 99%

New Multi-target Antagonists of 1A-, 1D-Adrenoceptors and 5-HT1A Receptors Reduce Human Hyperplastic Prostate Cell Growth and the Increase of Intraurethral Pressure

Nascimento-Viana

Carvalho

Nasciutti

et al. 2015

Journal of Pharmacology and Experimental Therapeutics

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Benign prostatic hyperplasia (BPH) is characterized by stromal cell proliferation and contraction of the periurethral smooth muscle, causing lower urinary tract symptoms. Current BPH treatment, based on monotherapy with a 1A -adrenoceptor antagonists, is helpful for many patients, but insufficient for others, and recent reports suggest that stimulation of a 1D -adrenoceptors and 5-hydroxytryptamine (serotonin) (5-HT) 1A receptors contributes to cell proliferation. In this study, we investigated the potential of three N-phenylpiperazine derivatives (LDT3, LDT5, and LDT8) as multi-target antagonists of BPH-associated receptors. The affinity and efficacy of LDTs were estimated in isometric contraction and competition-binding assays using tissues (prostate and aorta) and brain membrane samples enriched in specific on-or off-target receptors. LDTs' potency was estimated in intracellular Ca 21 elevation assays using cells overexpressing human a 1 -adrenoceptor subtypes. The antiproliferative effect of LDTs on prostate cells from BPH patients was evaluated by viable cell counting and 3-(4,5-dimethythiazol-2-yl)-2,5-diphenyl tetrazolium bromide assays. We also determined LDTs' effects on rat intraurethral and arterial pressure. LDT3 and LDT5 are potent antagonists of a 1A -, a 1D -adrenoceptors, and 5-HT 1A receptors (K i values in the nanomolar range), and fully inhibited phenylephrine-and 5-HT-induced proliferation of BPH cells. In vivo, LDT3 and LDT5 fully blocked the increase of intraurethral pressure (IUP) induced by phenylephrine at doses (ED 50 of 0.15 and 0.09 mg.kg 21 , respectively) without effect on basal mean blood pressure. LDT3 and LDT5 are multi-target antagonists of key receptors in BPH, and are capable of triggering both prostate muscle relaxation and human hyperplastic prostate cell growth inhibition in vitro. Thus, LDT3 and LDT5 represent potential new lead compounds for BPH treatment.

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Section: Discussionmentioning

confidence: 99%

New Multi-target Antagonists of 1A-, 1D-Adrenoceptors and 5-HT1A Receptors Reduce Human Hyperplastic Prostate Cell Growth and the Increase of Intraurethral Pressure

Nascimento-Viana

Carvalho

Nasciutti

et al. 2015

Journal of Pharmacology and Experimental Therapeutics

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“…Pulmonary fibrosis (PF) is a life-threatening disease that may benefit from simultaneously targeting multiple pathways to improve therapeutic efficacy. Combination therapy can achieve this, but its practicality is often limited by complicated pharmacokinetics and dosing schedules as well as extensive drug-drug interactions and adverse effects (2). Indeed, clinical trials using combination therapies for idiopathic PF (IPF) have yielded disappointing results, showing lack of efficacy or even worsening outcomes (3).…”

Section: Introductionmentioning

confidence: 99%

Cannabinoid CB1 receptor overactivity contributes to the pathogenesis of idiopathic pulmonary fibrosis

Çınar¹,

Gochuico²,

Iyer³

et al. 2017

JCI Insight

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“…It has been suggested that strategic combinations of agents targeting against the most critical alterations in cancer will be needed, or simply the use of more unspecific agents that modulate several relevant targets simultaneously (46,47). Not surprisingly, drug discovery has moved toward investigating multitarget drugs in the last decade, in a large part due to the development of cancer therapeutics (48)(49)(50). TBE-31 is an attractive compound for cancer prevention due to its antioxidative, anti-inflammatory response capabilities by inducing the Keap1/Nrf2/ARE pathway (25)(26)(27)(28)(29), and now inhibiting cell migration by targeting actin.…”

Section: Discussionmentioning

confidence: 99%

The Acetylenic Tricyclic Bis(cyano enone), TBE-31 Inhibits Non–Small Cell Lung Cancer Cell Migration through Direct Binding with Actin

Chan

Saito²,

Honda

et al. 2014

Cancer Prevention Research

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The migratory and invasive potential of the epithelial-derived tumor cells depends on epithelial-tomesenchymal transition (EMT) as well as the reorganization of the cell cytoskeleton. Here, we show that the tricyclic compound acetylenic tricyclic bis(cyano enone), TBE-31, directly binds to actin and inhibits linear and branched actin polymerization in vitro. Furthermore, we observed that TBE-31 inhibits stress fiber formation in fibroblasts as well as in non-small cell lung cancer cells during TGFb-dependent EMT. Interestingly, TBE-31 does not interfere with TGFb-dependent signaling or changes in E-cadherin and Ncadherin protein levels during EMT. Finally, we observed that TBE-31 inhibits fibroblast and non-small cell lung tumor cell migration with an IC 50 of 1.0 and 2.5 mmol/L, respectively. Taken together, our results suggest that TBE-31 targets linear actin polymerization to alter cell morphology and inhibit cell migration. Cancer Prev Res; 7(7); 727-37. Ó2014 AACR.

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Multi-Target Drugs: The Trend of Drug Research and Development

Cited by 216 publications

References 43 publications

New Multi-target Antagonists of 1A-, 1D-Adrenoceptors and 5-HT1A Receptors Reduce Human Hyperplastic Prostate Cell Growth and the Increase of Intraurethral Pressure

New Multi-target Antagonists of 1A-, 1D-Adrenoceptors and 5-HT1A Receptors Reduce Human Hyperplastic Prostate Cell Growth and the Increase of Intraurethral Pressure

Cannabinoid CB1 receptor overactivity contributes to the pathogenesis of idiopathic pulmonary fibrosis

The Acetylenic Tricyclic Bis(cyano enone), TBE-31 Inhibits Non–Small Cell Lung Cancer Cell Migration through Direct Binding with Actin

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