Discovery of Hedgehog Antagonists for Cancer Therapy.

Abstract:

BACKGROUND:The evolutionarily conserved Hedgehog (Hh) signaling cascade is one of the key mediators of embryonic development of many metazoans. This pathway has been extensively targeted by small molecule inhibitors as its misregulation leads to various malignancies and developmental disorders. Thus, blocking this pathway can be a novel therapeutic avenue for the treatment of Hedgehog-dependent cancers. This review covers the mechanism of hedgehog signaling in vertebrate cells, provides an overview of reported small molecule Hh pathway inhibitors, with the synthetic routes and SAR studies of some of them discussed briefly. METHODS:A comprehensive survey of literature related to synthetic and naturally occurring Hh signaling antagonists reported till date is presented. RESULTS:Given the selectivity of small molecules targeting, this pathway for cancer treatment compared to kinase, tubulin or HDAC inhibitors, several such antagonists have been discovered, of which some are in preclinical development and clinical studies. Most of the reported small molecules primarily antagonize the Smoothened receptor although agents targeting Gli1 transcription factor and Shh ligand have also been discovered. Till date, nine Smo antagonists have been evaluated in clinical trials.GDC- 0449/Vismodegib and NVP-LDE225/Erismodegib, were granted approval by the U.S. Food and Drug Administration (U.S. FDA) for the treatment of basal cell carcinoma. CONCLUSION:The challenge is to identify agents that target the pathway downstream of Smo and develop strategies to overcome acquired drug resistance to the current Smo inhibitors with deeper understanding of the resistance mechanisms.

journal_name

Curr Med Chem

authors

Khatra H,Bose C,Sinha S

doi

10.2174/0929867324666170316115500

subject

Has Abstract

pub_date

2017-01-01 00:00:00

pages

2033-2058

issue

19

eissn

0929-8673

issn

1875-533X

pii

CMC-EPUB-82327

journal_volume

24

pub_type

杂志文章,评审
  • Inhibitors of the sulfur assimilation pathway in bacterial pathogens as enhancers of antibiotic therapy.

    abstract::The rising emergence of antibiotic resistance urges the search for new strategies to defeat microorganisms that lead to persistent infections of the host. Tolerant to antibiotics, slowly replicating bacteria often cause latent and persistent infections that are the most challenging for pharmacological treatment. Persi...

    journal_title:Current medicinal chemistry

    pub_type: 杂志文章,评审

    doi:10.2174/0929867321666141112122553

    authors: Campanini B,Pieroni M,Raboni S,Bettati S,Benoni R,Pecchini C,Costantino G,Mozzarelli A

    更新日期:2015-01-01 00:00:00

  • Recent chemical and enzymatic approaches to the synthesis of glycosaminoglycan oligosaccharides.

    abstract::Glycosaminoglycans, highly charged polycarboxylated, polysulfated polysaccharides, are an important class of therapeutic agents and investigational drug candidates. Heparin has been widely used as a clinical anticoagulant for over 60 years. Low molecular weight heparins have begun to displace heparin and recently a sy...

    journal_title:Current medicinal chemistry

    pub_type: 杂志文章,评审

    doi:10.2174/0929867033456891

    authors: Karst NA,Linhardt RJ

    更新日期:2003-10-01 00:00:00

  • Developing FGFR4 inhibitors as potential anti-cancer agents via in silico design, supported by in vitro and cell-based testing.

    abstract::Fibroblast growth factor receptor-4 (FGFR4) is a tyrosine kinase with a range of important physiological functions. However, it is also frequently mutated in various cancers and is now generating significant interest as a potential therapeutic target. Unfortunately, biochemical characterization of its role in disease,...

    journal_title:Current medicinal chemistry

    pub_type: 杂志文章

    doi:10.2174/0929867311320100001

    authors: Ho HK,Németh G,Ng YR,Pang E,Szántai-Kis C,Zsákai L,Breza N,Greff Z,Horváth Z,Pató J,Szabadkai I,Szokol B,Baska F,Őrfî L,Ullrich A,Kéri G,Chua BT

    更新日期:2013-01-01 00:00:00

  • Pollution and Sun Exposure: A Deleterious Synergy. Mechanisms and Opportunities for Skin Protection.

    abstract:BACKGROUND:Pollutants are diverse chemical entities, including gases such as ozone and particulate matter PM. PM contains toxic chemicals such as polycyclic aromatic hydrocarbons (PAHs). Some PAHs can induce strong oxidative stress under UVA exposure. Pollution aggravates some skin diseases such as atopy or eczema, but...

    journal_title:Current medicinal chemistry

    pub_type: 杂志文章,评审

    doi:10.2174/0929867324666170918123907

    authors: Marrot L

    更新日期:2018-01-01 00:00:00

  • Adrenoceptors: non conventional target for breast cancer?

    abstract::Epinephrine and Norepinephrine, typically released during stress bind to nine different adrenoceptors (AR) which classically control the cardiovascular and respiratory systems. New targets were described for the many agonists and antagonists developed for these AR, as the central nervous system. During the last three ...

    journal_title:Current medicinal chemistry

    pub_type: 杂志文章,评审

    doi:10.2174/092986709788186048

    authors: Lüthy IA,Bruzzone A,Piñero CP,Castillo LF,Chiesa IJ,Vázquez SM,Sarappa MG

    更新日期:2009-01-01 00:00:00

  • New methods for medicinal chemistry--universal gene cloning and expression systems for production of marine bioactive metabolites.

    abstract::Natural products from symbiotic or commensal associations between marine invertebrate and microbial organisms show exceptional promise as pharmaceuticals in many therapeutic areas. An economic and sustainable global market supply due to difficulty of synthesis is cited as the main obstacle for exploitation of these ot...

    journal_title:Current medicinal chemistry

    pub_type: 杂志文章,评审

    doi:10.2174/092986706776055643

    authors: Dunlap WC,Jaspars M,Hranueli D,Battershill CN,Perić-Concha N,Zucko J,Wright SH,Long PF

    更新日期:2006-01-01 00:00:00

  • Genistein aglycone: a dual mode of action anti-osteoporotic soy isoflavone rebalancing bone turnover towards bone formation.

    abstract::Osteoporosis is characterized by reduced bone mass and structural deterioration of bone tissue leading to enhanced bone fragility and a consequent increase in fracture risk. Bone loss further increases in postmenopausal women when the ovaries stop making estrogens. Women undergoing treatment for osteoporosis require l...

    journal_title:Current medicinal chemistry

    pub_type: 杂志文章,评审

    doi:10.2174/092986710791959738

    authors: Bitto A,Polito F,Squadrito F,Marini H,D'Anna R,Irrera N,Minutoli L,Granese R,Altavilla D

    更新日期:2010-01-01 00:00:00

  • The influence of a half-marathon race upon cardiac troponin T release in adolescent runners.

    abstract:OBJECTIVES:Post-exercise cardiac troponin T (cTnT) release has been widely reported in adult athletes but limited data is available for adolescents. The aim of this study was to determine the incidence and magnitude of cTnT appearance in a large group of adolescent runners, and to determine any association between cTnT...

    journal_title:Current medicinal chemistry

    pub_type: 杂志文章

    doi:10.2174/092986711796642625

    authors: Nie J,George KP,Tong TK,Gaze D,Tian Y,Lin H,Shi Q

    更新日期:2011-01-01 00:00:00

  • Gossypol: prototype of inhibitors targeted to dinucleotide folds.

    abstract::Gossypol, a disesquiterpene from cottonseed, exhibits multiple biological properties, including male antifertility activity and anticancer activity. Gossypol also inhibits the growth of numerous parasitic organisms and shows antiviral activity against a number of enveloped viruses, including the AIDS virus. Derivative...

    journal_title:Current medicinal chemistry

    pub_type: 杂志文章,评审

    doi:10.2174/0929867003375119

    authors: Vander Jagt DL,Deck LM,Royer RE

    更新日期:2000-04-01 00:00:00

  • Cholesterol Efflux and Reverse Cholesterol Transport: Experimental Approaches.

    abstract:BACKGROUND:Cholesterol efflux as a key event in reverse cholesterol transport (RCT) is considered now as both diagnostic tool and a promising target for the treatment of atherosclerosis. Radioactive in vitro cholesterol efflux assay (CEA) is the gold standard for determination of efflux at cellular level. Fluorescent t...

    journal_title:Current medicinal chemistry

    pub_type: 杂志文章,评审

    doi:10.2174/0929867323666160809093009

    authors: Litvinov DY,Savushkin EV,Garaeva EA,Dergunov AD

    更新日期:2016-01-01 00:00:00

  • Nicotinamide adenine dinucleotide based therapeutics.

    abstract::Nicotinamide adenine dinucleotide (NAD), generally considered a key component involved in redox reactions, has been found to participate in an increasingly diverse range of cellular processes, including signal transduction, DNA repair, and post-translational protein modifications. In recent years, medicinal chemists h...

    journal_title:Current medicinal chemistry

    pub_type: 杂志文章,评审

    doi:10.2174/092986708783885282

    authors: Chen L,Petrelli R,Felczak K,Gao G,Bonnac L,Yu JS,Bennett EM,Pankiewicz KW

    更新日期:2008-01-01 00:00:00

  • Structural approaches to explain the selectivity of COX-2 inhibitors: is there a common pharmacophore?

    abstract::The identification and characterisation of the isoenzyme cyclooxygenase 2 (COX-2) stimulated investigations to develop efficient non-steroidal anti-inflammatory drugs with reduced side effects compared to standard NSAIDs. This review will focus on the structural features needed to achieve COX-2 selectivity. Five struc...

    journal_title:Current medicinal chemistry

    pub_type: 杂志文章,评审

    doi:10.2174/0929867003374237

    authors: Dannhardt G,Laufer S

    更新日期:2000-11-01 00:00:00

  • Effects and mechanism of organ protection by cardiotrophin-1.

    abstract::Cardiotrophin-1 (CT-1), a member of the interleukin (IL)-6 family, is reported to exhibit a plethora of pleiotropic effects in the heart such as cytoprotective, pro-proliferative and pro-fibrotic ones. An extensive research has been devoted on proliferative and profibrotic effects of CT-1 on the heart. Thus the presen...

    journal_title:Current medicinal chemistry

    pub_type: 杂志文章,评审

    doi:10.2174/092986713804806702

    authors: García-Cenador MB,Lopez-Novoa JM,Díez J,García-Criado FJ

    更新日期:2013-01-01 00:00:00

  • Sarcopenia, Aging and Prospective Interventional Strategies.

    abstract::Sarcopenia, or age-related muscle decline, occurs in most organisms and burdens both human health and the healthcare system. As our population ages, additional options for treating sarcopenia are needed. Mitochondrial dysfunction is implicated in the onset of sarcopenia, so therapies directed at improving mitochondria...

    journal_title:Current medicinal chemistry

    pub_type: 杂志文章,评审

    doi:10.2174/0929867324666170801095850

    authors: Waltz TB,Fivenson EM,Morevati M,Li C,Becker KG,Bohr VA,Fang EF

    更新日期:2018-01-01 00:00:00

  • Structure, signalling and physiologic role of adiponectin-dietary and exercise- related variations.

    abstract::Since its discovery in 1995 adiponectin has garnered considerable interest from the academic, clinical and biotech communities due to its proposed salutary anti-inflammatory, anti-diabetic, anti-atherogenic and cardioprotective properties. As a result our appreciation of adiponectin's structure and the importance of p...

    journal_title:Current medicinal chemistry

    pub_type: 杂志文章,评审

    doi:10.2174/092986712803833155

    authors: Hickman IJ,Whitehead JP

    更新日期:2012-01-01 00:00:00

  • The glioblastoma problem: targeting by combined medicinal chemistry approaches.

    abstract::Whilst knowledge of basic biology, diagnosis and prognosis of glioblastoma (GB - WHO grade IV) are steadily improving, advancements of therapy are discouragingly slow, with the only significant novelty during last ten years represented by introduction of temozolomide in chemotherapy. In order to analyze the current st...

    journal_title:Current medicinal chemistry

    pub_type: 杂志文章,评审

    doi:10.2174/0929867322666150530210700

    authors: Frosina G

    更新日期:2015-01-01 00:00:00

  • Mast cells as critical effectors of host immune defense against Gram-negative bacteria.

    abstract::Mast cells are best known as central effector cells in IgE-mediated type I allergic diseases including asthma and hay fever. An increasing amount of evidence, however, has demonstrated that mast cells are sentinel cells playing a critical role in host defense against invading microbes. Mast cells are located immediate...

    journal_title:Current medicinal chemistry

    pub_type: 杂志文章,评审

    doi:10.2174/092986712799828319

    authors: Matsuguchi T

    更新日期:2012-01-01 00:00:00

  • Association between polycystic ovary syndrome and metabolic syndrome.

    abstract::Polycystic ovary syndrome (PCOS) is the most common endocrine and metabolic disorder affecting women in reproductive age. Although the etiology of PCOS remains unclear, it is believed to result from genetic, environmental and behavioral interactions. Women with PCOS have higher lifetime risk for cardiovascular disease...

    journal_title:Current medicinal chemistry

    pub_type: 杂志文章,评审

    doi:10.2174/0929867321666140915141030

    authors: Vélez LM,Motta AB

    更新日期:2014-01-01 00:00:00

  • Environmental chemicals and breast cancer risk--a structural chemistry perspective.

    abstract::In modern industrialized societies, people are exposed to thousands of naturally occurring and synthetic chemicals throughout their lifetime. Although certain occupational chemicals are known to be carcinogenic in humans, it has been difficult to definitively determine the adverse health effects of many environmental ...

    journal_title:Current medicinal chemistry

    pub_type: 杂志文章,评审

    doi:10.2174/092986708786242930

    authors: Weyandt J,Ellsworth RE,Hooke JA,Shriver CD,Ellsworth DL

    更新日期:2008-01-01 00:00:00

  • Sudden infant death following hexavalent vaccination: a neuropathologic study.

    abstract::We examined a large number of sudden infant death syndrome victims in order to point out a possible causal relationship between a previous hexavalent vaccination and the sudden infant death. We selected 110 cases submitted to in-depth histological examination of the autonomic nervous system and provided with detailed ...

    journal_title:Current medicinal chemistry

    pub_type: 杂志文章

    doi:10.2174/09298673113206660289

    authors: Matturri L,Del Corno G,Lavezzi AM

    更新日期:2014-03-01 00:00:00

  • Fullerenes for applications in biology and medicine.

    abstract::Fullerenes as a unique class of carbon allotropes have been studied extensively for their distinctive material properties and potential technological applications, including those in biology and medicine. Since a major focus in the latter has been on drug development and formulation, in this paper we highlight some re...

    journal_title:Current medicinal chemistry

    pub_type: 杂志文章

    doi:10.2174/092986711795656225

    authors: Anilkumar P,Lu F,Cao L,Luo PG,Liu JH,Sahu S,Tackett KN,Wang Y,Sun YP

    更新日期:2011-01-01 00:00:00

  • Calcium metabolism & hypercalcemia in adults.

    abstract::Calcium is essential for many metabolic process, including nerve function, muscle contraction, and blood clotting. The metabolic pathways that contribute to maintain serum calcium levels are bone remodeling processes, intestinal absorption and secretion, and renal handling, but hypercalcemia occurs when at least 2 of ...

    journal_title:Current medicinal chemistry

    pub_type: 杂志文章

    doi:10.2174/092986711796642599

    authors: Lumachi F,Motta R,Cecchin D,Ave S,Camozzi V,Basso SM,Luisetto G

    更新日期:2011-01-01 00:00:00

  • Brain nitric oxide and its dual role in neurodegeneration/neuroprotection: understanding molecular mechanisms to devise drug approaches.

    abstract::Nitric oxide (NO) has been established as an important messenger molecule in various steps of brain physiology, from development to synaptic plasticity, learning and memory. However, NO has also been viewed as a major agent of neuropathology when, escaping controlled production it may directly or indirectly promote ox...

    journal_title:Current medicinal chemistry

    pub_type: 杂志文章,评审

    doi:10.2174/0929867033456792

    authors: Contestabile A,Monti B,Contestabile A,Ciani E

    更新日期:2003-10-01 00:00:00

  • Recent Advances in the Development of CBP/p300 Bromodomain Inhibitors.

    abstract::CBP and p300 are two closely related Histone Acetyltransferases (HATs) that interact with numerous transcription factors and act to increase the expression of their target genes. Both proteins contain a bromodomain flanking the HAT catalytic domain that is important in binding of CBP/p300 to chromatin, which offers an...

    journal_title:Current medicinal chemistry

    pub_type: 杂志文章,评审

    doi:10.2174/0929867326666190731141055

    authors: Xiong Y,Zhang M,Li Y

    更新日期:2020-01-01 00:00:00

  • NK-1 receptor antagonists: a new paradigm in pharmacological therapy.

    abstract::The neuropeptide substance P (SP) shows a widespread distribution in both the central and peripheral nervous systems and it is known that after binding to the neurokinin-1 (NK-1) receptors, SP regulates many biological functions in the central nervous system such as emotional behaviour, stress, depression, anxiety, em...

    journal_title:Current medicinal chemistry

    pub_type: 杂志文章,评审

    doi:10.2174/092986711795496746

    authors: Muñoz M,Coveñas R

    更新日期:2011-01-01 00:00:00

  • A slit in podocyte death.

    abstract::Recent advances have identified the podocyte as a key target in glomerular injury. The podocyte is a highly specialized cell which is responsible for the glomerular permselectivity for proteins in the kidney. Podocyte injury or loss leads to proteinuria. Apoptosis has been shown to contribute to renal cell loss, inclu...

    journal_title:Current medicinal chemistry

    pub_type: 杂志文章,评审

    doi:10.2174/092986708784911542

    authors: Moreno JA,Sanchez-Niño MD,Sanz AB,Lassila M,Holthofer H,Blanco-Colio LM,Egido J,Ruiz-Ortega M,Ortiz A

    更新日期:2008-01-01 00:00:00

  • Past and recent progress of molecular imaging probes for β-amyloid plaques in the brain.

    abstract::The deposition of β-amyloid (Aβ) plaques in the parenchymal and cortical brain is accepted as the main pathological hallmark of Alzheimer's disease (AD). According to the amyloid cascade hypothesis, the Aβ deposition in the brain appears to be a good diagnostic biomarker for AD and may also be a good predictive biomar...

    journal_title:Current medicinal chemistry

    pub_type: 杂志文章,评审

    doi:10.2174/09298673113209990216

    authors: Cui M

    更新日期:2014-01-01 00:00:00

  • New therapeutic targets for drug design against Trypanosoma cruzi, advances and perspectives.

    abstract::Chagas disease is one of the most important parasitic diseases in Latin America, affecting 16 to 18 million people. Nifurtimox and Benznidazol are drugs that are commonly used in its treatment; however, these drugs produce several adverse reactions and are not effective in the chronic phase of the disease. Therefore, ...

    journal_title:Current medicinal chemistry

    pub_type: 杂志文章,评审

    doi:10.2174/092986709788803303

    authors: Rivera G,Bocanegra-García V,Ordaz-Pichardo C,Nogueda-Torres B,Monge A

    更新日期:2009-01-01 00:00:00

  • Fungal Phytotoxins in Sustainable Weed Management.

    abstract::Fungal phytotoxins are natural secondary metabolites produced by plant pathogenic fungi during host-pathogen interactions. They have received considerable particular attention for elucidating disease etiology, and consequently to design strategies for disease control. Due to wide differences in their chemical structur...

    journal_title:Current medicinal chemistry

    pub_type: 杂志文章,评审

    doi:10.2174/0929867324666170426152331

    authors: Vurro M,Boari A,Casella F,Zonno MC

    更新日期:2018-01-01 00:00:00

  • Molecular targeted therapy in enteropancreatic neuroendocrine tumors: from biology to clinical practice.

    abstract::Advanced enteropancreatic (EP) neuroendocrine tumors (NETs) can be treated with several different therapies, including chemotherapy, biotherapy, and locoregional treatments. Over the last few decades, impressive progress has been made in the biotherapy field. Three main druggable molecular targets have been studied an...

    journal_title:Current medicinal chemistry

    pub_type: 杂志文章,评审

    doi:10.2174/09298673113209990237

    authors: Fazio N,Scarpa A,Falconi M

    更新日期:2014-01-01 00:00:00