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Editorial

Sulaiman AH, Musa R

Curr Drug Targets, 2019;20(2):145.
PMID: 30648501 DOI: 10.2174/138945012002181203145147
Matched MeSH terms: Molecular Targeted Therapy
Editorial: Advances in Psychopharmacological Treatment

Sulaiman AH, Musa R

Curr Drug Targets, 2018;19(8):855.
PMID: 29792134 DOI: 10.2174/138945011908180518113546
Matched MeSH terms: Molecular Targeted Therapy*
Tumor regression and modulation of gene expression via tumor-targeted tocotrienol niosomes

Tan DM, Fu JY, Wong FS, Er HM, Chen YS, Nesaretnam K

Nanomedicine (Lond), 2017 Oct;12(20):2487-2502.
PMID: 28972460 DOI: 10.2217/nnm-2017-0182

AIM: To develop 6-O-palmitoyl-ascorbic acid-based niosomes targeted to transferrin receptor for intravenous administration of tocotrienols (T3) in breast cancer.
MATERIALS & METHODS: Niosomes were prepared using film hydration and ultrasonication methods. Transferrin was coupled to the surface of niosomes via chemical linker. Nanovesicles were characterized for size, zeta potential, morphology, stability and biological efficacy.
RESULTS: When evaluated in MDA-MB-231 cells, entrapment of T3 in niosomes caused 1.5-fold reduction in IC50 value compared with nonformulated T3. In vivo, the average tumor volume of mice treated with tumor-targeted niosomes was 12-fold lower than that of untreated group, accompanied by marked downregulation of three genes involved in metastasis.
CONCLUSION: Findings suggested that tumor-targeted niosomes served as promising delivery system for T3 in cancer therapy.

Matched MeSH terms: Molecular Targeted Therapy/methods
Fulltext Therapeutic radionuclides in nuclear medicine: current and future prospects

Yeong CH, Cheng MH, Ng KH

J Zhejiang Univ Sci B, 2014 Oct;15(10):845-63.
PMID: 25294374 DOI: 10.1631/jzus.B1400131

The potential use of radionuclides in therapy has been recognized for many decades. A number of radionuclides, such as iodine-131 ((131)I), phosphorous-32 ((32)P), strontium-90 ((90)Sr), and yttrium-90 ((90)Y), have been used successfully for the treatment of many benign and malignant disorders. Recently, the rapid growth of this branch of nuclear medicine has been stimulated by the introduction of a number of new radionuclides and radiopharmaceuticals for the treatment of metastatic bone pain and neuroendocrine and other malignant or non-malignant tumours. Today, the field of radionuclide therapy is enjoying an exciting phase and is poised for greater growth and development in the coming years. For example, in Asia, the high prevalence of thyroid and liver diseases has prompted many novel developments and clinical trials using targeted radionuclide therapy. This paper reviews the characteristics and clinical applications of the commonly available therapeutic radionuclides, as well as the problems and issues involved in translating novel radionuclides into clinical therapies.

Matched MeSH terms: Molecular Targeted Therapy/trends*
Evaluation of the proteomic landscape of HPV E7‑induced alterations in human keratinocytes reveal therapeutically relevant pathways for cervical cancer

Gandhi S, Mohamad Razif MF, Othman S, Chakraborty S, Nor Rashid N

Mol Med Rep, 2023 Feb;27(2).
PMID: 36633133 DOI: 10.3892/mmr.2023.12933

The lack of specific and accurate therapeutic targets poses a challenge in the treatment of cervical cancer (CC). Global proteomics has the potential to characterize the underlying and intricate molecular mechanisms that drive the identification of therapeutic candidates for CC in an unbiased manner. The present study assessed human papillomavirus (HPV)‑induced proteomic alterations to identify key cancer hallmark pathways and protein‑protein interaction (PPI) networks, which offered the opportunity to evaluate the possibility of using these for targeted therapy in CC. Comparative proteomic profiling of HPV‑transfected (HPV16/18 E7), HPV‑transformed (CaSki and HeLa) and normal human keratinocyte (HaCaT) cells was performed using the liquid chromatography‑tandem mass spectrometry (LC‑MS/MS) technique. Both label‑free quantification and differential expression analysis were performed to assess differentially regulated proteins in HPV‑transformed and ‑transfected cells. The present study demonstrated that protein expression was upregulated in HPV‑transfected cells compared with in HPV‑transformed cells. This was probably due to the ectopic expression of E7 protein in the former cell type, in contrast to its constitutive expression in the latter cell type. Subsequent pathway visualization and network construction demonstrated that the upregulated proteins in HPV16/18 E7‑transfected cells were predominantly associated with a diverse array of cancer hallmarks, including the mTORC1 signaling pathway, MYC targets V1, hypoxia and glycolysis. Among the various proteins present in the cancer hallmark enrichment pathways, phosphoglycerate kinase 1 (PGK1) was present across all pathways. Therefore, PGK1 may be considered as a potential biomarker. PPI analysis demonstrated a direct interaction between p130 and polyubiquitin B, which may lead to the degradation of p130 via the ubiquitin‑proteasome proteolytic pathway. In summary, elucidation of the key signaling pathways in HPV16/18‑transfected and ‑transformed cells may aid in the design of novel therapeutic strategies for clinical application such as targeted therapy and immunotherapy against cervical cancer.

Matched MeSH terms: Molecular Targeted Therapy
Molecular targeted therapy: Treating cancer with specificity

Lee YT, Tan YJ, Oon CE

Eur J Pharmacol, 2018 Sep 05;834:188-196.
PMID: 30031797 DOI: 10.1016/j.ejphar.2018.07.034

Molecular targeted therapies are revolutionized therapeutics which interfere with specific molecules to block cancer growth, progression, and metastasis. Many molecular targeted therapies approved by the Food and Drug Administration (FDA), have demonstrated remarkable clinical success in the treatment of a myriad of cancer types including breast, leukemia, colorectal, lung, and ovarian cancers. This review provides an update on the different types of molecular targeted therapies used in the treatment of cancer, focusing on the fundamentals of molecular targeted therapy, its mode of action in cancer treatment, as well as its advantages and limitations.

Matched MeSH terms: Molecular Targeted Therapy/methods*
Anticancer activities of a benzimidazole compound through sirtuin inhibition in colorectal cancer

Tan YJ, Lee YT, Yeong KY, Petersen SH, Kono K, Tan SC, et al.

Future Med Chem, 2018 Sep 01;10(17):2039-2057.
PMID: 30066578 DOI: 10.4155/fmc-2018-0052

AIM: This study aims to investigate the mode of action of a novel sirtuin inhibitor (BZD9L1) and its associated molecular pathways in colorectal cancer (CRC) cells.
MATERIALS & METHODS: BZD9L1 was tested against metastatic CRC cell lines to evaluate cytotoxicity, cell cycle and apoptosis, senescence, apoptosis related genes and protein expressions, as well as effect against major cancer signaling pathways.
RESULTS & CONCLUSION: BZD9L1 reduced the viability, cell migration and colony forming ability of both HCT 116 and HT-29 metastatic CRC cell lines through apoptosis. BZD9L1 regulated major cancer pathways differently in CRC with different mutation profiles. BZD9L1 exhibited anticancer activities as a cytotoxic drug in CRC and as a promising therapeutic strategy in CRC treatment.

Matched MeSH terms: Molecular Targeted Therapy
Cellular crosstalk mechanism of Toll-like receptors in gingival overgrowth (review)

Subramani T, Rathnavelu V, Alitheen NB, Padmanabhan P

Int J Mol Med, 2015 May;35(5):1151-8.
PMID: 25812632 DOI: 10.3892/ijmm.2015.2144

Gingival overgrowth is an undesirable outcome of systemic medication and is evidenced by the accretion of collagenous components in gingival connective tissues along with diverse degrees of inflammation. Phenytoin therapy has been found to induce the most fibrotic lesions in gingiva, cyclosporine caused the least fibrotic lesions, and nifedipine induced intermediate fibrosis in drug‑induced gingival overgrowth. In drug‑induced gingival overgrowth, efficient oral hygiene is compromised and has negative consequences for the systemic health of the patients. Toll‑like receptors (TLRs) are involved in the effective recognition of microbial agents and play a vital role in innate immunity and inflammatory signaling responses. TLRs stimulate fibrosis and tissue repairs in several settings, although with evident differences between organs. In particular, TLRs exert a distinct effect on fibrosis in organs with greater exposure to TLR ligands, such as the gingiva. Cumulative evidence from diverse sources suggested that TLRs can affect gingival overgrowth in several ways. Numerous studies have demonstrated the expression of TLRs in gingival tissues and suggested its potential role in gingival inflammation, cell proliferation and synthesis of the extracellular matrix which is crucial to the development of gingival overgrowth. In the present review, we assessed the role of TLRs on individual cell populations in gingival tissues that contribute to the progression of gingival inflammation, and the involvement of TLRs in the development of gingival overgrowth. These observations suggest that TLRs provide new insight into the connection among infection, inflammation, drugs and gingival fibrosis, and are therefore efficient therapeutic target molecules. We hypothesize that TLRs are critical for the development and progression of gingival overgrowth, and thus blocking TLR expression may serve as a novel target for antifibrotic therapy.

Matched MeSH terms: Molecular Targeted Therapy
Fulltext Anti-neoplastic Potential of Flavonoids and Polysaccharide Phytochemicals in Glioblastoma

Atiq A, Parhar I

Molecules, 2020 Oct 23;25(21).
PMID: 33113890 DOI: 10.3390/molecules25214895

Clinically, gliomas are classified into four grades, with grade IV glioblastoma multiforme being the most malignant and deadly, which accounts for 50% of all gliomas. Characteristically, glioblastoma involves the aggressive proliferation of cells and invasion of normal brain tissue, outcomes as poor patient prognosis. With the current standard therapy of glioblastoma; surgical resection and radiotherapy followed by adjuvant chemotherapy with temozolomide, it remains fatal, because of the development of drug resistance, tumor recurrence, and metastasis. Therefore, the need for the effective therapeutic option for glioblastoma remains elusive. Previous studies have demonstrated the chemopreventive role of naturally occurring pharmacological agents through preventing or reversing the initiation phase of carcinogenesis or arresting the cancer progression phase. In this review, we discuss the role of natural phytochemicals in the amelioration of glioblastoma, with the aim to improve therapeutic outcomes, and minimize the adverse side effects to improve patient's prognosis and enhancing their quality of life.

Matched MeSH terms: Molecular Targeted Therapy
Fulltext Aberrant expression of the S1P regulating enzymes, SPHK1 and SGPL1, contributes to a migratory phenotype in OSCC mediated through S1PR2

Patmanathan SN, Johnson SP, Lai SL, Panja Bernam S, Lopes V, Wei W, et al.

Sci Rep, 2016 05 10;6:25650.
PMID: 27160553 DOI: 10.1038/srep25650

Oral squamous cell carcinoma (OSCC) is a lethal disease with a 5-year mortality rate of around 50%. Molecular targeted therapies are not in routine use and novel therapeutic targets are required. Our previous microarray data indicated sphingosine 1-phosphate (S1P) metabolism and signalling was deregulated in OSCC. In this study, we have investigated the contribution of S1P signalling to the pathogenesis of OSCC. We show that the expression of the two major enzymes that regulate S1P levels were altered in OSCC: SPHK1 was significantly upregulated in OSCC tissues compared to normal oral mucosa and low levels of SGPL1 mRNA correlated with a worse overall survival. In in vitro studies, S1P enhanced the migration/invasion of OSCC cells and attenuated cisplatin-induced death. We also demonstrate that S1P receptor expression is deregulated in primary OSCCs and that S1PR2 is over-expressed in a subset of tumours, which in part mediates S1P-induced migration of OSCC cells. Lastly, we demonstrate that FTY720 induced significantly more apoptosis in OSCC cells compared to non-malignant cells and that FTY720 acted synergistically with cisplatin to induce cell death. Taken together, our data show that S1P signalling promotes tumour aggressiveness in OSCC and identify S1P signalling as a potential therapeutic target.

Matched MeSH terms: Molecular Targeted Therapy
Critical role of HOX transcript antisense intergenic RNA (HOTAIR) in gliomas

Angelopoulou E, Paudel YN, Piperi C

J Mol Med (Berl), 2020 11;98(11):1525-1546.
PMID: 32978667 DOI: 10.1007/s00109-020-01984-x

Despite extensive research, gliomas are associated with high morbidity and mortality, mainly attributed to the rapid growth rate, excessive invasiveness, and molecular heterogeneity, as well as regenerative potential of cancer stem cells. Therefore, elucidation of the underlying molecular mechanisms and the identification of potential molecular diagnostic and prognostic biomarkers are of paramount importance. HOX transcript antisense intergenic RNA (HOTAIR) is a well-studied long noncoding RNA, playing an emerging role in tumorigenesis of several human cancers. A growing amount of preclinical and clinical evidence highlights the pro-oncogenic role of HOTAIR in gliomas, mainly attributed to the enhancement of proliferation and migration, as well as inhibition of apoptosis. In vitro and in vivo studies demonstrate that HOTAIR modulates the activity of specific transcription factors, such as MXI1, E2F1, ATF5, and ASCL1, and regulates the expression of cell cycle-associated genes along with related signaling pathways, like the Wnt/β-catenin axis. Moreover, it can interact with specific miRNAs, including miR-326, miR-141, miR-148b-3p, miR-15b, and miR-126-5p. Of importance, HOTAIR has been demonstrated to enhance angiogenesis and affect the permeability of the blood-tumor barrier, thus modulating the efficacy of chemotherapeutic agents. Herein, we provide evidence on the functional role of HOTAIR in gliomas and discuss the benefits of its targeting as a novel approach toward glioma treatment.

Matched MeSH terms: Molecular Targeted Therapy
Current approaches in antiviral drug discovery against the Flaviviridae family

Baharuddin A, Hassan AA, Sheng GC, Nasir SB, Othman S, Yusof R, et al.

Curr Pharm Des, 2014;20(21):3428-44.
PMID: 24001228

Viruses belonging to the Flaviviridae family primarily spread through arthropod vectors, and are the major causes of illness and death around the globe. The Flaviviridae family consists of 3 genera which include the Flavivirus genus (type species, yellow fever virus) as the largest genus, the Hepacivirus (type species, hepatitis C virus) and the Pestivirus (type species, bovine virus diarrhea). The flaviviruses (Flavivirus genus) are small RNA viruses transmitted by mosquitoes and ticks that take over host cell machinery in order to propagate. However, hepaciviruses and pestiviruses are not antropod-borne. Despite the extensive research and public health concern associated with flavivirus diseases, to date, there is no specific treatment available for any flavivirus infections, though commercially available vaccines for yellow fever, Japanese encephalitis and tick-born encephalitis exist. Due to the global threat of viral pandemics, there is an urgent need for new drugs. In many countries, patients with severe cases of flavivirus infections are treated only by supportive care, which includes intravenous fluids, hospitalization, respiratory support, and prevention of secondary infections. This review discusses the strategies used towards the discovery of antiviral drugs, focusing on rational drug design against Dengue virus (DENV), West Nile virus (WNV), Japanese encephalitis virus (JEV), Yellow Fever virus (YFV) and Hepatitis C virus (HCV). Only modified peptidic, nonpeptidic, natural compounds and fragment-based inhibitors (typically of mass less than 300 Da) against structural and non-structural proteins are discussed.

Matched MeSH terms: Molecular Targeted Therapy/methods
Fulltext Surface functionalisation of poly-APO-b-polyol ester cross-linked copolymers as core-shell nanoparticles for targeted breast cancer therapy

Tajau R, Rohani R, Abdul Hamid SS, Adam Z, Mohd Janib SN, Salleh MZ

Sci Rep, 2020 12 10;10(1):21704.
PMID: 33303818 DOI: 10.1038/s41598-020-78601-x

Polymeric nanoparticles (NPs) are commonly used as nanocarriers for drug delivery, whereby their sizes can be altered for a more efficient delivery of therapeutic active agents with better efficacy. In this work, cross-linked copolymers acted as core-shell NPs from acrylated palm olein (APO) with polyol ester were synthesized via gamma radiation-induced reversible addition-fragmentation chain transfer (RAFT) polymerisation. The particle diameter of the copolymerised poly(APO-b-polyol ester) core-shell NPs was found to be less than 300 nm, have a low molecular weight (MW) of around 24 kDa, and showed a controlled MW distribution of a narrow polydispersity index (PDI) of 1.01. These properties were particularly crucial for further use in designing targeted NPs, with inclusion of peptide for the targeted delivery of paclitaxel. Moreover, the characterisation of the synthesised NPs using Fourier Transform-Infrared (FTIR) and Neutron Magnetic Resonance (NMR) analyses confirmed the possession of biodegradable hydrolysed ester in its chemical structures. Therefore, it can be concluded that the synthesised NPs produced may potentially contribute to better development of a nano-structured drug delivery system for breast cancer therapy.

Matched MeSH terms: Molecular Targeted Therapy
Cancer prevention and therapy through the modulation of transcription factors by bioactive natural compounds

Shanmugam MK, Lee JH, Chai EZ, Kanchi MM, Kar S, Arfuso F, et al.

Semin Cancer Biol, 2016 10;40-41:35-47.
PMID: 27038646 DOI: 10.1016/j.semcancer.2016.03.005

The association between chronic inflammation and cancer development has been well documented. One of the major obstacles in cancer treatment is the persistent autocrine and paracrine activation of pro-inflammatory transcription factors such as nuclear factor-κB, signal transducer and activator of transcription 3, activator protein 1, fork head box protein M1, and hypoxia-inducible factor 1α in a wide variety of tumor cell lines and patient specimens. This, in turn, leads to an accelerated production of cellular adhesion molecules, inflammatory cytokines, chemokines, anti-apoptotic molecules, and inducible nitric oxide synthase. Numerous medicinal plant-derived compounds have made a tremendous impact in drug discovery research endeavors, and have been reported to modulate the activation of diverse oncogenic transcription factors in various tumor models. Moreover, novel therapeutic combinations of standard chemotherapeutic drugs with these agents have significantly improved patient survival by making cancer cells more susceptible to chemotherapy and radiotherapy. In this review, we critically analyze the existing literature on the modulation of diverse transcription factors by various natural compounds and provide views on new directions for accelerating the discovery of novel drug candidates derived from Mother Nature.

Matched MeSH terms: Molecular Targeted Therapy
Fulltext Impact of HMGB1, RAGE, and TLR4 in Alzheimer's Disease (AD): From Risk Factors to Therapeutic Targeting

Paudel YN, Angelopoulou E, Piperi C, Othman I, Aamir K, Shaikh MF

Cells, 2020 02 07;9(2).
PMID: 32046119 DOI: 10.3390/cells9020383

Alzheimer's disease (AD) is a devastating neurodegenerative disorder and a leading cause of dementia, with accumulation of amyloid-beta (Aβ) and neurofibrillary tangles (NFTs) as defining pathological features. AD presents a serious global health concern with no cure to date, reflecting the complexity of its pathogenesis. Recent evidence indicates that neuroinflammation serves as the link between amyloid deposition, Tau pathology, and neurodegeneration. The high mobility group box 1 (HMGB1) protein, an initiator and activator of neuroinflammatory responses, has been involved in the pathogenesis of neurodegenerative diseases, including AD. HMGB1 is a typical damage-associated molecular pattern (DAMP) protein that exerts its biological activity mainly through binding to the receptor for advanced glycation end products (RAGE) and toll-like receptor 4 (TLR4). RAGE and TLR4 are key components of the innate immune system that both bind to HMGB1. Targeting of HMGB1, RAGE, and TLR4 in experimental AD models has demonstrated beneficial effects in halting AD progression by suppressing neuroinflammation, reducing Aβ load and production, improving spatial learning, and inhibiting microglial stimulation. Herein, we discuss the contribution of HMGB1 and its receptor signaling in neuroinflammation and AD pathogenesis, providing evidence of its beneficial effects upon therapeutic targeting.

Matched MeSH terms: Molecular Targeted Therapy*
Fulltext Identification of putative drug targets for human sperm-egg interaction defect using protein network approach

Sabetian S, Shamsir MS

BMC Syst Biol, 2015;9:37.
PMID: 26187737 DOI: 10.1186/s12918-015-0186-7

Sperm-egg interaction defect is a significant cause of in-vitro fertilization failure for infertile cases. Numerous molecular interactions in the form of protein-protein interactions mediate the sperm-egg membrane interaction process. Recent studies have demonstrated that in addition to experimental techniques, computational methods, namely protein interaction network approach, can address protein-protein interactions between human sperm and egg. Up to now, no drugs have been detected to treat sperm-egg interaction disorder, and the initial step in drug discovery research is finding out essential proteins or drug targets for a biological process. The main purpose of this study is to identify putative drug targets for human sperm-egg interaction deficiency and consider if the detected essential proteins are targets for any known drugs using protein-protein interaction network and ingenuity pathway analysis.

Matched MeSH terms: Molecular Targeted Therapy*
Fulltext Clinical validity of clinicopathological and prognostic significance of circulating tumor cells in head and neck squamous cell carcinoma

Jayaraj R, Shetty S, Kumaraswamy C, Raymond G, Ram M R, Govind SK, et al.

Oral Oncol, 2020 10;109:104727.
PMID: 32327312 DOI: 10.1016/j.oraloncology.2020.104727
Matched MeSH terms: Molecular Targeted Therapy
Identifying Potential Therapeutics for Osteoporosis by Exploiting the Relationship between Mevalonate Pathway and Bone Metabolism

Hasan WNW, Chin KY, Jolly JJ, Ghafar NA, Soelaiman IN

Endocr Metab Immune Disord Drug Targets, 2018;18(5):450-457.
PMID: 29683099 DOI: 10.2174/1871530318666180423122409

BACKGROUND: Osteoporosis is a silent skeletal disease characterized by low bone mass and destruction of skeletal microarchitecture, leading to an increased fracture risk. This occurs due to an imbalance in bone remodelling, whereby the rate of bone resorption is greater than bone formation. Mevalonate pathway, previously known to involve in cholesterol synthesis, is an important regulatory pathway for bone remodelling.
OBJECTIVE: This review aimed to provide an overview of the relationship between mevalonate pathway and bone metabolism, as well as agents which act through this pathway to achieve their therapeutic potential.
DISCUSSION: Mevalonate pathway produces farnesyl pyrophosphate and geranylgeranyl pyrophosphate essential in protein prenylation. An increase in protein prenylation favours bone resorption over bone formation. Non-nitrogen containing bisphosphonates inhibit farnesyl diphosphate synthase which produces farnesyl pyrophosphate. They are used as the first line therapy for osteoporosis. Statins, a well-known class of cholesterol-lowering agents, inhibit 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA) reductase, the rate-determining enzyme in the mevalonate pathway. It was shown to increase bone mineral density and prevent fracture in humans. Tocotrienol is a group of vitamin E commonly found in palm oil, rice bran and annatto bean. It causes degradation of HMG-CoA reductase. Many studies demonstrated that tocotrienol prevented bone loss in animal studies but its efficacy has not been tested in humans.
CONCLUSION: Mevalonate pathway can be exploited to develop effective antiosteoporosis agents.

Matched MeSH terms: Molecular Targeted Therapy
Molecular targets in the discovery and development of novel antimetastatic agents: current progress and future prospects

Wong MS, Sidik SM, Mahmud R, Stanslas J

Clin Exp Pharmacol Physiol, 2013 May;40(5):307-19.
PMID: 23534409 DOI: 10.1111/1440-1681.12083

Tumour invasion and metastasis have been recognized as major causal factors in the morbidity and mortality among cancer patients. Many advances in the knowledge of cancer metastasis have yielded an impressive array of attractive drug targets, including enzymes, receptors and multiple signalling pathways. The present review summarizes the molecular pathogenesis of metastasis and the identification of novel molecular targets used in the discovery of antimetastatic agents. Several promising targets have been highlighted, including receptor tyrosine kinases, effector molecules involved in angiogenesis, matrix metalloproteinases (MMPs), urokinase plasminogen activator, adhesion molecules and their receptors, signalling pathways (e.g. phosphatidylinositol 3-kinase, phospholipase Cγ1, mitogen-activated protein kinases, c-Src kinase, c-Met kinases and heat shock protein. The discovery and development of potential novel therapeutics for each of the targets are also discussed in this review. Among these, the most promising agents that have shown remarkable clinical outcome are anti-angiogenic agents (e.g. bevacizumab). Newer agents, such as c-Met kinase inhibitors, are still undergoing preclinical studies and are yet to have their clinical efficacy proven. Some therapeutics, such as first-generation MMP inhibitors (MMPIs; e.g. marimastat) and more selective versions of them (e.g. prinomastat, tanomastat), have undergone clinical trials. Unfortunately, these drugs produced serious adverse effects that led to the premature termination of their development. In the future, third-generation MMPIs and inhibitors of signalling pathways and adhesion molecules could form valuable novel classes of drugs in the anticancer armamentarium to combat metastasis.

Matched MeSH terms: Molecular Targeted Therapy/trends
Molecularly targeted therapies for asthma: Current development, challenges and potential clinical translation

Sulaiman I, Lim JC, Soo HL, Stanslas J

Pulm Pharmacol Ther, 2016 Oct;40:52-68.
PMID: 27453494 DOI: 10.1016/j.pupt.2016.07.005

Extensive research into the therapeutics of asthma has yielded numerous effective interventions over the past few decades. However, adverse effects and ineffectiveness of most of these medications especially in the management of steroid resistant severe asthma necessitate the development of better medications. Numerous drug targets with inherent airway smooth muscle tone modulatory role have been identified for asthma therapy. This article reviews the latest understanding of underlying molecular aetiology of asthma towards design and development of better antiasthma drugs. New drug candidates with their putative targets that have shown promising results in the preclinical and/or clinical trials are summarised. Examples of these interventions include restoration of Th1/Th2 balance by the use of newly developed immunomodulators such as toll-like receptor-9 activators (CYT003-QbG10 and QAX-935). Clinical trials revealed the safety and effectiveness of chemoattractant receptor-homologous molecule expressed on Th2 cells (CRTH2) antagonists such as OC0000459, BI-671800 and ARRY-502 in the restoration of Th1/Th2 balance. Regulation of cytokine activity by the use of newly developed biologics such as benralizumab, reslizumab, mepolizumab, lebrikizumab, tralokinumab, dupilumab and brodalumab are at the stage of clinical development. Transcription factors are potential targets for asthma therapy, for example SB010, a GATA-3 DNAzyme is at its early stage of clinical trial. Other candidates such as inhibitors of Rho kinases (Fasudil and Y-27632), phosphodiesterase inhibitors (GSK256066, CHF 6001, roflumilast, RPL 554) and proteinase of activated receptor-2 (ENMD-1068) are also discussed. Preclinical results of blockade of calcium sensing receptor by the use of calcilytics such as calcitriol abrogates cardinal signs of asthma. Nevertheless, successful translation of promising preclinical data into clinically viable interventions remains a major challenge to the development of novel anti-asthmatics.

Matched MeSH terms: Molecular Targeted Therapy

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