Review Molecularly targeted therapies for asthma: Current development, challenges and potential clinical translation Ibrahim Sulaiman, Jonathan Chee Woei Lim, Hon Liong Soo, Johnson Stanslas * Pharmacotherapeutics Unit, Department of Medicine, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, Serdang, Selangor, Malaysia article info Article history: Received 9 May 2016 Received in revised form 14 July 2016 Accepted 20 July 2016 Available online 22 July 2016 Keywords: Asthma Inflammation Airway remodelling Anti-asthmatics Targets Chemical compounds studied in this article: Bis-(5-amidino-2-benzimidazolyl)-methane (PubChem CID: 46936860) Calcitriol (PubChem CID: 5280453) JNJ-39758979 (PubChem CID: 24994634) JNJ-7777120 (PubChem CID: 4908365) PF-3893787 (PubChem CID: 24745335) Y-27632 (PubChem CID: 448042) Fasudil (PubChem CID: 3547) Roflumilast (PubChem CID: 449193) YM-341619 (PubChem CID: 10321901) Afzelin (PubChem CID: 5316673) abstract 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 summar- ised. Examples of these interventions include restoration of Th 1 /Th 2 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 Th 1 /Th 2 balance. Regulation of cytokine activity by the use of newly developed biologics such as benralizumab, reslizumab, mepolizumab, lebrikizumab, tralokinumab, dupilumab and brodalu- mab 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. © 2016 Elsevier Ltd. All rights reserved. Contents 1. Introduction ....................................................................................................................... 53 2. Pathophysiology of asthma .......................................................................................................... 53 3. Current asthma therapies ........................................................................................................... 54 4. Emerging drug targets .............................................................................................................. 55 4.1. Target receptors .............................................................................................................. 55 4.1.1. Toll-like receptor activators ................................................. ........................................... 55 4.1.2. Chemoattractant receptor-homologous molecule expressed on Th2 cells (CRTH2) ........................ ..................... 55 4.1.3. Proteinase-activated receptor 2 (PAR-2) ............................................ ...................................... 55 4.1.4. Calcium sensing receptor (CaSR) antagonism .............................................................................. 56 4.1.5. H4 receptor antagonism ................................................... ............................................ 57 * Corresponding author. Pharmacotherapeutics Unit, Department of Medicine, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, 43400 Serdang, Selangor, Malaysia. Tel.: þ60 3 89472310; fax: þ60 3 89472759. E-mail addresses: rcxjs@upm.edu.my, jstanslas@yahoo.co.uk (J. Stanslas). Contents lists available at ScienceDirect Pulmonary Pharmacology & Therapeutics journal homepage: www.elsevier.com/locate/ypupt http://dx.doi.org/10.1016/j.pupt.2016.07.005 1094-5539/© 2016 Elsevier Ltd. All rights reserved. Pulmonary Pharmacology & Therapeutics 40 (2016) 52e68