New Drugs and Emerging Therapeutic Targets in the Endothelin Signaling Pathway and Prospects for Personalized Precision Medicine
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Physiol. Res. 67 (Suppl. 1): S37-S54, 2018 https://doi.org/10.33549/physiolres.933872 REVIEW New Drugs and Emerging Therapeutic Targets in the Endothelin Signaling Pathway and Prospects for Personalized Precision Medicine A. P. DAVENPORT1, R. E. KUC1, C. SOUTHAN2, J. J. MAGUIRE1 1Experimental Medicine and Immunotherapeutics, University of Cambridge, Addenbrooke's Hospital, Cambridge, United Kingdom, 2Deanery of Biomedical Sciences, University of Edinburgh, Edinburgh, United Kingdom Received January 26, 2018 Accepted March 29, 2018 Summary Key words During the last thirty years since the discovery of endothelin-1, Allosteric modulators • Biased signaling • G-protein coupled the therapeutic strategy that has evolved in the clinic, mainly in receptors • Endothelin-1 • Monoclonal antibodies • Pepducins • the treatment of pulmonary arterial hypertension, is to block the Single nucleotide polymorphisms action of the peptide either at the ETA subtype or both receptors using orally active small molecule antagonists. Recently, there Corresponding author has been a rapid expansion in research targeting ET receptors A. P. Davenport, Experimental Medicine and Immunotherapeutics, using chemical entities other than small molecules, particularly University of Cambridge, Addenbrooke's Hospital, Cambridge, monoclonal antibody antagonists and selective peptide agonists CB2 0QQ, United Kingdom. Fax: 01223 762576. E-mail: and antagonists. While usually sacrificing oral bio-availability, [email protected] these compounds have other therapeutic advantages with the potential to considerably expand drug targets in the endothelin Introduction pathway and extend treatment to other pathophysiological conditions. Where the small molecule approach has been During the last thirty years since the discovery retained, a novel strategy to combine two vasoconstrictor of endothelin-1 (ET-1), the therapeutic strategy that has targets, the angiotensin AT1 receptor as well as the ETA receptor evolved in the clinic, mainly in the treatment of in the dual antagonist sparsentan has been developed. pulmonary arterial hypertension (PAH), is to block the A second emerging strategy is to combine drugs that have two action of the peptide at the ETA subtype using different targets, the ETA antagonist ambrisentan with the ambrisentan (Letairis, Volibris, LU208075) or by phosphodiesterase inhibitor tadalafil, to improve the treatment of blocking both receptors using bosentan (Tracleer, pulmonary arterial hypertension. The solving of the crystal Ro47-0203) and macitentan (Opsumit, ACT-064992). All structure of the ETB receptor has the potential to identify three drugs are orally active small molecule antagonists allosteric binding sites for novel ligands. A further key advance is (Maguire and Davenport 2014). The timelines for key the experimental validation of a single nucleotide polymorphism discoveries in the ET signaling pathway (the three ET that has genome wide significance in five vascular diseases and peptides, two receptors and the endothelin converting that significantly increases the amount of big endothelin-1 enzymes (ECE), ECE-1 and ECE-2 are shown in precursor in the plasma. This observation provides a rationale for Figure 1, together with the most widely used selective testing this single nucleotide polymorphism to stratify patients for peptide ligands used to characterize the receptors in vitro allocation to treatment with endothelin agents and highlights the and in vivo. potential to use personalized precision medicine in the endothelin field. PHYSIOLOGICAL RESEARCH • ISSN 0862-8408 (print) • ISSN 1802-9973 (online) 2018 Institute of Physiology of the Czech Academy of Sciences, Prague, Czech Republic Fax +420 241 062 164, e-mail: [email protected], www.biomed.cas.cz/physiolres S38 Davenport et al. Vol. 67 Fig. 1. The timelines for key discoveries in the ET signaling pathway: the three ET peptides, ETA and ETB receptors and endothelin converting enzymes, ECE-1 and ECE-2. The twenty-one amino acid sarafotoxins S6a, b, c, d, identified in the venom of the snake Atractaspis engaddensis that have a high degree of sequence similarity, are also shown. Timelines for the identification of key 1,3,11,15 pharmaceutical agents are listed: ETB agonists [Ala ]-ET-1, BQ3020 and sarafotoxin S6c; ETA antagonists BQ123 and FR139317; bosentan, the first ETA/ETB antagonist approved for clinical use; ETB antagonist BQ788; ETA antagonist ambrisentan; the next generation of ETA/ETB antagonists, macitentan; the crystal structure of the ETB receptor. Fig. 2. ET signaling pathway, showing established and emerging pharmacological targets together with corresponding agents. Recently, there has been a rapid expansion in these compounds have other therapeutic advantages with research targeting ET receptors using chemical entities the potential to considerably expand drug targets in other than small molecules, namely monoclonal antibody the ET pathway and extend treatment to other antagonists and selective peptide agonists and antagonists pathophysiological conditions. Where the small molecule (Fig. 2). While usually sacrificing oral bio-availability, approach has been retained, the novel strategy is to 2018 New Drugs and Therapeutic Targets S39 combine two vasoconstrictor targets, the angiotensin AT1 clinical study, the local action of intra-lesion as well as the ETA receptors in a dual antagonist, administration of BQ-788 in five melanoma patients sparsentan (Komers et al. 2017). A second emerging found that excised treated lesions exhibited decreased strategy is to use two separate drugs, the ETA antagonist anti-apoptotic markers and ETB receptors compared with ambrisentan with the phosphodiesterase (PDE) 5 inhibitor saline controls. In one patient, treated for longer than one tadalafil, to improve the treatment of PAH (Galie et al. week, lesion growth was inhibited (Wouters et al. 2015). 2015) (Fig. 2). For endothelin research the most recent In this setting BQ788 was tolerated. These results suggest milestones in scientific progress are shown in Figure 1 that ETB receptors may play a key role in melanoma and culminating in the solving of the crystal structure of the represents a new therapeutic target. ETB receptor that has the potential to identify allosteric The MAP-kinase (MAPK) pathway is binding sites for further novel ligands (Shihoya et al. deregulated in the majority of malignant melanomas but 2016, Shihoya et al. 2017). Finally, a further key advance therapeutic targeting of the primary driver of hyper-active is the experimental validation of a single nucleotide MAPK signaling, BRAF, while initially effective in polymorphism (SNP) that has genome wide significance patients, owing to patient heterogeneity can lead to in five vascular diseases that significantly increases the resistance. ET-1 gene expression was found to be amount of big ET precursor in the plasma (Gupta et al. enhanced in tumors of patients on BRAF treatment and 2017). This study provides a rationale for testing for this this was proposed as a mechanism of resistance. SNP to stratify patients for allocation to treatment with Treatment with bosentan overcomes the ET-1 signaling ET compounds and demonstrates the potential for the use pathway and prolongs BRAF-inhibitor responses (Smith of precision medicine in the ET field. This review et al. 2017). focusses on a concise update of drugs in the ET field and other reviews should be consulted for more details on ET Therapeutic monoclonal antibodies directed signaling pathways (Davenport et al. 2016, Houde et al. against the ETB receptor: Rendomab-B1 2016, Czopek et al. 2016). and B4 ETB peptide antagonist BQ788 (ENB001, Class A G-protein coupled receptors (GPCRs) ENB Therapeutics) in melanoma that include the ET sub-types are targets of about one third of all current medicines used in the clinic. The BQ-788 has been established as a highly development of monoclonal antibodies (MABs) has been selective peptide ETB antagonist both in vitro and in vivo a major growth area with over fifty approved for clinical in the clinic and is now being explored in a range of use. In addition to being highly selective for the target clinical conditions (Davenport et al. 2016). The ET protein, MABs can have less off-target actions. They signaling pathway has been implicated in a number of have a very long plasma half-life compared with small cancers. In particular, the ETB receptor is overexpressed molecules, leading to a prolonged time course of action in melanoma (Asundi et al. 2011), a cancer that develops of several months and to improved patient compliance. from pigment-containing melanocytes where ET has The majority of MABs to GPCRs tend to bind to a role in proliferation and melanin synthesis and typically extracellular regions and therefore can stabilize different occurs in the skin. It is an aggressive cancer, conformational states compared with small molecule characterized by its capacity to metastasize, leading to an ligands that bind to transmembrane domains. MABs may increase in mortality rates and affects about 340,000 cause an immunogenic response in human patients, patients in the US and Europe. The transformation of reducing their therapeutic efficacy, but this can be melanocytes to melanoma cells is often associated with mitigated by using human-derived sequences (Hutchings an increased capacity to proliferate. It is thought that ETB et al. 2017). The main disadvantage of MABs is that receptors are a driver of melanoma progression and there can be