Novel Drug Targets in 2019

NEWS & ANALYSIS

TARGET WATCH Finally, there are two new drugs with novel MoA targets that are not included in Table 1 because the targets are small molecules. Novel drug targets in 2019 Andexanet alfa binds to anticoagulants in the factor Xa inhibitor class, acting as an antidote, The high rate of new drug approvals in volanesorsen, an antisense oligonucleotide and pegvaliase is a recombinant enzyme 2018 (Nat. Rev. Drug Discov. 18, 328; 2019) that degrades apolipoprotein CIII (apo CIII) replacement therapy for phenylketonuria that continued in 2019. To investigate the mRNA, and givosiran, a small interfering metabolizes phenylalanine. mechanistic novelty of new drugs approved RNA (siRNA) that degrades the mRNA for 1 1 1 in the United States, the European Union 5-aminolevulinate synthase — or restore Sorin Avram , Liliana Halip , Ramona Curpan and Tudor I. Oprea2 ✉ and Japan last year, we annotated their protein function through promotion 1Department of Computational Chemistry, mechanism of action (MoA) biomolecular of exon skipping, as with golodirsen, “Coriolan Dragulescu” Institute of Chemistry, targets (as defined in Nat. Rev. Drug Discov. which binds to exon 53 of dystrophin Timisoara, Romania. 16, 19–34; 2017), based on package inserts pre-mRNA. From a platform perspective, 2Department of Internal Medicine and UNM Comprehensive Cancer Center, University of and primary literature. Here, we highlight two targets are for antibody–drug conjugates, New Mexico School of Medicine, Albuquerque, the novel MoA targets for these drugs; that enfortumab vedotin and polatuzumab NM, USA. is, the targets that had not previously been vedotin, which enable the highly toxic, ✉e-mail: [email protected] modulated by an approved drug (Table 1). microtubule-disrupting agent vedotin to be https://doi.org/10.1038/d41573-020-00052-w

Four targets are in the well-established delivered to cancer cells that express nectin 4 Acknowledgements transporter class, including two transporters or CD79B, respectively. This article is part of a series from the NIH Common Fund Illuminating the Druggable Genome (IDG) programme. in the SLC superfamily, SLC9A3 and SLC5A1. From a therapeutic standpoint, nine of The goal of IDG is to catalyse research on understudied There are also three RNA targets, reflecting the novel MoA targets address rare diseases. proteins from druggable gene families by providing reagents, phenotypes and a mineable database; focusing on GPCRs, the strengthening clinical validation of Five of these targets are genetic disorders with kinases and ion channels. For more information, see https:// oligonucleotide-based therapeutic platforms. haematological manifestations, including druggablegenome.net/. Different classes of oligonucleotides two new targets for sickle cell disease: the Competing interests can degrade the target RNA — as with haemoglobin subunit-α and P-selectin. The authors declare no competing interests.

Table 1 | Drugs with novel macromolecular targets approved in 2019 Drug Properties Mechanism of action target Target class Indication Approval (gene name) agency Tenapanor Small-molecule inhibitor Sodium/hydrogen exchanger 3 Transporter IBS with constipation FDA (SLC9A3) Sotagliflozin Small-molecule inhibitor Sodium/glucose cotransporter 1 Transporter Type 1 diabetes EMA (SLC5A1) Voxelotora Small-molecule inhibitor Haemoglobin subunit-α (HBA1) Transporter Sickle cell disease FDA of HbS polymerization Selinexora Small-molecule inhibitor Exportin 1 (XPO1) Transporter Multiple myeloma FDA Volanesorsena Degrading ASO Apolipoprotein CIII mRNA RNA Chylomicronaemia syndrome EMA (APOC3) Golodirsena Exon-skipping ASO Exon 53 of dystrophin pre-mRNA RNA Duchenne muscular dystrophy FDA (DMD) Givosirana siRNA 5-Aminolevulinate synthase RNA Acute hepatic porphyria FDA mRNA (ALAS1) Bremelanotide Peptide agonist Melanocortin receptor 4 (MC4R) GPCR Hypoactive sexual desire FDA disorder Roxadustat Small-molecule inhibitor Egl nine homologues 1, 2, 3 Enzyme Anaemia in chronic kidney PMDA (EGLN1, EGLN2, EGLN3) disease and refractory anaemia Luspatercepta Recombinant fusion Growth/differentiation factors 8 Cytokine Anaemia due to β-thalassaemia FDA protein and 11 (MSTN, GDF11) Romosozumab Humanized mAb Sclerostin (SOST) Bone morphogenetic Postmenopausal osteoporosis FDA protein Crizanlizumaba Humanized mAb P-selectin (SELP) Ca2+-dependent Vaso-occlusive crisis in sickle FDA receptor cell disease Enfortumab ADC Nectin 4 (NECTIN4) Tumour-associated Urothelial carcinoma FDA vedotin antigen Polatuzumab ADC B cell antigen receptor complex- Tumour-associated Diffuse large B cell lymphoma FDA , vedotina associated protein beta chain antigen EMA (CD79B) ADC, antibody–drug conjugate; ASO, antisense oligonucleotide; EMA , European Medicines Agency; FDA , US Food and Drug Administration; GPCR , G protein- coupled receptor; HbS, haemoglobin S; IBS, irritable bowel syndrome; mAb, monoclonal antibody; PMDA , Japanese Pharmaceutical and Medical Devices Agency. aOrphan drug.

300 | May 2020 | volume 19 www.nature.com/nrd