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Marine-Derived Anticancer Agents: Clinical Benefits, Innovative

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Marine-Derived Anticancer Agents: Clinical Benefits, Innovative marine drugs Review Marine-Derived Anticancer Agents: Clinical Benefits, Innovative Mechanisms, and New Targets Renato B. Pereira 1 , Nikolai M. Evdokimov 2, Florence Lefranc 3, Patrícia Valentão 1 , Alexander Kornienko 4, David M. Pereira 1 , Paula B. Andrade 1,* and Nelson G. M. Gomes 1,* 1 REQUIMTE/LAQV, Laboratório de Farmacognosia, Departamento de Química, Faculdade de Farmácia, Universidade do Porto, R. Jorge Viterbo Ferreira, n◦ 228, 4050-313 Porto, Portugal; [email protected] (R.B.P.); valentao@ff.up.pt (P.V.); dpereira@ff.up.pt (D.M.P.) 2 Department of Chemistry and Biochemistry, University of California, Santa Barbara, CA 93106, USA; [email protected] 3 Department of Neurosurgery, Hôpital Erasme, Université Libre de Bruxelles, 808 Route de Lennik, 1070 Brussels, Belgium; fl[email protected] 4 Department of Chemistry and Biochemistry, Texas State University, San Marcos, TX 78666, USA; [email protected] * Correspondence: pandrade@ff.up.pt (P.B.A.); ngomes@ff.up.pt (N.G.M.G.); Tel.: +351-22-042-8654 (P.B.A.); +351-122-042-8500 (N.G.M.G.) Received: 15 May 2019; Accepted: 30 May 2019; Published: 2 June 2019 Abstract: The role of the marine environment in the development of anticancer drugs has been widely reviewed, particularly in recent years. However, the innovation in terms of clinical benefits has not been duly emphasized, although there are important breakthroughs associated with the use of marine-derived anticancer agents that have altered the current paradigm in chemotherapy. In addition, the discovery and development of marine drugs has been extremely rewarding with significant scientific gains, such as the discovery of new anticancer mechanisms of action as well as novel molecular targets. Approximately 50 years since the approval of cytarabine, the marine-derived anticancer pharmaceutical pipeline includes four approved drugs and eighteen agents in clinical trials, six of which are in late development. Thus, the dynamic pharmaceutical pipeline consisting of approved and developmental marine-derived anticancer agents offers new hopes and new tools in the treatment of patients afflicted with previously intractable types of cancer. Keywords: cytarabine; trabectedin; eribulin; brentuximab vedotin; plitidepsin; lurbinectedin; plinabulin; marizomib; plocabulin; antibody–drug conjugates 1. An Overview on Fifty Years of Marine-Derived Drug Discovery Soon after the landmark discovery of the DNA double helix structure, the isolation of two arabinose-containing nucleosides from the sponge Cryptotethya crypta [1] was the first step for the development of cytarabine (1) (Figure1), the first approved marine-derived drug [ 2]. Immune to the new paradigm set by the emergence of combinatorial chemistry and the advent of high throughput screening in the 1990s [3], natural product researchers switched from the terrestrial environment to the oceans, with more than 28,600 marine natural products reported as a result of their efforts [4]. With over 50% of the new bioactive marine natural products isolated during the period of 1985–2012 exhibiting cytotoxicity toward experimental models of cancer [5], marine bioprospection has been particularly rewarding in the area of cancer, with four chemotherapeutic agents already approved and eighteen additional drug candidates enriching the oncological pipeline (Table1). The development of these anticancer drugs corroborated the unmeasurable impact of natural products on the current Mar. Drugs 2019, 17, 329; doi:10.3390/md17060329 www.mdpi.com/journal/marinedrugs Mar. Drugs 2019, 17, 329 2 of 21 chemotherapeuticMar. Drugs 2019, 17, armamentarium,329 with 49% of anticancer agents approved prior to 20142 of being 21 classified2014 being either classified as natural either products as natural or products directly derivedor directly therefrom derived therefrom [6]. In fact, [6]. theIn fact, chemical the chemical diversity of drugsdiversity compared of drugs to compared natural products to natural and products synthetic and synthetic libraries haslibraries shown has thatshown the that chemical the chemical diversity of naturaldiversity products of natural is products more closely is more aligned closely withaligned drugs with thandrugs synthetic than synthetic libraries libraries [7], [7], in contrastin contrast with thewith common the common assumption assumption that most that most drugs drugs have have a purely a purely synthetic synthetic origin origin [6]. [6]. Despite Despite the the inherent inherent limitationslimitations associated associated with with the the drug drug discovery discovery and and development development fromfrom marinemarine sources, the progress progress in analyticalin analytical instrumentation instrumentation [8], anticancer [8], anticancer screening screening platforms platforms [9], [9], scalable scalable synthetic synthetic approaches approaches [10 ], and[10], antibody–drug and antibody–drug conjugates conjugates (ADCs) (ADCs) [11] allowed [11] allowed the broadening the broadening of the of clinical the clinical arsenal arsenal for cancerfor treatment.cancer treatment. In addition In toaddition the evident to the clinical evident benefits, clinical additionalbenefits, additional scientific scientific gains have gains been have witnessed been withwitnessed the development with the development of these innovative of these anticancerinnovative agents.anticancer agents. HO H2N OH O O N NH O NH2 O O O O HO H H N O O O HO O S O O H H HO OH N O O O O Cytarabine (1) O O OH O Trabectedin (2) Eribulin (3) H S O O H O N N O O N N HO H N N O O O O N N O O H H O N NH O H 2 Brentuximab Vedotin (4) N O H O O O N N O O H N O O O O HN O OH NH O O NH O O O O HO O N HN NH NH O HO N O O H O S O NH O H O O N N O N Cl Plitidepsin (5) O OH H Lurbinectedin (6) Plinabulin (7) Salinosporamide A (8) S O H O H N N N O N N O O O O O O N O Monomethyl Auristatin F (10) H OH O H N N H O O O O H O O N N NH2 H2N N O O O O O N Plocabulin (9) N O H S PF-06380101 (11) Figure 1. Structures of marine-derived licensed drugs and clinical candidates. Figure 1. Structures of marine-derived licensed drugs and clinical candidates. Mar. Drugs 2019, 17, 329 3 of 21 Table 1. Marine-derived chemotherapeutic pipeline. 1. Compound Name Lead Compound Chemical Class Molecular Target Cancer Conditions (Trademark) (Source) APPROVED Cytarabine Spongothymidine Nucleoside DNA polymerase Leukemia; lymphomatous meningitis (Cytosar-U®; DepoCyt®) (Sponge) Trabectedin Trabectedin Alkaloid DNA minor groove Soft tissue sarcoma; ovarian cancer (Yondelis®) (Tunicate) Eribulin mesylate Halichondrin B Metastatic breast cancer; advanced Macrolide Microtubules (Halaven®) (Sponge) liposarcoma Brentuximab vedotin Dolastatin 10 ADC a CD30 and microtubules sALCL c; Hodgkin lymphoma (Adcetris®) (Mollusk/cyanobacterium) (MMAE) b PHASE 3 Plitidepsin Plitidepsin Depsipeptide Rac1 and JNK activation Relapsed/refractory multiple myeloma (Aplidin®) (Tunicate) Lurbinectedin Trabectedin Alkaloid DNA minor groove Ovarian cancer; SCLC d (Zepsyre®) Halimide Plinabulin Diketopiperazine Microtubules NSCLC e; CIN f (Fungus) Salinosporamide A Salinosporamide A γ-lactam-β-lactone 20S proteasome Newly diagnosed glioblastoma Marizomib (Bacterium) Polatuzumab vedotin Dolastatin 10 ADC (MMAE) CD79b and microtubules DLBCL g DCDS-4501A Depatuxizumab vedotin Dolastatin 10 ADC (MMAF h) EGFR and microtubules Newly diagnosed glioblastoma ABT-414 Mar. Drugs 2019, 17, 329 4 of 21 Table 1. Cont. Compound Name Lead Compound Chemical Class Molecular Target Cancer Conditions (Trademark) (Source) PHASE 2 PM060184 PM060184 Polyketide Microtubules Advanced colorectal cancer Plocabulin (Sponge) Carcinoma, transitional cell; urinary bladder, Enfortumab vedotin Dolastatin 10 ADC (MMAE) Nectin-4 and microtubules urologic, renal pelvis, ureteral and urethral ASG-22ME neoplasms; urothelial cancer; Metastatic gpNMB over-expressing triple negative breast cancer; recurrent osteosarcoma; Glembatumumab vedotin Dolastatin 10 ADC (MMAE) gpNMB and microtubules recurrent uveal melanoma; stage IV uveal CDX-011 melanoma AJCC v7; melanoma; squamous cell carcinoma of the lung AGS-16C3F Dolastatin 10 ADC (MMAF) ENPP3 and microtubules Metastatic renal cell carcinoma GSK2857916 Dolastatin 10 ADC (MMAF) BCMA Multiple myeloma NSCLC; Ovary, cervical, endometrium, Tisotumab vedotin Tissue factor and Dolastatin 10 ADC (MMAE) bladder, prostate and esophagus cancer; (HuMax®-TF-ADC) microtubules squamous cell carcinoma of the head and neck Ladiratuzumab vedotin Dolastatin 10 ADC (MMAE) LIV-1 and microtubules Breast cancer SGN-LIV1A Telisotuzumab vedotin Recurrent and stage IV squamous cell lung Dolastatin 10 ADC (MMAE) c-Met ABBV-399 carcinoma; NSCLC PHASE 1 Advanced solid tumors; undifferentiated pleomorphic sarcoma; squamous cell ABBV-085 Dolastatin 10 ADC (MMAE) LRRC15 carcinoma of the head and neck; breast carcinoma AGS-67E Dolastatin 10 ADC (MMAE) CD37 and microtubules Refractory/relapsed lymphoid malignancy SLITRK6 and ASG-15ME Dolastatin 10 ADC (MMAE) Metastatic urothelial cancer microtubules Advanced solid tumors; triple negative and PF-06647020 Dolastatin 10 ADC (PF-06380101) PTK7 and microtubules metastatic breast cancer 1 Based on the latest stage of clinical development registered on the US clinical trials database (recruiting; active, not recruiting; not yet recruiting; and enrolling by invitation) and/or EU clinical trials (ongoing). a Antibody–drug conjugate; b monomethyl auristatin E; c systemic anaplastic large-cell lymphoma; d small-cell lung cancer; e non-small-cell lung
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