Hepcidin Therapeutics
Abstract
:1. Systemic Iron Homeostasis
2. Hepcidin: The Key Iron Regulatory Hormone
3. Disorders with Hepcidin Deficiency
3.1. Hereditary Hemochromatosis
3.2. Iron-Loading Anemias
3.3. Chronic Liver Diseases
4. Disorders with Hepcidin Resistance or Ferroportin Deficiency
5. Disorders with Systemic Hepcidin Overexpression
5.1. Iron-Refractory Iron Deficiency Anemia
5.2. Anemia of Inflammation
5.3. Castleman Disease
6. Disorders with Local Hepcidin Overexpression
7. The Need for Hepcidin Therapeutics
7.1. Narrowing the Management Gap in Iron Overload Disorders Linked to Hepcidin Deficiency
7.2. Narrowing the Management Gap in Anemias and Other Disorders Linked to Hepcidin Overexpression
8. Inducers of Hepcidin Expression
8.1. Recombinant BMP6
8.2. TMPRSS6-Silencing Oligonucleotides
8.3. Small Molecule Hepcidin Inducers
9. Hepcidin Agonists
9.1. Minihepcidins
9.2. Other Hepcidin Derivatives
10. Inhibitors of Ferroportin Activity
11. Inhibitors of Hepcidin Expression
11.1. Inhibitors of BMP6/HJV
11.2. Small Molecule Inhibitors of BMP/SMAD Signaling
11.3. Neutralizing Antibodies against IL-6 Receptor or IL-6
11.4. Small Molecule Inhibitors of JAK/STAT3 Signaling
11.5. Sex Hormones
11.6. Vitamin D
12. Hepcidin Antagonists
12.1. Direct Hepcidin Inhibitors
12.2. Ferroportin-Binding Hepcidin Inhibitors
13. Conclusions
Funding
Conflicts of Interest
References
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Disorders | |||||||||
---|---|---|---|---|---|---|---|---|---|
Hepcidin Deficiency | Hepcidin Resistance or Ferroportin Deficiency | Systemic Hepcidin Overexpression | Local Hepcidin Overexpression | ||||||
HH | Iron-Loading Anemias | CLD | Ferroportin Hemochromatosis | Ferroportin Disease | IRIDA | AI | Castleman Disease | Cancer | |
Hepcidin | ↓ | ↓ | ↓ | ↑ | ↑ | ↑ | ↑ | ↑ | ↑ (in cancer cells) |
Intestinal Fe absorption | ↑ | ↑ | ↑ | ↑ | ↑ | ↓ | ↓ | ↓ | Normal |
Macrophage Fe release | ↑ | ↑ | ↑ | ↑ | ↓ | ↓ | ↓ | ↓ | Normal |
Serum Fe | ↑ | ↑ | ↑ | ↑ | ↓ | ↓ | ↓ | ↓ | Normal |
Tissue Fe | ↑ | ↑ | ↑ | ↑ | ↑ | Normal | Normal | Normal | Normal |
Drug | Target | Evidence | Reference | |
---|---|---|---|---|
In vitro studies | Genistein (small molecule) | STAT3 | Hepatoma cells | Zhen et al. 2013 [72] |
Ipriflavone (small molecule) | Histone deacetylase, BMP-, STAT3-dependent genes | Hepatoma cells | Gaun et al. 2014 [73] | |
Vorinostat (small molecule) | Histone deacetylase, BMP-, STAT3-dependent genes | Hepatoma cells | Gaun et al. 2014 [73] Mleczko-Sanecka et al. 2017 [75] | |
Diclofenac (small molecule) | Not specified; independent of PTGIS and cyclooxygenases | Hepatoma cells | Mleczko-Sanecka et al. 2017 [75] | |
Icariin (small molecule) | SMAD1/5/8, STAT3 | Hepatoma cells | Zhang et al. 2016 [77] | |
Resveratrol, querqetin, kaemferol, naringenin, epi-galoo-catechin-3-gallate (small molecules) | Nrf2 | Hepatoma cells | Bayele et al. 2015 [78] | |
Sorafenib, wortmannin, rapamycin, metformin (small molecules) | Ras/RAF/MAPK and mTOR signaling | Hepatoma cells, Primary hepatocytes | Mleczko-Sanecka et al. 2014 [79] | |
Preclinical studies | BMP6 | BMP receptors | Mouse model of adult HH | Corradini et al. 2010 [64] |
siRNAs | Matriptase-2 | Mouse model of adult HH Mouse model of β-thalassemia | Schmidt et al. 2013 [65] | |
Antisense oligonucleotides (ASOs) | Matriptase-2 | Mouse model of β- thalassemia | Guo et al. 2013 [66] | |
GalNac-ASOs | Matriptase-2 | Mouse model of β- thalassemia, splenectomised | Schmidt et al. 2018 [70] | |
Progesterone, epitiostanol, mifepristone | PRMC-1 | Zebrafish | Li et al. 2016 [71] | |
Ipriflavone (small molecule) | BMP-, STAT3-dependent genes | Wild type mice | Gaun et al. 2014 [73] | |
Icariin (small molecule) | SMAD1/5/8, STAT3 | Wild type mice | Zhang et al. 2016 [77] | |
Epimedin C (small molecule) | SMAD1/5/8, STAT3 | Wild type mice | Zhang et al. 2016 [77] | |
Resveratrol, querqetin, kaemferol, naringenin, epi-gallo-catechin-3-gallate (small molecules) | Nrf2 | Wild type rats | Bayele et al. 2015 [78] | |
Adenine (small molecule) | SMAD1/5/8 and cAMP/PKA | Mouse model of adult HH | Zhang et al. 2018 [80] | |
Clinical trials | IONIS-TMPRSS6-Lrx (Antisense oligonucleotide) By: Ionis Pharmaceuticals Inc. | Matriptase-2 | Healthy subjects—Phase 1 (Active) | ClinicalTrials.gov Identifier: NCT03165864 |
Drug | Target | Evidence | Reference | |
---|---|---|---|---|
Preclinical studies | Palmitoyl-ri-hep9 (minihepcidin) | Ferroportin | Mouse model of juvenile HH | Preza et al. 2011 [83] |
PR65 (minihepcidin) | Ferroportin | Wild type mice Mouse model of juvenile HH | Ramos et al. 2012 [84] | |
PR73 (minihepcidin) | Ferroportin | Mouse model of adult HH Mouse model of adult HH, bacteria-infected | Arezes et al. 2015 [88] Lunova et al. 2017 [86] Stefanova et al. 2017 [89] Michels et al. 2017 [90] Stefanova et al. 2018 [91] | |
M004, M009 (minihepcidins) | Ferroportin | Mouse model of β-thalassemia Mouse model of polycythemia vera | Casu et al. 2016 [92] | |
Clinical trials | LJPC-401 (hepcidin formulation) By: La Jolla Pharmaceutical Company | Ferroportin | HH, β-thalassemic patients-Phase 1 (Completed) Phase 2 (Recruiting) | Phase 1: Lal et al. 2018 [93] (congress presentation) Phase 2: ClinicalTrials.gov Identifiers NCT03395704, NCT03381833 |
PTG-300 (hepcidin formulation) By: Protagonist Therapeutics Inc. | Ferroportin | Healthy subjects—Phase 1 (Completed) Phase 2 expected to start end of 2018 | Bourne et al. 2018 [94] Nicholls et al. 2018 [95] (congress presentations) |
Drug | Target | Evidence | Reference | |
---|---|---|---|---|
Clinical trials | VIT-2763 (small molecule) By: Vifor Pharma | Ferroportin | Phase 1 planned in 2018 | http://www.viforpharma.com/en/media/press-releases/201802/2167159 |
Drug | Target | Evidence | Reference | |
---|---|---|---|---|
In vitro studies | Genistein (small molecule) | BMP6 | Macrophages | Abreu et al. 2018 [97] |
Erythroferrone | BMP6 | Hepatoma cells | Arezes et al. 2018 [24] | |
sHJV.Fc (antibody-like fused protein) | BMP6 | Hepatoma cells, Kidney cells | Babitt et al. 2007 [101] Andriopoulos et al. 2009 [102] | |
Dorsomorphin (small molecule) | Type I BMP receptors (ALK2/3/6) | Hepatoma cells | Yu et al. 2008 [106] | |
LDN-193189 (dorsomorphin derivative) | Type I BMP receptors (mainly ALK2) | Primary hepatocytes | Theurl et al. 2011 [15] | |
LDN-212854 (dorsomorphin derivative) | Type I BMP receptors (mainly ALK2) | Hepatoma cells | Mohedas et al. 2013 [111] | |
Spironolactone (aldosterone antagonist used to treat hypertension) | BMP/SMAD signaling? | Hepatoma cells Primary hepatocytes | Mleczko-Sanecka et al. 2017 [75] | |
Imatinib (tyrosine kinase inhibitor used in cancer therapy) | BMP/SMAD signaling? | Hepatoma cells Primary hepatocytes | Mleczko-Sanecka et al. 2017 [75] | |
AG490, PpYLKTK, curcumin (small molecules) | STAT3 | Differentiated hepatocytes | Fatih et al. 2010 [131] | |
Aspirin (cyclooxygenase inhibitor for pain treatment) | JAK2, STAT3 | Microglia cells Pheochromocytoma cells | Li et al. 2016 [134] Huang et al. 2018 [135] | |
Angelica sinensis polysaccharide (small molecule) | SMAD4, STAT3/5 | Hepatoma cells | Wang et al. 2017 [139] | |
GDP | STAT3 | Hepatoma cells Colorectal adenocarcinoma cells | Angmo et al. 2017 [145] | |
17β-Estradiol | Estrogen responsive promoter | Hepatoma cells | Yang et al. 2012 [156] | |
Calcitriol | Vitamin D receptor | Hepatoma cells Leukemia cells | Bacchetta et al. 2014 [161] Zughaier et al. 2014 [162] | |
Preclinical studies | Heparin | BMP6 | Wild type mice | Poli et al. 2011 [96] |
Glycol-split heparin | BMP6 | Mouse model of AI BMP6 knockout mice | Poli et al. 2014 [98] | |
Oversulfated heparin | BMP6 | Mouse model of AI | Poli et al. 2014 [99] | |
sHJV.Fc (antibody-like fused protein) | BMP6 | Mouse model of human SPTB Rat model of AI | Babitt et al. 2007 [101] Andriopoulos et al. 2009 [102] Theurl et al. 2011 [15] | |
ABT-207 (monoclonal Ab) | HJV | Wild type rats Cynomolgus monkeys | Boser et al. 2015 [103] | |
H5F9-AM8 (monoclonal Ab) | HJV | Mouse models of IRIDA and IA Rat model of AI, wild type rats Cynomolgus monkeys | Boser et al. 2015 [103] Kovac et al. 2016 [104] | |
Dorsomorphin (small molecule) | Type I BMP receptors (ALK2/3/6) | Zebrafish embryos | Yu et al. 2008 [106] | |
LDN-193189 (dorsomorphin derivative) | Type I BMP receptors (ALK2/3/6) | Rat model of AI Mouse model of AI | Theurl et al. 2011 [15] Theurl et al. 2014 [61] Mayeur et al. 2015 [107] | |
Myricetin | SMAD 1/5/8 | Wild type mice | Mu et al. 2016 [112] | |
DS79182026 (small molecule) | ALK2 | Mouse model of AI | Fukuda et al. 2017 [115] Sasaki et al. 2018 [116] | |
TP-0184 (small molecule) | ALK2 | Mouse model of AI | Peterson et al. 2015 [118] Peterson et al. 2016 [117] | |
Momelotinib (JAK1/2 inhibitor for myelofibrosis treatment) | ALK2 | Rat model of AI | Asshoff et al. 2017 [121] | |
Spironolactone (aldosterone antagonist used to treat hypertension) | BMP/SMAD signaling? | Wild type mice | Mleczko-Sanecka et al. 2017 [75] | |
Imatinib (tyrosine kinase inhibitor used in cancer therapy) | BMP/SMAD signaling? | Wild type mice | Mleczko-Sanecka et al. 2017 [75] | |
Tocilizumab (monoclonal Ab for rheumatoid arthritis treatment) | IL-6 | Cynomolgus monkey model of AI Mouse model of cancer anemia | Hashizume et al. 2010 [129] Noguchi-Sasaki et al. 2016 [130] | |
MR16-1 (monoclonal Ab) | IL-6 | Mouse model of cancer anemia | Noguchi-Sasaki et al. 2016 [130] | |
AG490 (small molecule) | STAT3 | Wild type mice | Zhang et al. 2011 [132] | |
Maresin 1 (ω-3 fatty acid derivative) | STAT3 | Mouse model of AI | Marcon et al. 2013 [136] Wang et al. 2016 [137] | |
Angelica sinensis polysaccharide (small molecule) | SMAD4, STAT3/5 | Rat model of IDA Rat model of AI | Liu et al. 2012 [138] Wang et al. 2017 [139] Wang et al. 2018 [140] | |
H2S (gasotransmitter) | JAK2/STAT3 | Mouse model of AI | Xin et al. 2016 [142] Wang et al. 2017 [143] | |
GDP | STAT3 | Mouse model of AI | Angmo et al. 2017 [145] | |
Testosterone | SMAD1/4 or EGFR signaling | Liver-specific hepcidin-overexpressing mice Bmp6-/- mice Mouse model of AI | Guo et al. 2013 [147] Latour et al. 2014 [146] Guo et al. 2016 [149] | |
Clinical trials | LY3113593 (monoclonal Ab) By: Eli Lilly and Company | BMP6 | Healthy subjects, CKD patients—Phase 1 (Completed) | ClinicalTrials.gov Identifiers: NCT02144285, NCT02604160 |
sHJV.Fc (antibody-like fused protein) By: FerruMax Pharmaceuticals | BMP6 | CKD patients—Phase 1 (Discontinued) | ClinicalTrials.gov Identifiers: NCT01873534, NCT02228655 | |
TP-0184 (small molecule) By: Tolero Pharmaceuticals Inc. | ALK2 | Advanced solid tumor patients—Phase 1 (Active) | ClinicalTrials.gov Identifier: NCT03429218 | |
Momelotinib (JAK1/2 inhibitor used to treat myelofibrosis) | ALK2 | Myelofibrosis patients—Phase 1/2 (Completed) | Pardanani et al. 2013 [119] | |
Tocilizumab (monoclonal Ab for rheumatoid arthritis treatment) | IL-6 | Rheumatoid arthritis patients Castleman disease patients | Song et al. 2010 [127] Song et al. 2013 [124] Isaacs et al. 2013 [125] Suzuki et al. 2017 [126] | |
Siltuximab (monoclonal Ab for neoplastic disease treatment) | IL-6 | Castleman disease patients | Casper et al. 2015 [128] | |
Curcumin (small molecule) | STAT3 | Healthy subjects | Laine et al. 2017 [133] | |
Testosterone | SMAD1/4 or EGFR signaling | Type 2 diabetes patients with hypogonadotropic hypogonadism | Dhindsa et al. 2016 [153] | |
17β-Estradiol | Estrogen responsive promoter | Patients with growth hormone deficiency/hyperthyroidism/ hyperprolactinemia Premenopausal women | Lehtihet et al. 2016 [157] Bajbouj et al. 2018 [158] | |
Vitamin D2 | Vitamin D receptor | Healthy subjects | Bacchetta et al. 2014 [161] | |
Vitamin D3 | Vitamin D receptor | CKD patients Healthy subjects Critically ill patients | Zughaier et al. 2014 [162] Smith et al. 2017 [163] Smith et al. 2018 [164] |
Drug | Target | Evidence | Reference | |
---|---|---|---|---|
In vitro studies | Fursultiamine (small molecule) | Ferroportin | Kidney cells | Fung et al. 2013 [180] |
Quinoxaline (small molecule) | Ferroportin | Kidney cells, breast cells, leukemia cells | Ross et al. 2017 [181] | |
Preclinical studies | LY2928057 (monoclonal Ab) | Ferroportin | Cynomolgus monkeys | Witcher et al. 2013 [182] |
Clinical trials | LY2787106 (monoclonal Ab) By: Eli Lily and Company | Hepcidin | Patients with cancer-associated anemia—Phase 1 (Completed) | Vadhan-Raj et al. 2017 [170] |
PRS-080 (Pegylated anticalin) By: Pieris Pharmaceuticals GmbH | Hepcidin | Anemic CKD patients—Phase 1b/2a (Recruiting) | ClinicalTrials.gov Identifiers: NCT02754167, NCT03325621 | |
NOX-H94 (Pegylated spiegelmer) | Hepcidin | Healthy subjects—Phase 1 (Completed) Endotoxemia-induced in volunteers—Phase 1 (Completed) Patients with cancer-associated anemia—Phase 2a (Completed) ESA-hyporesponsive anemia in CKD patients—Phase 2b (Completed) | Boyce et al. 2016 [176] Van Eijk et al. 2014 [177] Macdougall et al. 2015 [178] Georgiev et al. 2014 [179] | |
LY2928057 (monoclonal Ab) By: Eli Lily and Company | Ferroportin | Healthy subjects and hemodialyzed patients—Phase 1 (Completed) | Barrington et al. 2016 [183] |
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Katsarou, A.; Pantopoulos, K. Hepcidin Therapeutics. Pharmaceuticals 2018, 11, 127. https://doi.org/10.3390/ph11040127
Katsarou A, Pantopoulos K. Hepcidin Therapeutics. Pharmaceuticals. 2018; 11(4):127. https://doi.org/10.3390/ph11040127
Chicago/Turabian StyleKatsarou, Angeliki, and Kostas Pantopoulos. 2018. "Hepcidin Therapeutics" Pharmaceuticals 11, no. 4: 127. https://doi.org/10.3390/ph11040127
APA StyleKatsarou, A., & Pantopoulos, K. (2018). Hepcidin Therapeutics. Pharmaceuticals, 11(4), 127. https://doi.org/10.3390/ph11040127