The ALK-2 Inhibitor, TP-0184, Demonstrates High Distribution to the Liver Contributing to Significant Preclinical Efficacy in Mouse Models of Anemia of Chronic Disease

Peterson, Peter; Kim, Wontak; Haws, Hillary; Whatcott, Clifford J.; Siddiqui‐Jain, Adam; Bearss, David J.; Warner, Steven L.

doi:10.1182/blood.v128.22.263.263

Cited by 6 publications

(3 citation statements)

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“…The drug is currently undergoing a phase 1 clinical trial to determine its maximum tolerated dose and dose-limiting toxicities in patients with advanced solid tumors (ClinicalTrials.gov Identifier: NCT03429218). In preclinical mouse models of inflammation- and cancer-induced anemia, TP-0184 decreased hepatic hepcidin mRNA and improved hemoglobinization [117,118].…”

Section: Inhibitors Of Hepcidin Expressionmentioning

confidence: 99%

Hepcidin Therapeutics

Κατσαρού

Pantopoulos

2018

Pharmaceuticals

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Hepcidin is a key hormonal regulator of systemic iron homeostasis and its expression is induced by iron or inflammatory stimuli. Genetic defects in iron signaling to hepcidin lead to “hepcidinopathies” ranging from hereditary hemochromatosis to iron-refractory iron deficiency anemia, which are disorders caused by hepcidin deficiency or excess, respectively. Moreover, dysregulation of hepcidin is a pathogenic cofactor in iron-loading anemias with ineffective erythropoiesis and in anemia of inflammation. Experiments with preclinical animal models provided evidence that restoration of appropriate hepcidin levels can be used for the treatment of these conditions. This fueled the rapidly growing field of hepcidin therapeutics. Several hepcidin agonists and antagonists, as well as inducers and inhibitors of hepcidin expression have been identified to date. Some of them were further developed and are currently being evaluated in clinical trials. This review summarizes the state of the art.

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Section: Inhibitors Of Hepcidin Expressionmentioning

confidence: 99%

Hepcidin Therapeutics

Κατσαρού

Pantopoulos

2018

Pharmaceuticals

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“…Consequently, these compounds also hit other targets. Current clinical candidates include KER-047 (Keros Therapeutics), INCB00928 (Incyte), BLU-782 (Blueprint Medicines), BCX9250 and BCX9499 (BioCryst Pharmaceuticals), Saracatinib (AZD0530; Astra Zeneca), a RARγ agonist Palovarotene , E6201 , Momelotinib , Itacnosertib , and Mubritinib (TAK-165) to name just a few.…”

Section: Bmp Inhibitorsmentioning

confidence: 99%

Small-Molecule Probes as Pharmacological Tools for the Bone Morphogenetic Protein Signaling Pathway

Riege,

Herschel,

Fenkl

et al. 2023

ACS Pharmacol. Transl. Sci.

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The bone morphogenetic protein (BMP) pathway is highly conserved and plays central roles in health and disease. The quality and quantity of its signaling outputs are regulated at multiple levels, offering pharmacological options for targeted modulation. Both target-centric and phenotypic drug discovery (PDD) approaches were applied to identify small-molecule BMP inhibitors and stimulators. In this Review, we accumulated and systematically classified the different reported chemotypes based on their targets as well as modes-of-action, and herein we illustrate the discovery history of selected candidates. A comprehensive summary of available biochemical, cellular, and in vivo activities is provided for the most relevant BMP modulators, along with recommendations on their preferred use as chemical probes to study BMP-related (patho)physiological processes. There are a number of high-quality probes used as BMP inhibitors that potently and selectively interrogate the kinase activities of distinct type I (16 chemotypes available) and type II receptors (3 chemotypes available). In contrast, only a few high-quality BMP stimulator modalities have been introduced to the field due to a lack of profound target knowledge. FK506-derived macrolides such as calcineurin-sparing FKBP12 inhibitors currently represent the best-characterized chemical tools for direct activation of BMP-SMAD signaling at the receptor level. However, several PDD campaigns succeeded in expanding the druggable space of BMP stimulators. Albeit the majority of them do not entirely fulfill the strict chemical probe criteria, many chemotypes exhibit unique and unrecognized mechanisms as pathway potentiators or synergizers, serving as valuable pharmacological tools for BMP perturbation.

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“…LDN-193189 is a selective inhibitor of the BMP kinase type 1 receptor [13]. TP-0184 is an ALK-2 inhibitor that reduces hepcidin mRNA and improves Hb concentration in preclinical studies in mice [14]. Modified heparin with reduced anticoagulation ability binds BMP-6 and blocks hepcidin expression, as demonstrated in in vitro and in vivo animal models [15,16].…”

Section: Drugs/substances Affecting Bmp6 Pathwaymentioning

confidence: 99%

Perspectives for the therapy of anemia of chronic diseases

Michalak

2020

Acta Haematologica Polonica

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The incidence of anemia of chronic disease (ACD) is underestimated, increases with age, and affects about 30% of the elderly. ACD treatment is currently based on the pharmacotherapy of diseases that caused anemia, erythropoiesis-stimulating agents, and parenteral administration of iron supplementation in case of iron deficiency. Increasing knowledge on the pathophysiology of ACD has resulted in the burst of research on the development of new drugs that are focused on three main areas. The first group of drugs includes substances that inhibit hepcidin transcription, namely direct and indirect bone morphogenetic protein 6 (BMP6) inhibitors and/or SMAD signaling pathway inhibitors, and drugs that regulate hepcidin transcription through STAT3 signaling pathway. The second group of drugs includes direct hepcidin inhibitors (e.g., aptamers, anticalin proteins, monoclonal antibodies) or substances that inhibit the binding of hepcidin to ferroportin. The third group of drugs improves erythropoiesis mainly by upregulation of erythropoietin and/or inhibition of proinflammatory cytokines. In the latter group, hypoxia-inducing factor stabilizers and IL-6 or TNFα antagonists are particularly important. This article discusses new drug groups and substances that are in different phases of development, including both preclinical and clinical studies, and focuses on the prospects of their use in ACD.

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The ALK-2 Inhibitor, TP-0184, Demonstrates High Distribution to the Liver Contributing to Significant Preclinical Efficacy in Mouse Models of Anemia of Chronic Disease

Cited by 6 publications

References 0 publications

Hepcidin Therapeutics

Hepcidin Therapeutics

Small-Molecule Probes as Pharmacological Tools for the Bone Morphogenetic Protein Signaling Pathway

Perspectives for the therapy of anemia of chronic diseases

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