Discovery of Molidustat (BAY 85‐3934): A Small‐Molecule Oral HIF‐Prolyl Hydroxylase (HIF‐PH) Inhibitor for the Treatment of Renal Anemia

Beck, Hartmut; Jeske, Mario; Thede, Kai; Stoll, Friederike; Flamme, Ingo; Akbaba, Metin; Ergüden, Jens-Kerim; Karig, Gunter; Keldenich, Jörg; Oehme, Felix; Militzer, Hans‐Christian; Hartung, Ingo V.; Thuß, Uwe

doi:10.1002/cmdc.201700783

Cited by 58 publications

(56 citation statements)

References 35 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The activation of HIF pathways may be clinically desirable in renal anemia and ischemia 26,35 . Several small-molecule compounds are in clinical trials to treat anemia in CKD patients, notably roxadustat (FG-4592) 36 , daprodustat (GSK1278863) 37 , vadadustat (AKB-6548) 38 and molidustat (BAY 85–3934) 39 . All of these are PHD inhibitors which boost HIF-2α protein levels, leading to increased HIF-2 activity and the production of endogenous EPO 29 .…”

Section: Resultsmentioning

confidence: 99%

Bidirectional modulation of HIF-2 activity through chemical ligands

et al. 2019

Nat Chem Biol

View full text Add to dashboard Cite

Hypoxia‐inducible factor‐2 (HIF‐2) is a heterodimeric transcription factor formed through dimerization between an oxygen‐sensitive subunit HIF‐2α subunit and its obligate partner subunit ARNT. Enhanced HIF‐2 activity drives some cancers, while reduced activity causes anemia in chronic kidney disease. Therefore, modulation of HIF‐2 activity via direct‐binding ligands could provide many new therapeutic benefits. Here, we explored HIF‐2α chemical ligands using combined crystallographic, biophysical, and cell‐based functional studies. We found chemically unrelated antagonists to employ the same mechanism of action. Their binding displaced residue M252 from inside the HIF‐2α PAS‐B pocket toward the ARNT subunit to weaken heterodimerization. We also identified first‐in‐class HIF‐2α agonists and found they significantly displaced pocket residue Y281. Its dramatic side‐chain movement increases heterodimerization stability and transcriptional activity. Our findings show that despite binding to the same HIF‐2α PAS‐B pocket, ligands can manifest as inhibitors versus activators by mobilizing different pocket residues to allosterically alter HIF‐2α‐ARNT heterodimerization. This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

show abstract

Section: Resultsmentioning

confidence: 99%

Bidirectional modulation of HIF-2 activity through chemical ligands

et al. 2019

Nat Chem Biol

View full text Add to dashboard Cite

show abstract

“…In healthy volunteers, molidustat was shown to be rapidly absorbed with a maximum plasma concentration of 1 h after drug intake and to elicit dosedependent increases in endogenous EPO after single increasing doses [12]. Molidustat is metabolized via glucuronidation and eliminated in urine as pharmacologically inactive glucuronide [13].…”

Section: Introductionmentioning

confidence: 99%

Effects of oral iron and calcium supplement on the pharmacokinetics and pharmacodynamics of molidustat: an oral HIF–PH inhibitor for the treatment of renal anaemia

Lentini

Kaiser

Kapsa

et al. 2020

Eur J Clin Pharmacol

View full text Add to dashboard Cite

Purpose The present studies assessed the drug-drug interaction of molidustat, a hypoxia-inducible factor prolyl hydroxylase inhibitor, with iron and calcium supplements, which are common medications in patients with anaemia due to chronic kidney disease (CKD). Methods Forty-two healthy men received molidustat alone (fasted or fed) or combined with oral iron(II) or calcium(II), given immediately before or between 4 h before and 1 h after molidustat in three randomized, open-label, crossover studies (12-15 participants per study). Molidustat AUC and C max were assessed as the main pharmacokinetic parameters, and endogenous erythropoietin (EPO) was measured to evaluate pharmacodynamics. Results Depending on prandial state, concomitant intake of iron(II) reduced molidustat AUC and C max by 50-75% and 46-84%, respectively, and EPO AUC (0-24) and C max by 31-44% and 36-48%, respectively. The influence of iron(II) declined with increasing the time interval to the intake of molidustat, with reductions in molidustat AUC and C max of 9% and 10%, respectively, when iron(II) intake occurred 4 h before molidustat. Accordingly, effects on endogenous EPO were less pronounced with increased time separation between oral iron(II) and molidustat intake. Calcium(II) reduced molidustat AUC and C max by 15% and 47%, respectively, without influence on EPO response. All treatments were well tolerated. Conclusions In contrast to concomitant oral intake of calcium, the effect of oral iron supplements on molidustat pharmacokinetics and pharmacodynamics should be considered, and the two agents should be administered with an appropriate time separation.

show abstract

“…4. Molidustat [157], developed by Bayer, has a preferential sensitivity for PHD2 [145]. In a report by Nishide et al, this inhibitor also diminished LLC tumor growth that was linked to enhanced blood vessel maturation and an increase in their functionality [146].…”

Section: Roxadustatmentioning

confidence: 99%

Hif-Prolyl Hydroxylase Domain Proteins (Phds) in Cancer – Potential Targets for Anti-Tumor Therapy?

Gaete¹,

Rodríguez²,

Watts³

et al. 2020

Preprint

View full text Add to dashboard Cite

Solid tumors are typically associated with unbridled proliferation of malignant cells, accompanied by an immature and dysfunctional tumor-associated vascular network. Consequent impairment in transport of nutrients and oxygen eventually leads to a hypoxic environment wherein cells must adapt to survive and overcome these stresses. Hypoxia inducible factors (HIFs) are central transcription factors in the hypoxia response and drive the expression of a vast number of survival genes in cancer cells and in cells in the tumor microenvironment. HIFs are tightly controlled by a class of oxygen sensors, the HIF-prolyl hydroxylase domain proteins (PHDs), which hydroxylate HIFs, thereby marking them for proteasomal degradation. Remarkable and intense research during the past decade has revealed that, contrary to expectations, PHDs are often overexpressed in many tumor types and that inhibition of PHDs can lead to decreased tumor growth, impaired metastasis and diminished tumor-associated immune-tolerance. Therefore, PHDs represent an attractive therapeutic target in cancer research. Multiple PHD inhibitors have been developed that have either been recently accepted in China as erythropoiesis stimulating agents (ESA) or are currently in phase III trials. We review here the function of HIFs and PHDs in cancer and related therapeutic opportunities.

show abstract

Discovery of Molidustat (BAY 85‐3934): A Small‐Molecule Oral HIF‐Prolyl Hydroxylase (HIF‐PH) Inhibitor for the Treatment of Renal Anemia

Cited by 58 publications

References 35 publications

Bidirectional modulation of HIF-2 activity through chemical ligands

Bidirectional modulation of HIF-2 activity through chemical ligands

Effects of oral iron and calcium supplement on the pharmacokinetics and pharmacodynamics of molidustat: an oral HIF–PH inhibitor for the treatment of renal anaemia

Hif-Prolyl Hydroxylase Domain Proteins (Phds) in Cancer – Potential Targets for Anti-Tumor Therapy?

Contact Info

Product

Resources

About