A prototype nonpeptidyl, hydrazone class, thrombopoietin receptor agonist, SB-559457, is toxic to primary human myeloid leukemia cells

Eltrombopag inhibits the proliferation of leukemia cells via reduction of intracellular iron and induction of differentiation

“…9,10 One study using a close chemical derivative of EP found a toxic effect on myeloid leukemia cells, suggesting that the entire substance class, including EP itself, may possess antileukemic activity. 11 Studies using cell lines further suggested that the growth-inhibitory effect of EP is not related to expression levels of TPO-R. 12 However, this hypothesis has not yet been formally tested, and the mechanism through which EP exerts its potential antileukemic effect is not known. The concentrations at which EP inhibits leukemia cell proliferation in vitro are clinically achievable with few side effects and have led to desirable increases in circulating platelet counts in healthy volunteers.…”

Discovery and Characterization of Nonpeptidyl Agonists of the Tissue-Protective Erythropoietin Receptor

“…The design of the initial library was facilitated by the structureactivity relationship (SAR) information available from small molecule (Qureshi et al, 1999;Goldberg et al, 2002) and allosteric peptide (Naranda et al, 1999(Naranda et al, , 2002 agonists of the EPO receptor, and allosteric small molecule agonists of the structurally related TPOR (Erickson-Miller et al, 2005;Desjardins et al, 2006;Dziewanowska et al, 2007;Kim et al, 2007;Kalota and Gewirtz, 2010;Abe et al, 2011) as well as structural data on the receptors (Livnah et al, 1996(Livnah et al, , 1999Carr et al, 2001). An initial hit was identified based on receptor interaction and EPO-like functional activity, and subsequent compound designs for developing an SAR for in vitro neuroprotection focused on 1,2,4-triazolo[1,5-a]pyrimidines.…”

“…All the small molecule TPOR agonists reported to date activate the receptor by binding to allosteric sites outside of the native ligand-binding site and proximal to residues near the plasma membrane (Desjardins et al, 2006;Dziewanowska et al, 2007;Kim et al, 2007;Erickson-Miller et al, 2009;Kalota and Gewirtz, 2010;Abe et al, 2011), suggesting that allosteric compounds may have more promise as therapeutic agents targeting the EPO receptor when compared with compounds binding at the orthosteric sites. The allosteric TPOR agonists described to date are also smaller than the previously described orthosteric EPOR agonists, supporting the potential to design compounds that cross the BBB.…”

“…Agonists of several cytokine receptors, including the receptors for granulocyte colony-stimulating factor (G-CSF) (Tian et al, 1998) and thrombopoietin (TPO) (Erickson-Miller et al, 2005;Desjardins et al, 2006;Dziewanowska et al, 2007;Kim et al, 2007;Kalota and Gewirtz, 2010;Abe et al, 2011) have been described, and the TPO receptor (TPOR) agonist eltrombopag is approved by the U.S. Food and Drug Administration for the treatment of thrombocytopenia (Kuter, 2013). The feasibility of discovering small molecule agonists of receptors for EPO was also supported by the small allosteric peptide agonists that activated the EPOR/EPOR homodimer and triggered EPO-like biologic activity (Naranda et al, 1999;Naranda et al, 2002).…”

Current treatment options for primary immune thrombocytopenia

“…In addition, TOP-RAs are expressed on nerve cells, with in vitro studies demonstrating that TPO inhibits NGF neuronal differentiation and ERK signaling [102]. On the other hand, TPO appears to have cardioprotective components [103] and anti-leukemic effects [104]. Meanwhile, several other peptides, nonpeptides and minibodies (small antibodies) have been designed to stimulate the production of platelets (Table 2).…”