Identification of a Pharmacophore for Thrombopoietic Activity of Small, Non-Peptidyl Molecules. 2. Rational Design of Naphtho[1,2-<i>d</i>]imidazole Thrombopoietin Mimics

Duffy, Kevin J.; Price, Alan T.; Delorme, Evelyne; Dillon, Susan B.; Duquenne, Céline; Erickson‐Miller, Connie L.; Giampa, Leslie; Huang, Yaoxin; Keenan, Richard M.; Lamb, Peter; Liu, Nannan; Miller, Stephen G.; Rosen, Jon; Shaw, Anthony N.; Smith, Heather; Wiggall, Kenneth J.; Zhang, Lihua; Luengo, Juan I.

doi:10.1021/jm0255365

Cited by 55 publications

(30 citation statements)

References 4 publications

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“…33,34 The structure of EP has these 3 elements and supports the ability of EP to reduce intracellular iron and potentially other polyvalent cations. 35,36 Given that EP has a chelator backbone that is not iron specific, it is likely that EP chelates other polyvalent cations such as zinc and copper.…”

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confidence: 73%

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

Roth

Will

Simkin

et al. 2012

Blood

146

123

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Eltrombopag (EP) is a small-molecule, nonpeptide thrombopoietin receptor (TPO-R) agonist that has been approved recently for the treatment of thrombocytopenia in patients with chronic immune thrombocytopenic purpura. Prior studies have shown that EP stimulates megakaryopoiesis in BM cells from patients with acute myeloid leukemia and myelodysplastic syndrome, and the results also suggested that it may inhibit leukemia cell growth. In the present study, we studied the effects of EP on leukemia cell proliferation and the mechanism of its antiproliferative effects. We found that EP leads to a decreased cell division rate, a block in G 1 phase of cell cycle, and increased differentiation in human and murine leukemia cells. Because EP is species specific in that it can only bind TPO-R in human and primate cells, these findings further suggested that the antileukemic effect is independent of TPO-R. We found that treatment with EP leads to a reduction in free intracellular iron in leukemic cells in a dose-dependent manner. Experimental increase of intracellular iron abrogated the antiproliferative and differentiation-inducing effects of EP, demonstrating that its antileukemic effects are mediated through modulation of intracellular iron content. Finally, determination of EP's antileukemic activity in vivo demonstrated its ability to prolong survival in 2 mouse models of leukemia. (Blood. 2012;120(2):386-394) IntroductionSurvival in acute myeloid leukemia (AML) and high-risk myelodysplastic syndrome (MDS) has remained poor despite recent efforts to treat patients with novel therapeutic regimens. [1][2][3][4] In addition, complications secondary to thrombocytopenia and bleeding occur frequently in AML and MDS, leading to significant morbidity and mortality. 5,6 Given that the median age of patients with AML is close to 70 years, novel antileukemia agents with limited BM toxicity are needed to improve outcomes.Eltrombopag (EP) is an oral, nonpeptide, small-molecule thrombopoietin receptor (TPO-R) agonist that has proven efficacy in treating chronic immune thrombocytopenic purpura (ITP) and hepatitis C-related thrombocytopenia. 7,8 Despite concerns that some leukemia blast cells express TPO-R, we and others have reported previously that EP does not stimulate leukemia or MDS cell growth, but may rather lead to a modest inhibition while continuing to stimulate normal megakaryopoiesis in BM samples of patients with AML or MDS. 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 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 hav...

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mentioning

confidence: 73%

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

Roth

Will

Simkin

et al. 2012

Blood

146

123

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“…However, unlike rhTPO, NIP-004 displays species specificity. Recently, nonpeptidyl small molecule compounds such as benzodiazepine derivatives, 22 hydrazinonaphthalenes and azonaphthalenes, 23,24 and substituted thiazole 25 and xanthocillins 26 have been reported as possessing TPO-like activity. In some cases, c-Mpl agonists such as SB394725 exhibit species specificity.…”

Section: Discussionmentioning

confidence: 99%

A novel nonpeptidyl human c-Mpl activator stimulates human megakaryopoiesis and thrombopoiesis

Nakamura

Miyakawa

Miyamura

et al. 2006

Blood

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“…A number of hydrazinonaphthalene derivatives [74][75][76][77] were initially identified and these lead compounds were modified to enhance their pharmacologic and biologic properties [78,79]. One molecule which evolved from this process was eltrombopag (SB-497115, Promacta, Revolade).…”

Section: Eltrombopagmentioning

confidence: 99%

The biology of thrombopoietin and thrombopoietin receptor agonists

2013

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Thrombopoietin (TPO) is the major physiological regulator of platelet production. TPO binds the TPO receptor, activates JAK and STAT pathways, thus stimulating megakaryocyte growth and platelet production. There is no ''sensor'' of the platelet count; rather TPO is produced in the liver at a constant rate and cleared by TPO receptors on platelets. TPO levels are inversely proportional to the rate of platelet production. Early recombinant TPO molecules were potent stimulators of platelet production and increased platelets in patients with immune thrombocytopenia, chemotherapy-induced thrombocytopenia, myelodysplastic syndromes and platelet apheresis donors. Neutralizing antibodies formed against one recombinant protein and ended their development. A second generation of TPO receptor agonists, romiplostim and eltrombopag, has been developed. Romiplostim is an IgG heavy chain into which four TPO agonist peptides have been inserted. Eltrombopag is an oral small molecule. These activate the TPO receptor by different mechanisms to increase megakaryocyte growth and platelet production. After administration of either to healthy volunteers, there is a delay of 5 days before the platelet count rises and subsequently reaches a peak after 12-14 days. Both have been highly effective in treating ITP and hepatitis C thrombocytopenia. Studies in a wide variety of other thrombocytopenic conditions are underway.

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Identification of a Pharmacophore for Thrombopoietic Activity of Small, Non-Peptidyl Molecules. 2. Rational Design of Naphtho[1,2-d]imidazole Thrombopoietin Mimics

Cited by 55 publications

References 4 publications

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

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

A novel nonpeptidyl human c-Mpl activator stimulates human megakaryopoiesis and thrombopoiesis

The biology of thrombopoietin and thrombopoietin receptor agonists

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