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Dive into the research topics where Janeta Popovici-Muller is active.

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Featured researches published by Janeta Popovici-Muller.


Science | 2013

An Inhibitor of Mutant IDH1 Delays Growth and Promotes Differentiation of Glioma Cells

D. Rohle; Janeta Popovici-Muller; Nicolaos Palaskas; Sevin Turcan; Christian Grommes; Carl Campos; Jennifer Tsoi; Owen Clark; Barbara Oldrini; Evangelia Komisopoulou; Kaiko Kunii; Alicia Pedraza; Stefanie Schalm; Lee Silverman; Alexandra Miller; Fang Wang; Hua Yang; Yue Chen; Andrew Kernytsky; Marc K. Rosenblum; Wei Liu; Scott A. Biller; Shinsan M. Su; Cameron Brennan; Timothy A. Chan; Thomas G. Graeber; Katharine E. Yen; Ingo K. Mellinghoff

IDHology Among the most exciting drug targets to emerge from cancer genome sequencing projects are two related metabolic enzymes, isocitrate dehydrogenases 1 and 2 (IDH1, IDH2). Mutations in the IDH1 and IDH2 genes are common in certain types of human cancer. Whether inhibition of mutant IDH activity might offer therapeutic benefits is unclear (see the Perspective by Kim and DeBerardinis). F. Wang et al. (p. 622, published online 4 April) isolated a small molecule that selectively inhibits mutant IDH2, describe the structural details of its binding to the mutant enzyme, and show that this compound suppresses the growth of patient-derived leukemia cells harboring the IDH2 mutation. Rohle et al. (p. 626, published online 4 April) show that a small molecule inhibitor of IDH1 selectively slows the growth of patient-derived brain tumor cells with the IDH1 mutation. A small molecule that inhibits a mutant enzyme in tumors slows malignant growth by inducing cancer cell differentiation. [Also see Perspective by Kim and DeBerardinis] The recent discovery of mutations in metabolic enzymes has rekindled interest in harnessing the altered metabolism of cancer cells for cancer therapy. One potential drug target is isocitrate dehydrogenase 1 (IDH1), which is mutated in multiple human cancers. Here, we examine the role of mutant IDH1 in fully transformed cells with endogenous IDH1 mutations. A selective R132H-IDH1 inhibitor (AGI-5198) identified through a high-throughput screen blocked, in a dose-dependent manner, the ability of the mutant enzyme (mIDH1) to produce R-2-hydroxyglutarate (R-2HG). Under conditions of near-complete R-2HG inhibition, the mIDH1 inhibitor induced demethylation of histone H3K9me3 and expression of genes associated with gliogenic differentiation. Blockade of mIDH1 impaired the growth of IDH1-mutant—but not IDH1–wild-type—glioma cells without appreciable changes in genome-wide DNA methylation. These data suggest that mIDH1 may promote glioma growth through mechanisms beyond its well-characterized epigenetic effects.


Science | 2013

Targeted Inhibition of Mutant IDH2 in Leukemia Cells Induces Cellular Differentiation

Fang Wang; Jeremy Travins; Byron DeLaBarre; Virginie Penard-Lacronique; Stefanie Schalm; Erica Hansen; Kimberly Straley; Andrew Kernytsky; Wei Liu; Camelia Gliser; Hua Yang; Stefan Gross; Erin Artin; Véronique Saada; Elena Mylonas; Cyril Quivoron; Janeta Popovici-Muller; Jeffrey O. Saunders; Francesco G. Salituro; Shunqi Yan; Stuart Murray; Wentao Wei; Yi Gao; Lenny Dang; Marion Dorsch; Sam Agresta; David P. Schenkein; Scott A. Biller; Shinsan M. Su; Stéphane de Botton

IDHology Among the most exciting drug targets to emerge from cancer genome sequencing projects are two related metabolic enzymes, isocitrate dehydrogenases 1 and 2 (IDH1, IDH2). Mutations in the IDH1 and IDH2 genes are common in certain types of human cancer. Whether inhibition of mutant IDH activity might offer therapeutic benefits is unclear (see the Perspective by Kim and DeBerardinis). F. Wang et al. (p. 622, published online 4 April) isolated a small molecule that selectively inhibits mutant IDH2, describe the structural details of its binding to the mutant enzyme, and show that this compound suppresses the growth of patient-derived leukemia cells harboring the IDH2 mutation. Rohle et al. (p. 626, published online 4 April) show that a small molecule inhibitor of IDH1 selectively slows the growth of patient-derived brain tumor cells with the IDH1 mutation. A small molecule that inhibits a mutant enzyme in tumors slows malignant growth by inducing cancer cell differentiation. [Also see Perspective by Kim and DeBerardinis] A number of human cancers harbor somatic point mutations in the genes encoding isocitrate dehydrogenases 1 and 2 (IDH1 and IDH2). These mutations alter residues in the enzyme active sites and confer a gain-of-function in cancer cells, resulting in the accumulation and secretion of the oncometabolite (R)-2-hydroxyglutarate (2HG). We developed a small molecule, AGI-6780, that potently and selectively inhibits the tumor-associated mutant IDH2/R140Q. A crystal structure of AGI-6780 complexed with IDH2/R140Q revealed that the inhibitor binds in an allosteric manner at the dimer interface. The results of steady-state enzymology analysis were consistent with allostery and slow-tight binding by AGI-6780. Treatment with AGI-6780 induced differentiation of TF-1 erythroleukemia and primary human acute myelogenous leukemia cells in vitro. These data provide proof-of-concept that inhibitors targeting mutant IDH2/R140Q could have potential applications as a differentiation therapy for cancer.


Nature | 2014

Mutant IDH inhibits HNF-4α to block hepatocyte differentiation and promote biliary cancer

Supriya K. Saha; Christine A. Parachoniak; Krishna S. Ghanta; Julien Fitamant; Kenneth N. Ross; Mortada S. Najem; Sushma Gurumurthy; Esra A. Akbay; Daniela Sia; Helena Cornella; Oriana Miltiadous; Chad Walesky; Vikram Deshpande; Andrew X. Zhu; Katharine E. Yen; Kimberly Straley; Jeremy Travins; Janeta Popovici-Muller; Camelia Gliser; Cristina R. Ferrone; Udayan Apte; Josep M. Llovet; Kwok-Kin Wong; Sridhar Ramaswamy; Nabeel Bardeesy

Mutations in isocitrate dehydrogenase 1 (IDH1) and IDH2 are among the most common genetic alterations in intrahepatic cholangiocarcinoma (IHCC), a deadly liver cancer. Mutant IDH proteins in IHCC and other malignancies acquire an abnormal enzymatic activity allowing them to convert α-ketoglutarate (αKG) to 2-hydroxyglutarate (2HG), which inhibits the activity of multiple αKG-dependent dioxygenases, and results in alterations in cell differentiation, survival, and extracellular matrix maturation. However, the molecular pathways by which IDH mutations lead to tumour formation remain unclear. Here we show that mutant IDH blocks liver progenitor cells from undergoing hepatocyte differentiation through the production of 2HG and suppression of HNF-4α, a master regulator of hepatocyte identity and quiescence. Correspondingly, genetically engineered mouse models expressing mutant IDH in the adult liver show an aberrant response to hepatic injury, characterized by HNF-4α silencing, impaired hepatocyte differentiation, and markedly elevated levels of cell proliferation. Moreover, IDH and Kras mutations, genetic alterations that co-exist in a subset of human IHCCs, cooperate to drive the expansion of liver progenitor cells, development of premalignant biliary lesions, and progression to metastatic IHCC. These studies provide a functional link between IDH mutations, hepatic cell fate, and IHCC pathogenesis, and present a novel genetically engineered mouse model of IDH-driven malignancy.


ACS Medicinal Chemistry Letters | 2012

Discovery of the First Potent Inhibitors of Mutant IDH1 That Lower Tumor 2-HG in Vivo

Janeta Popovici-Muller; Jeffrey O. Saunders; Francesco G. Salituro; Jeremy Travins; Shunqi Yan; Fang Zhao; Stefan Gross; Lenny Dang; Katharine E. Yen; Hua Yang; Kimberly Straley; Shengfang Jin; Kaiko Kunii; Valeria Fantin; Shunan Zhang; Qiongqun Pan; Derek Shi; Scott A. Biller; Shinsan M. Su

Optimization of a series of R132H IDH1 inhibitors from a high throughput screen led to the first potent molecules that show robust tumor 2-HG inhibition in a xenograft model. Compound 35 shows good potency in the U87 R132H cell based assay and ∼90% tumor 2-HG inhibition in the corresponding mouse xenograft model following BID dosing. The magnitude and duration of tumor 2-HG inhibition correlates with free plasma concentration.


Journal of Biological Chemistry | 2014

Biochemical, Cellular and Biophysical Characterization of a Potent Inhibitor of Mutant Isocitrate Dehydrogenase IDH1

Mindy I. Davis; Stefan Gross; Min Shen; Kimberly Straley; Rajan Pragani; Wendy A. Lea; Janeta Popovici-Muller; Byron DeLaBarre; Erin Artin; Natasha Thorne; Douglas S. Auld; Zhuyin Li; Lenny Dang; Matthew B. Boxer; Anton Simeonov

Background: IDH1 R132H, implicated in glioblastoma and AML, produces the oncometabolite 2-HG. Results: A detailed binding mechanism of a small molecule inhibitor (ML309) is proposed. Conclusion: ML309 competes with α-KG but is uncompetitive with NADPH and rapidly and reversibly affects cellular 2-HG levels. Significance: Understanding IDH1 R132H inhibition sets the stage for targeting IDH1 R132H for the treatment of cancer. Two mutant forms (R132H and R132C) of isocitrate dehydrogenase 1 (IDH1) have been associated with a number of cancers including glioblastoma and acute myeloid leukemia. These mutations confer a neomorphic activity of 2-hydroxyglutarate (2-HG) production, and 2-HG has previously been implicated as an oncometabolite. Inhibitors of mutant IDH1 can potentially be used to treat these diseases. In this study, we investigated the mechanism of action of a newly discovered inhibitor, ML309, using biochemical, cellular, and biophysical approaches. Substrate binding and product inhibition studies helped to further elucidate the IDH1 R132H catalytic cycle. This rapidly equilibrating inhibitor is active in both biochemical and cellular assays. The (+) isomer is active (IC50 = 68 nm), whereas the (−) isomer is over 400-fold less active (IC50 = 29 μm) for IDH1 R132H inhibition. IDH1 R132C was similarly inhibited by (+)-ML309. WT IDH1 was largely unaffected by (+)-ML309 (IC50 >36 μm). Kinetic analyses combined with microscale thermophoresis and surface plasmon resonance indicate that this reversible inhibitor binds to IDH1 R132H competitively with respect to α-ketoglutarate and uncompetitively with respect to NADPH. A reaction scheme for IDH1 R132H inhibition by ML309 is proposed in which ML309 binds to IDH1 R132H after formation of the IDH1 R132H NADPH complex. ML309 was also able to inhibit 2-HG production in a glioblastoma cell line (IC50 = 250 nm) and had minimal cytotoxicity. In the presence of racemic ML309, 2-HG levels drop rapidly. This drop was sustained until 48 h, at which point the compound was washed out and 2-HG levels recovered.


ACS Medicinal Chemistry Letters | 2018

Discovery of AG-120 (Ivosidenib): A First-in-Class Mutant IDH1 Inhibitor for the Treatment of IDH1 Mutant Cancers

Janeta Popovici-Muller; Rene M. Lemieux; Erin Artin; Jeffrey O. Saunders; Francesco G. Salituro; Jeremy Travins; Giovanni Cianchetta; Zhenwei Cai; Ding Zhou; Dawei Cui; Ping Chen; Kimberly Straley; Erica Tobin; Fang Wang; Muriel D. David; Virginie Penard-Lacronique; Cyril Quivoron; Véronique Saada; Stéphane de Botton; Stefan Gross; Lenny Dang; Hua Yang; Luke Utley; Yue Chen; Hyeryun Kim; Shengfang Jin; Zhiwei Gu; Gui Yao; Zhiyong Luo; Xiaobing Lv

Somatic point mutations at a key arginine residue (R132) within the active site of the metabolic enzyme isocitrate dehydrogenase 1 (IDH1) confer a novel gain of function in cancer cells, resulting in the production of d-2-hydroxyglutarate (2-HG), an oncometabolite. Elevated 2-HG levels are implicated in epigenetic alterations and impaired cellular differentiation. IDH1 mutations have been described in an array of hematologic malignancies and solid tumors. Here, we report the discovery of AG-120 (ivosidenib), an inhibitor of the IDH1 mutant enzyme that exhibits profound 2-HG lowering in tumor models and the ability to effect differentiation of primary patient AML samples ex vivo. Preliminary data from phase 1 clinical trials enrolling patients with cancers harboring an IDH1 mutation indicate that AG-120 has an acceptable safety profile and clinical activity.


Blood | 2017

AG-348 enhances pyruvate kinase activity in red blood cells from patients with pyruvate kinase deficiency

Charles Kung; Jeff Hixon; Penelope Kosinski; Giovanni Cianchetta; Gavin Histen; Yue Chen; Collin Hill; Stefan Gross; Yaguang Si; Kendall Johnson; Byron DeLaBarre; Zhiyong Luo; Zhiwei Gu; Gui Yao; Huachun Tang; Cheng Fang; Yingxia Xu; Xiaobing Lv; Scott A. Biller; Shin-San Michael Su; Hua Yang; Janeta Popovici-Muller; Francesco G. Salituro; Lee Silverman; Lenny Dang

Pyruvate kinase (PK) deficiency is a rare genetic disease that causes chronic hemolytic anemia. There are currently no targeted therapies for PK deficiency. Here, we describe the identification and characterization of AG-348, an allosteric activator of PK that is currently in clinical trials for the treatment of PK deficiency. We demonstrate that AG-348 can increase the activity of wild-type and mutant PK enzymes in biochemical assays and in patient red blood cells treated ex vivo. These data illustrate the potential for AG-348 to restore the glycolytic pathway activity in patients with PK deficiency and ultimately lead to clinical benefit.


Nature | 2015

Corrigendum: Mutant IDH inhibits HNF-4α to block hepatocyte differentiation and promote biliary cancer

Supriya K. Saha; Christine A. Parachoniak; Krishna S. Ghanta; Julien Fitamant; Kenneth N. Ross; Mortada S. Najem; Sushma Gurumurthy; Esra A. Akbay; Daniela Sia; Helena Cornella; Oriana Miltiadous; Chad Walesky; Vikram Deshpande; Andrew X. Zhu; Katharine E. Yen; Kimberly Straley; Jeremy Travins; Janeta Popovici-Muller; Camelia Gliser; Cristina R. Ferrone; Udayan Apte; Josep M. Llovet; Kwok-Kin Wong; Sridhar Ramaswamy; Nabeel Bardeesy

This corrects the article DOI: 10.1038/nature13441


Cancer Research | 2014

Abstract 1194: IDH1 mutant inhibitor induces cellular differentiation and offers a combination benefit with Ara-C in a primary human Idh1 mutant AML xenograft model

Kate Ellwood-Yen; Yue Chen; Fang Wang; Rene M. Lemieux; Janeta Popovici-Muller; Hua Yang; Kimberly Straley; Sung Choe; Marion Dorsch; Sam Agresta; David P. Schenkein; Scott A. Biller; Michael Su

Proceedings: AACR Annual Meeting 2014; April 5-9, 2014; San Diego, CAnnSomatic point mutations in isocitrate dehydrogenase 1/2 have a gain-of-function neomorphic activity that converts alpha-ketoglutarate to the oncometabolite, R (-)-2-hydroxyglutarate (2HG). Prospective studies of AML patients carrying IDH mutations have shown that intracellular concentrations of 2HG can range from 3-10 mM. This abnormal level of 2HG results in dysregulation of alpha-ketoglutarate dependent enzymes leading to alterations in the epigenetic state of hematopoietic progenitor/stem cells and functionally blocks their ability to fully differentiate.nnWe have developed a potent and selective, orally available IDH1 mutant inhibitor AGI-14100, that is able to reduce intracellular 2HG concentrations to baseline levels found in wildtype cells.nnWe next treated a primary human IDH1 (R132H)/FLT3-ITD mutant xenograft model with AGI-14100 either alone or in combination with Ara-c. In these studies, AGI-14100 alone significantly decreased tumor burden in the peripheral blood after 1 month of continuous BID treatment. In combination with a short-term, low-dose course of Ara-C, we also observed a decrease in the bone marrow tumor burden that was better than either treatment alone. Furthermore, this response was sustainable for >3 weeks even after dosing of both drugs had been terminated. Taken together, these data suggest that inhibition of mutant IDH1with AGI-14100 and low dose Ara-c could provide a combination benefit for patients with AML.nnCitation Format: Kate Ellwood-Yen, Yue Chen, Fang Wang, Rene Lemieux, Janeta Popovici-Muller, Hua Yang, Kimberly Straley, Sung Choe, Marion Dorsch, Sam Agresta, David Schenkein, Scott Biller, Michael Su. IDH1 mutant inhibitor induces cellular differentiation and offers a combination benefit with Ara-C in a primary human Idh1 mutant AML xenograft model. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1194. doi:10.1158/1538-7445.AM2014-1194


Nature | 2015

Erratum: Corrigendum: Mutant IDH inhibits HNF-4α to block hepatocyte differentiation and promote biliary cancer

Supriya K. Saha; Christine A. Parachoniak; Krishna S. Ghanta; Julien Fitamant; Kenneth N. Ross; Mortada S. Najem; Sushma Gurumurthy; Esra A. Akbay; Daniela Sia; Helena Cornella; Oriana Miltiadous; Chad Walesky; Vikram Deshpande; Andrew X. Zhu; Katharine E. Yen; Kimberly Straley; Jeremy Travins; Janeta Popovici-Muller; Camelia Gliser; Cristina R. Ferrone; Udayan Apte; Josep M. Llovet; Kwok-Kin Wong; Sridhar Ramaswamy; Nabeel Bardeesy

This corrects the article DOI: 10.1038/nature13441

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Anton Simeonov

National Institutes of Health

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Matthew B. Boxer

National Institutes of Health

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Min Shen

National Institutes of Health

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Mindy I. Davis

National Institutes of Health

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