New IDH1 mutant inhibitors for treatment of acute myeloid leukemia

Okoye-Okafor, Ujunwa Cynthia; Bartholdy, Boris; Cartier, Jessy; Gao, Enoch; Pietrak, Beth; Rendina, Alan R.; Rominger, Cynthia M.; Quinn, Chad; Smallwood, Angela; Wiggall, Kenneth J.; Reif, Alexander; Schmidt, Stanley J.; Qi, Hongwei; Zhao, Huizhen; Joberty, Gérard; Faelth-Savitski, Maria; Bantscheff, Marcus; Drewes, Gerard; Duraiswami, Chaya; Brady, Pat; Groy, Arthur; Narayanagari, Swathi Rao; Antony-Debré, Iléana; Mitchell, Kelly; Wang, Heng Rui; Kao, Yun Ruei; Christopeit, Maximilian; Carvajal, Luis A.; Barreyro, Laura; Paietta, Elisabeth; Makishima, Hideki; Will, Britta; Concha, N.O.; Adams, Nicholas D.; Schwartz, Benjamin J.; McCabe, Michael T.; Maciejewski, Jaroslaw P.; Verma, Amit; Steidl, Ulrich

doi:10.1038/nchembio.1930

Cited by 156 publications

(229 citation statements)

References 59 publications

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“…AGI-6780, a selective sulfonamide inhibitor of the mutant IDH2 enzyme, lowered 2HG levels and induced differentiation of TF-1 erythroleukemia cells and primary human AML cells harboring the IDH2 R140Q mutation (17), providing in vitro evidence that inhibition of the mutant IDH2 enzyme can reverse some of the phenotypic changes it induces. Others have reported similar findings with mutant IDH1 inhibitor tool compounds in AML models (22).…”

Section: Introductionsupporting

confidence: 68%

AG-221, a First-in-Class Therapy Targeting Acute Myeloid Leukemia Harboring Oncogenic IDH2 Mutations

et al. 2017

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Somatic gain-of-function mutations in isocitrate dehydrogenases (IDH) 1 and 2 are found in multiple hematologic and solid tumors, leading to accumulation of the oncometabolite (R)-2-hydroxyglutarate (2HG). 2HG competitively inhibits α-ketoglutarate-dependent dioxygenases, including histone demethylases and methylcytosine dioxygenases of the TET family, causing epigenetic dysregulation and a block in cellular differentiation. In vitro studies have provided proof of concept for mutant IDH inhibition as a therapeutic approach. We report the discovery and characterization of AG-221, an orally available, selective, potent inhibitor of the mutant IDH2 enzyme. AG-221 suppressed 2HG production and induced cellular differentiation in primary human IDH2 mutation-positive acute myeloid leukemia (AML) cells ex vivo and in xenograft mouse models. AG-221 also provided a statistically significant survival benefit in an aggressive IDH2 R140Q -mutant AML xenograft mouse model. These findings supported initiation of the ongoing clinical trials of AG-221 in patients with IDH2 mutation-positive advanced hematologic malignancies. SIGNIFICANCE:Mutations in IDH1/2 are identified in approximately 20% of patients with AML and contribute to leukemia via a block in hematopoietic cell differentiation. We have shown that the targeted inhibitor AG-221 suppresses the mutant IDH2 enzyme in multiple preclinical models and induces differentiation of malignant blasts, supporting its clinical development. Cancer Discov; 7(5); 478-93.

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Section: Introductionsupporting

confidence: 68%

AG-221, a First-in-Class Therapy Targeting Acute Myeloid Leukemia Harboring Oncogenic IDH2 Mutations

et al. 2017

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“…Aromatic or hydrophilic residues are poorly tolerated. The urea linkage is essential, as replacement with an amide in either orientation (13, 36) reduces activity, as does N-methylation (16). These data suggest the urea may be a site for specific interaction of the compounds with mutant IDH1.…”

Section: Acs Medicinal Chemistry Lettersmentioning

confidence: 93%

Discovery of 8-Membered Ring Sulfonamides as Inhibitors of Oncogenic Mutant Isocitrate Dehydrogenase 1

Law

Stark

Liu

et al. 2016

ACS Med. Chem. Lett.

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Evidence suggests that specific mutations of isocitrate dehydrogenases 1 and 2 (IDH1/2) are critical for the initiation and maintenance of certain tumor types and that inhibiting these mutant enzymes with small molecules may be therapeutically beneficial. In order to discover mutant alleleselective IDH1 inhibitors with chemical features distinct from existing probes, we screened a collection of small molecules derived from diversity-oriented synthesis. The assay identified compounds that inhibit the IDH1-R132H mutant allele commonly found in glioma. Here, we report the discovery of a potent (IC 50 = 50 nM) series of IDH1-R132H inhibitors having 8-membered ring sulfonamides as exemplified by the compound BRD2879. The inhibitors suppress (R)-2-hydroxyglutarate production in cells without apparent toxicity. Although the solubility and pharmacokinetic properties of the specific inhibitor BRD2879 prevent its use in vivo, the scaffold presents a validated starting point for the synthesis of future IDH1-R132H inhibitors having improved pharmacological properties. KEYWORDS: BRD2879, isocitrate dehydrogenase, 2-hydroxyglutarate, glioma, AML, cancer, diversity-oriented synthesis, high-throughput screening, allele-selective probe, small-molecule probe S ystematic efforts to characterize the genomes of patient tumors are revealing the genomic alterations that cause and maintain different cancers. Somatic mutations in the genes encoding the isocitrate dehydrogenases IDH1 and IDH2 have been found in >70% of grade II−III gliomas and secondary glioblastomas, 1,2 ∼17% of acute myeloid leukemias (AML), 3,4 ∼56% of central and periosteal chondrosarcoma, 5 and sporadically in other tumor types. Mutations are nearly always heterozygous and occur frequently at codons IDH1-R132, IDH2-R172, or IDH2-R140. IDH enzymes normally catalyze the interconversion of isocitrate and α-ketoglutarate (α-KG), but these mutations unmask an otherwise cryptic NADPH-dependent ketoreductase activity, allowing the enzyme to reduce α-KG to (R)-2-hydroxyglutarate (R-2HG). 3,6 As a result, R-2HG levels are elevated >50-fold in samples from patients with IDH mutations. 3 The pathogenesis of IDH mutant tumors is thought to center on the ability of R-2HG to act as an "oncometabolite". Due to its structural similarity to α-KG, R-2HG competitively inhibits several α-KG-dependent dioxygenases when present at the high concentrations observed in IDH mutant tumors. In particular, R-2HG impairs DNA demethylation through inhibition of TET2, 7 impairs histone demethylation through inhibition of various lysine demethylases, 8,9 and modulates hypoxic stress response through activation of EGLN1. 10 These molecular changes are thought to cause the enhanced proliferation and impaired differentiation observed in IDH mutant tumors. The mutual exclusivity of IDH and TET2 mutations in AML tumors 7 and the ability of exogenous R-2HG to induce leukemogenesis in blood cells 11 further implicate R-2HG as a critical mediator in how mutant IDH contributes to AML. In IDH1 muta...

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“…Tetrahydropyrazolopyridines were discovered as novel allosteric inhibitors of mutant isocitrate dehydrogenase 1 (IDH1) and were shown to affect proliferation of primary IDH1 mutant acute myeloid leukemia cells (60). Virtual screening identified compounds bearing a tetrahydropyrazolopyridines ring as potential novel antagonist for activin, a TGF-b protein (61), and for the G-protein-coupled NK3 receptor (62).…”

mentioning

confidence: 99%

Inhibitors of pendrin anion exchange identified in a small molecule screen increase airway surface liquid volume in cystic fibrosis

Haggie

Phuan²,

Tan³

et al. 2016

FASEB j.

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Pendrin (SLC26A4) is a Cl 2 /anion exchanger expressed in the epithelium of inflamed airways where it is thought to facilitate Cl 2 absorption and HCO 3 2 secretion. Studies using pendrin knockout mice and airway epithelial cells from hearing-impaired subjects with pendrin loss of function suggest involvement of pendrin in inflammatory lung diseases, including cystic fibrosis (CF), perhaps by regulation of airway surface liquid (ASL) volume. Here we identified small-molecule pendrin inhibitors and demonstrated their efficacy in increasing ASL volume. A cell-based, functional high-throughput screen of ∼36,000 synthetic small molecules produced 3 chemical classes of inhibitors of human pendrin. After structure-activity studies, tetrahydropyrazolopyridine and pyrazolothiophenesulfonamide compounds reversibly inhibited pendrin-facilitated Cl 2 exchange with SCN 2 , I 2 , NO 3 2 , and HCO 3 2 with drug concentration causing 50% inhibition down to ∼2.5 mM. In well-differentiated primary cultures of human airway epithelial cells from non-CF and CF subjects, treatment with IL-13, which causes inflammation with strong pendrin up-regulation, strongly increased Cl 2 /HCO 3 2 exchange and the increase was blocked by pendrin inhibition. Pendrin inhibition significantly increased ASL depth (by ∼8 mm) in IL-13-treated non-CF and CF cells but not in untreated cells. These studies implicate the involvement of pendrin-facilitated Cl 2 / HCO 3 2 in the regulation of ASL volume and suggest the utility of pendrin inhibitors in inflammatory lung diseases, including CF

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New IDH1 mutant inhibitors for treatment of acute myeloid leukemia

Cited by 156 publications

References 59 publications

AG-221, a First-in-Class Therapy Targeting Acute Myeloid Leukemia Harboring Oncogenic IDH2 Mutations

AG-221, a First-in-Class Therapy Targeting Acute Myeloid Leukemia Harboring Oncogenic IDH2 Mutations

Discovery of 8-Membered Ring Sulfonamides as Inhibitors of Oncogenic Mutant Isocitrate Dehydrogenase 1

Inhibitors of pendrin anion exchange identified in a small molecule screen increase airway surface liquid volume in cystic fibrosis

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