scholarly journals Potential Mitochondrial Isocitrate Dehydrogenase R140Q Mutant Inhibitor from Traditional Chinese Medicine against Cancers

2014 ◽  
Vol 2014 ◽  
pp. 1-10 ◽  
Author(s):  
Wen-Yuan Lee ◽  
Kuan-Chung Chen ◽  
Hsin-Yi Chen ◽  
Calvin Yu-Chian Chen
Keyword(s):  
Isocitrate Dehydrogenase ◽  
Point Mutations ◽  
Docking Simulation ◽  
Myelogenous Leukemia ◽  
Mutant Protein ◽  
Binding Affinities ◽  
Isocitrate Dehydrogenase 1 ◽  
Lead Compounds ◽  
Arginine Residues ◽  
Acute Myelogenous

A recent research of cancer has indicated that the mutant of isocitrate dehydrogenase 1 and 2 (IDH1and2) genes will induce various cancers, including chondrosarcoma, cholangiocarcinomas, and acute myelogenous leukemia due to the effect of point mutations in the active-site arginine residues of isocitrate dehydrogenase (IDH), such as IDH1/R132, IDH2/R140, and IDH2/R172. As the inhibition for those tumor-associated mutant IDH proteins may induce differentiation of those cancer cells, these tumor-associated mutant IDH proteins can be treated as a drug target proteins for a differentiation therapy against cancers. In this study, we aim to identify the potent TCM compounds from the TCM Database@Taiwan as lead compounds of IDH2 R140Q mutant inhibitor. Comparing to the IDH2 R140Q mutant protein inhibitor, AGI-6780, the top two TCM compounds, precatorine and abrine, have higher binding affinities with target protein in docking simulation. After MD simulation, the top two TCM compounds remain as the same docking poses under dynamic conditions. In addition, precatorine is extracted fromAbrus precatoriusL., which represents the cytotoxic and proapoptotic effects for breast cancer and several tumor lines. Hence, we propose the TCM compounds, precatorine and abrine, as potential candidates as lead compounds for further study in drug development process with the IDH2 R140Q mutant protein against cancer.

scholarly journals Cancer-associated metabolite 2-hydroxyglutarate accumulates in acute myelogenous leukemia with isocitrate dehydrogenase 1 and 2 mutations

2010 ◽  
Vol 207 (2) ◽  
pp. 339-344 ◽  
Author(s):  
Stefan Gross ◽  
Rob A. Cairns ◽  
Mark D. Minden ◽  
Edward M. Driggers ◽  
Mark A. Bittinger ◽  
...  
Keyword(s):  
Isocitrate Dehydrogenase ◽  
Acute Myelogenous Leukemia ◽  
Nicotinamide Adenine Dinucleotide Phosphate ◽  
Myelogenous Leukemia ◽  
Oxidative Decarboxylation ◽  
Gain Of Function ◽  
Isocitrate Dehydrogenase 1 ◽  
Acute Myelogenous ◽  
Idh1 Mutations ◽  
Mutant Idh1

Mutations in isocitrate dehydrogenase 1 and 2 (IDH1/2), are present in most gliomas and secondary glioblastomas, but are rare in other neoplasms. IDH1/2 mutations are heterozygous, and affect a single arginine residue. Recently, IDH1 mutations were identified in 8% of acute myelogenous leukemia (AML) patients. A glioma study revealed that IDH1 mutations cause a gain-of-function, resulting in the production and accumulation of 2-hydroxyglutarate (2-HG). Genotyping of 145 AML biopsies identified 11 IDH1 R132 mutant samples. Liquid chromatography-mass spectrometry metabolite screening revealed increased 2-HG levels in IDH1 R132 mutant cells and sera, and uncovered two IDH2 R172K mutations. IDH1/2 mutations were associated with normal karyotypes. Recombinant IDH1 R132C and IDH2 R172K proteins catalyze the novel nicotinamide adenine dinucleotide phosphate (NADPH)–dependent reduction of α-ketoglutarate (α-KG) to 2-HG. The IDH1 R132C mutation commonly found in AML reduces the affinity for isocitrate, and increases the affinity for NADPH and α-KG. This prevents the oxidative decarboxylation of isocitrate to α-KG, and facilitates the conversion of α-KG to 2-HG. IDH1/2 mutations confer an enzymatic gain of function that dramatically increases 2-HG in AML. This provides an explanation for the heterozygous acquisition of these mutations during tumorigenesis. 2-HG is a tractable metabolic biomarker of mutant IDH1/2 enzyme activity.

Detection of High Incidence of H-RAS Oncogene Point Mutations in Acute Myelogenous Leukemia

1993 ◽  
Vol 43 (2) ◽  
pp. 151-153 ◽  
Author(s):  
Nobutaka Imamura ◽  
Atsushi Kuramoto ◽  
Hideki Ishihara ◽  
Shoichi Shimizu
Keyword(s):  
Acute Myelogenous Leukemia ◽  
Point Mutations ◽  
Myelogenous Leukemia ◽  
Ras Oncogene ◽  
High Incidence ◽  
Acute Myelogenous

scholarly journals In SilicoInvestigation of Potential Pyruvate Kinase M2 Regulators from Traditional Chinese Medicine against Cancers

2014 ◽  
Vol 2014 ◽  
pp. 1-14 ◽  
Author(s):  
Kuan-Chung Chen ◽  
Kuen-Bao Chen ◽  
Hsin-Yi Chen ◽  
Calvin Yu-Chian Chen
Keyword(s):  
Virtual Screening ◽  
Drug Development ◽  
Pyruvate Kinase ◽  
Md Simulation ◽  
Docking Simulation ◽  
Target Protein ◽  
Binding Affinities ◽  
Pyruvate Kinase M2 ◽  
Lead Compounds ◽  
The Stability

A recent research in cancer research demonstrates that tumor-specific pyruvate kinase M2 (PKM2) plays an important role in chromosome segregation and mitosis progression of tumor cells. To improve the drug development of TCM compounds, we aim to identify potent TCM compounds as lead compounds of PKM2 regulators. PONDR-Fit protocol was utilized to predict the disordered disposition in the binding domain of PKM2 protein before virtual screening as the disordered structure in the protein may cause the side effect and downregulation of the possibility of ligand to bind with target protein. MD simulation was performed to validate the stability of interactions between PKM2 proteins and each ligand after virtual screening. The top TCM compounds, saussureamine C and precatorine, extracted fromLycium chinenseMill. andAbrus precatoriusL., respectively, have higher binding affinities with target protein in docking simulation than control. They have stable H-bonds with residues A:Lys311 and some other residues in both chains of PKM2 protein. Hence, we propose the TCM compounds, saussureamine C and precatorine, as potential candidates as lead compounds for further study in drug development process with the PKM2 protein against cancer.

scholarly journals Mutation of the p53 gene in human acute myelogenous leukemia

Blood ◽  
1991 ◽  
Vol 77 (7) ◽  
pp. 1500-1507 ◽  
Author(s):  
JM Slingerland ◽  
MD Minden ◽  
S Benchimol
Keyword(s):  
Acute Myelogenous Leukemia ◽  
P53 Protein ◽  
Point Mutations ◽  
P53 Gene ◽  
Myelogenous Leukemia ◽  
Wild Type ◽  
P53 Expression ◽  
Coding Sequence ◽  
Acute Myelogenous ◽  
Blast Cells

Abstract Heterogeneity of p53 protein expression is seen in blast cells of patients with acute myelogenous leukemia (AML). p53 protein is detected in the blasts of certain AML patients but not in others. We have identified p53 protein variants with abnormal mobility on gel electrophoresis and/or prolonged half-life (t 1/2). We have sequenced the p53 coding sequence from primary blast cells of five AML patients and from the AML cell line (OCIM2). In OCIM2, a point mutation in codon 274 was identified that changes a valine residue to aspartic acid. A wild type p53 allele was not detected in these cells. Two point mutations (codon 135, cysteine to serine; codon 246, methionine to valine) were identified in cDNA from blasts of one AML patient. Both mutations were present in blast colonies grown from single blast progenitor cells, indicating that individual leukemia cells had sustained mutation of both p53 alleles. The cDNAs sequenced from blast samples of four other patients, including one with prolonged p53 protein t 1/2 and one with no detectable p53 protein, were fully wild type. Thus, the heterogeneity of p53 expression cannot be explained in all cases by genetic change in the p53 coding sequence. The prolonged t 1/2 of p53 protein seen in some AML blasts may therefore reflect changes not inherent to p53. A model is proposed in which mutational inactivation of p53, although not required for the evolution of neoplasia, would confer a selective advantage, favoring clonal outgrowth during disease progression.

scholarly journals An acidic residue buried in the dimer interface of isocitrate dehydrogenase 1 (IDH1) helps regulate catalysis and pH sensitivity

2020 ◽  
Author(s):  
Lucas A. Luna ◽  
Zachary Lesecq ◽  
Katharine A. White ◽  
An Hoang ◽  
David A. Scott ◽  
...  
Keyword(s):  
Conformational Changes ◽  
Isocitrate Dehydrogenase ◽  
Point Mutations ◽  
Catalytic Efficiency ◽  
Ph Sensitivity ◽  
Isocitrate Dehydrogenase 1 ◽  
Dimer Interface ◽  
Molecular Determinants ◽  
Show Evidence ◽  
Ionizable Residues

ABSTRACTIsocitrate dehydrogenase 1 (IDH1) catalyzes the reversible NADP+-dependent conversion of isocitrate to α-ketoglutarate (α-KG) to provide critical cytosolic substrates and drive NADPH-dependent reactions like lipid biosynthesis and glutathione regeneration. In biochemical studies, the forward reaction is studied at neutral pH, while the reverse reaction is typically characterized in more acidic buffers. This led us to question whether IDH1 catalysis is pH-regulated, which would have functional implications under conditions that alter cellular pH, like apoptosis, hypoxia, cancer, and neurodegenerative diseases. Here, we show evidence of catalytic regulation of IDH1 by pH, identifying a trend of increasing kcat values for α-KG production upon increasing pH in the buffers we tested. To understand the molecular determinants of IDH1 pH sensitivity, we used the pHinder algorithm to identify buried ionizable residues predicted to have shifted pKa values. Such residues can serve as pH sensors, with changes in protonation states leading to conformational changes that regulate catalysis. We identified an acidic residue buried at the IDH1 dimer interface, D273, with a predicted pKa value upshifted into the physiological range. D273 point mutations had decreased catalytic efficiency and, importantly, loss of pH-regulated catalysis. Based on these findings, we conclude that IDH1 activity is regulated, at least in part, by pH. We show this regulation is mediated by at least one buried acidic residue ∼12 Å from the IDH1 active site. By establishing mechanisms of regulation of this well-conserved enzyme, we highlight catalytic features that may be susceptible to pH changes caused by cell stress and disease.

scholarly journals Structural Biology of Mutant IDH2 Inhibition

2014 ◽  
Vol 70 (a1) ◽  
pp. C799-C799
Author(s):  
Byron DeLaBarre ◽  
Fang Wang ◽  
Jeremy Travins ◽  
Stefan Gross ◽  
Erin Artin ◽  
...  
Keyword(s):  
Active Sites ◽  
Tight Binding ◽  
Point Mutations ◽  
Myelogenous Leukemia ◽  
Cancer Therapies ◽  
Idh Mutations ◽  
Genes Encoding ◽  
Potential Applications ◽  
Acute Myelogenous

A number of human cancers harbor somatic point mutations in the genes encoding isocitrate dehydrogenases- 1 and -2 (IDH1, IDH2)[1]. 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). 2HG is a potent inhibitor of DNA methylating enzymes such as TET2[2]. This suggests a connection between cancer related IDH mutations and aberrant epigenetics. As such, IDH represents an important new druggable target in the pursuit of novel cancer therapies. We have 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[3]. While structures of IDH1 and IDH2 were known, this is the first ever structure of an inhibited IDH protein and shows a novel conformation of IDH2. 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 (AML) 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.

Analysis of FLT3-activating mutations in 979 patients with acute myelogenous leukemia: association with FAB subtypes and identification of subgroups with poor prognosis

Blood ◽  
2002 ◽  
Vol 99 (12) ◽  
pp. 4326-4335 ◽  
Author(s):  
Christian Thiede ◽  
Christine Steudel ◽  
Brigitte Mohr ◽  
Markus Schaich ◽  
Ulrike Schäkel ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Acute Myelogenous Leukemia ◽  
Point Mutations ◽  
Disease Free Survival ◽  
Myelogenous Leukemia ◽  
Tyrosine Kinase Domain ◽  
Prognostic Impact ◽  
Constitutive Activation ◽  
Juxtamembrane Region ◽  
Acute Myelogenous

Constitutive activation of the FLT3 receptor tyrosine kinase, either by internal tandem duplication (ITD) of the juxtamembrane region or by point mutations in the second tyrosine kinase domain (TKD), has been described in patients with acute myelogenous leukemia (AML). We analyzed the prevalence and the potential prognostic impact of FLT3 mutations in 979 AML patients. Results were correlated with cytogenetic data and the clinical response. FLT3-ITD mutations were found in 20.4% and FLT3-TKD mutations in 7.7% of the patients. Each mutation was associated with similar clinical characteristics and was more prevalent in patients with normal karyotype. Significantly more FLT3 aberrations were found in patients with FAB M5, and fewer were found in patients with FAB M2 and M6. Although less frequent in patients with cytogenetic aberrations, FLT3-ITDs were found in 13 of 42 patients with t(15;17) and in 9 of 10 patients with t(6;9). The prevalence of the ITD allele on the DNA level was heterogeneous, ranging from faint mutant bands in some patients to predominant mutant bands in others. Based on quantitative analysis, the mutant–wild-type (wt) ratio ranged from 0.03 to 32.56 (median, 0.78). Patients with a high mutant/wt ratio (ie, greater than 0.78) had significantly shorter overall and disease-free survival, whereas survival in patients with ratios below 0.78 did not differ from those without FLT3 aberrations. Multivariate analysis confirmed a high mutant/wt ratio to be a strong independent prognostic factor. Taken together, these data confirm that FLT mutations represent a common alteration in adult AML. Constitutive activation may be associated with monocytoid differentiation. A high mutant/wt ratio in ITD-positive patients appears to have a major impact on the prognostic relevance.

scholarly journals Rare occurrence of N-ras point mutations in Philadelphia chromosome positive chronic myeloid leukemia

Blood ◽  
1989 ◽  
Vol 73 (4) ◽  
pp. 1028-1032 ◽  
Author(s):  
SJ Collins ◽  
M Howard ◽  
DF Andrews ◽  
E Agura ◽  
J Radich
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Blast Crisis ◽  
Philadelphia Chromosome ◽  
Point Mutations ◽  
Myelogenous Leukemia ◽  
Nucleotide Sequencing ◽  
Ras Oncogene ◽  
Acute Myelogenous

Point mutations of the N-ras oncogene are relatively common in acute myelogenous leukemia (AML) cells, occurring in some 25% to 50% of patient samples. We used a technique involving the direct nucleotide sequencing of in vitro amplified N-ras genomic fragments to determine the frequency of N-ras point mutations in chronic myeloid leukemia (CML) cells at various stages of the disease. This approach will detect N-ras point mutations in a mixed population of cells if the mutation is present in 25% or more of the cells. We could not demonstrate any point mutation at N-ras codons 12,13 or 59–63 in any of the 44 CML cases analyzed, which included 21 blast crisis samples. In contrast with AML N-ras point mutations are exceedingly rare in CML.

N-ras mutations in adult de novo acute myelogenous leukemia: prevalence and clinical significance

Blood ◽  
1990 ◽  
Vol 76 (4) ◽  
pp. 801-807 ◽  
Author(s):  
JP Radich ◽  
KJ Kopecky ◽  
CL Willman ◽  
J Weick ◽  
D Head ◽  
...  
Keyword(s):  
Clinical Significance ◽  
Acute Myelogenous Leukemia ◽  
De Novo ◽  
Point Mutations ◽  
Myelogenous Leukemia ◽  
Ras Mutation ◽  
Ras Mutations ◽  
Acute Myelogenous ◽  
Polymerase Chain ◽  
De Novo Aml

Point mutations of the N-ras proto-oncogenes have been previously detected in 20% to 60% of samples of acute myelogenous leukemia (AML), but the clinical significance of these mutations is presently unclear. We directly sequenced polymerase chain reaction (PCR) amplified N-ras fragments to determine the frequency of N-ras point mutations in 55 adult patients with de novo AML. Mutations were present in 8 of 55 (15%) patients. These mutations were usually in codon 12, 13, or 61, but one patient had mutations in both codons 13 and 61, and another had an unusual point mutation in N-ras codon 60. A comparison of patients with and without N-ras mutations showed no statistically significant differences in pretreatment clinical variables, response to induction therapy, or survival, except for a possibly higher percentage of FAB M4 subtypes in patients with the N-ras mutation. These data together with previous reports suggest that the presence of N-ras point mutations do not clearly define a unique clinical or biologic subset of AML patients.

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