The novel Isatin analog KS99 targets stemness markers in acute myeloid leukemia

Annageldiyev, Charyguly; Gowda, Raghavendra; Patel, Trupti; Bhattacharya, Priyanjali; Tan, Su‐Fern; Iyer, Soumya; Desai, Dhimant; Dovat, Sinisa; Feith, David J.; Amin, Shantu; Claxton, David F.; Sharma, Arti

doi:10.3324/haematol.2018.212886

Cited by 16 publications

(17 citation statements)

References 54 publications

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“…The characteristics of the 11 patients with AML are shown in Table S1. Cells were treated with vehicle control, ISC-4, AraC or combo, and apoptosis was detected with Annexin V/7AAD staining as described previously (25). ISC-4 induced significant apoptosis in a dose-dependent manner with 3, 6, and 10 µM ISC-4 concentrations (Figure 3C).…”

Section: Isc-4 Induces Apoptosis In Primary Human Aml Cells and Enhanmentioning

confidence: 77%

“…Given the above data, we were interested to know the effect of ISC-4 on LSCs. It has been previously demonstrated that LSCs in AML are found within CD123 + , CD96 + , or TIM-3 + cellular fractions (25,(55)(56)(57)(58)(59). Therefore, we focused our experiments on these cell populations.…”

Section: Discussionmentioning

confidence: 99%

“…Primary human AML and normal cells were cultured in the serum-free expansion medium (SFEM) (Stem Cell Technologies, Vancouver, BC, Canada) supplemented with recombinant human stem cell factor (SCF), Interleukin 3 (IL-3), FMS-like tyrosine kinase ligand (FLT3-L), Granulocyte colony-stimulating factor (G-CSF), and granulocyte-macrophage colony-stimulating factor (GM-CSF). All cytokines were purchased from Shenandoah Biotechnology, Warwick, PA. StemRegenin1 (SR1) (ChemieTek, Indianapolis, IN), and UM729 (Selleckchem, Houston, TX) were added to maintain the "stemness" of primary cells for stem cell assays (25). All cultures were supplemented with 1% Penicillin and Streptomycin and stored in a humidified 37 • C incubator with 5% CO 2 .…”

Section: Aml Patient Samplesmentioning

confidence: 99%

“…A syngeneic C1498-dsRed-Luc and human xenograft U937 mouse models of AML were established as described previously (25). Cohorts of syngeneic mouse model were generated by transplanting luciferase-expressing mouse leukemia, C1498-dsRed-Luc cells into B6 (Cg)-Tyrc-2J/J (Albino B6) mice (The Jackson Laboratory, Bar Harbor, ME).…”

Section: Preclinical Therapeutic Efficacy Of Isc-4 In Xenotransplantamentioning

confidence: 99%

“…When leukemia burden was clearly detectable by Bioluminescence Imaging (BLI), mice with equivalent bioluminescent signals were randomized into two treatment groups: vehicle control (DMSO) and ISC-4 (7 mg/kg). The whole-body leukemic burden was monitored by BLI throughout the study as described previously (25). The study was terminated, and all mice were euthanized when control mice displayed disease-related morbidity at day 27.…”

Section: Preclinical Therapeutic Efficacy Of Isc-4 In Xenotransplantamentioning

confidence: 99%

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The PI3K/AKT Pathway Inhibitor ISC-4 Induces Apoptosis and Inhibits Growth of Leukemia in Preclinical Models of Acute Myeloid Leukemia

et al. 2020

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Acute myeloid leukemia is a heterogeneous disease with a 5-year survival rate of 28.3%, and current treatment options constrained by dose-limiting toxicities. One of the key signaling pathways known to be frequently activated and dysregulated in AML is PI3K/AKT. Its dysregulation is associated with aggressive cell growth and drug resistance. We investigated the activity of Phenybutyl isoselenocyanate (ISC-4) in primary cells obtained from newly diagnosed AML patients, diverse AML cell lines, and normal cord blood cells. ISC-4 significantly inhibited survival and clonogenicity of primary human AML cells without affecting normal cells. We demonstrated that ISC-4-mediated p-Akt inhibition caused apoptosis in primary AML (CD34 +) stem cells and enhanced efficacy of cytarabine. ISC-4 impeded leukemia progression with improved overall survival in a syngeneic C1498 mouse model with no obvious toxic effects on normal myelopoiesis. In U937 xenograft model, bone marrow cells exhibited significant reduction in human CD45 + cells in ISC-4 (∼87%) or AraC (∼89%) monotherapy groups compared to control. Notably, combination treatment suppressed the leukemic infiltration significantly higher than the single-drug treatments (∼94%). Together, the present findings suggest that ISC-4 might be a promising agent for AML treatment.

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Section: Isc-4 Induces Apoptosis In Primary Human Aml Cells and Enhanmentioning

confidence: 77%

Section: Discussionmentioning

confidence: 99%

Section: Aml Patient Samplesmentioning

confidence: 99%

Section: Preclinical Therapeutic Efficacy Of Isc-4 In Xenotransplantamentioning

confidence: 99%

Section: Preclinical Therapeutic Efficacy Of Isc-4 In Xenotransplantamentioning

confidence: 99%

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The PI3K/AKT Pathway Inhibitor ISC-4 Induces Apoptosis and Inhibits Growth of Leukemia in Preclinical Models of Acute Myeloid Leukemia

et al. 2020

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3D‐QSAR and scaffold hopping based designing of benzo[d]ox‐azol‐2(3H)‐one and 2‐oxazolo[4,5‐b]pyridin‐2(3H)‐one derivatives as selective aldehyde dehydrogenase 1A1 inhibitors: Synthesis and biological evaluation

Verma

Narendra

Raju

et al. 2022

Archiv der Pharmazie

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Aldehyde dehydrogenase 1 (ALDH1A1), an oxidoreductase class of enzymes, is overexpressed in various types of cancer cell lines and is the major cause of resistance to the Food and Drug Administration (FDA)‐approved drug, cyclophosphamide (CP). In cancer conditions, CP undergoes a sequence of biotransformations to form an active metabolite, aldophosphamide, which further biotransforms to its putative cytotoxic metabolite, phosphoramide mustard. However, in resistant cancer conditions, aldophosphamide is converted into its inactive metabolite, carboxyphosphamide, via oxidation with ALDH1A1. Herein, to address the issue of ALDH1A1 mediated CP resistance, we report a series of benzo[d]oxazol‐2(3H)‐one and 2‐oxazolo[4,5‐b]pyridin‐2(3H)‐one derivatives as selective ALDH1A1 inhibitors. These inhibitors were designed using a validated 3D‐quantitative structure activity relationship (3D‐QSAR) model coupled with scaffold hopping. The 3D‐QSAR model was developed using reported indole‐2,3‐diones based ALDH1A1 inhibitors, which provided field points in terms of electrostatic, van der Waals and hydrophobic potentials required for selectively inhibiting ALDH1A1. The most selective indole‐2,3‐diones‐based compound, that is, cmp 3, was further considered for scaffold hopping. Two top‐ranked bioisosteres, that is, benzo[d]oxazol‐2(3H)‐one and 2‐oxazolo[4,5‐b]pyridin‐2(3H)‐one, were selected for designing new inhibitors by considering the field pattern of 3D‐QSAR. All designed molecules were mapped perfectly on the 3D‐QSAR model and found to be predictive with good inhibitory potency (pIC50 range: 7.5–6.8). Molecular docking was carried out for each designed molecule to identify key interactions that are required for ALDH1A1 inhibition and to authenticate the 3D‐QSAR result. The top five inhibitor‐ALDH1A1 complexes were also submitted for molecular dynamics simulations to access their stability. In vitro enzyme assays of 21 compounds suggested that these compounds are selective toward ALDH1A1 over the other two isoforms, that is, ALDH2 and ALDH3A1. All the compounds were found to be at least three and two times more selective toward ALDH1A1 over ALDH2 and ALDH3A1, respectively. All the compounds showed an IC50 value in the range of 0.02–0.80 μM, which indicates the potential for these to be developed as adjuvant therapy for CP resistance.

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Acute Myeloid Leukemia Stem Cells: Origin, Characteristics, and Clinical Implications

Long

Golla

Sharma

et al. 2022

Stem Cell Rev and Rep

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The novel Isatin analog KS99 targets stemness markers in acute myeloid leukemia

Cited by 16 publications

References 54 publications

The PI3K/AKT Pathway Inhibitor ISC-4 Induces Apoptosis and Inhibits Growth of Leukemia in Preclinical Models of Acute Myeloid Leukemia

The PI3K/AKT Pathway Inhibitor ISC-4 Induces Apoptosis and Inhibits Growth of Leukemia in Preclinical Models of Acute Myeloid Leukemia

3D‐QSAR and scaffold hopping based designing of benzo[d]ox‐azol‐2(3H)‐one and 2‐oxazolo[4,5‐b]pyridin‐2(3H)‐one derivatives as selective aldehyde dehydrogenase 1A1 inhibitors: Synthesis and biological evaluation

Acute Myeloid Leukemia Stem Cells: Origin, Characteristics, and Clinical Implications

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