Publications by authors named "William L Heaton"

We discovered that the survival and growth of many primary acute myeloid leukemia (AML) samples and cell lines, but not normal CD34+ cells, are dependent on SIRT5, a lysine deacylase implicated in regulating multiple metabolic pathways. Dependence on SIRT5 is genotype-agnostic and extends to RAS- and p53-mutated AML. Results were comparable between SIRT5 knockdown and SIRT5 inhibition using NRD167, a potent and selective SIRT5 inhibitor.

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Normal human bone marrow cells are critical for studies of hematopoiesis and as controls to assess toxicity. As cells from commercial vendors are expensive, many laboratories resort to cancer-free bone marrow specimens obtained during staging or to umbilical cord blood cells, which may be abnormal or reflect a much younger age group compared to the disease samples under study. We piloted the use of femoral heads as an alternative and inexpensive source of normal bone marrow.

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Pancreatic ductal adenocarcinoma (PDAC) is an aggressive, incurable cancer with a 20% 1 year survival rate. While standard-of-care therapy can prolong life in a small fraction of cases, PDAC is inherently resistant to current treatments, and novel therapies are urgently required. Histone deacetylase (HDAC) inhibitors are effective in killing pancreatic cancer cells in in vitro PDAC studies, and although there are a few clinical studies investigating combination therapy including HDAC inhibitors, no HDAC drug or combination therapy with an HDAC drug has been approved for the treatment of PDAC.

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Article Synopsis
  • Myelofibrosis is a serious blood disorder linked to mutations in the JAK/STAT signaling pathway, leading to symptoms that JAK inhibitors can alleviate but do not cure.
  • Researchers conducted a study to explore the role of nuclear-cytoplasmic transport (NCT) in myelofibrosis, identifying a potential new therapeutic target using cell lines and mouse models.
  • The study found that inhibiting NCT significantly reduced cell viability in myelofibrosis and improved the effects of ruxolitinib, suggesting that NCT could enhance treatment outcomes for patients.
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Tumor necrosis factor alpha (TNF) is increased in myelofibrosis (MF) and promotes survival of malignant over normal cells. The mechanisms altering TNF responsiveness in MF cells are unknown. We show that the proportion of marrow (BM) cells expressing TNF is increased in MF compared to controls, with the largest differential in primitive cells.

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Pharmacologic blockade of the activation of signal transducer and activator of transcription 3 (STAT3) in tyrosine kinase inhibitor (TKI)-resistant chronic myeloid leukemia (CML) cell lines characterized by kinase-independent resistance was shown to re-sensitize CML cells to TKI therapy, suggesting that STAT3 inhibitors in combination with TKIs are an effective combinatorial therapeutic for the treatment of CML. Benzoic acid- and hydroxamic acid-based STAT3 inhibitors SH-4-054 and SH-5-007, developed previously in our laboratory, demonstrated promising activity against these resistant CML cell lines. However, pharmacokinetic studies in murine models (CD-1 mice) revealed that both SH-4-054 and SH-5-007 are susceptible to glutathione conjugation at the para position of the pentafluorophenyl group via nucleophilic aromatic substitution (SN Ar).

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  • Researchers are investigating how some chronic myeloid leukemia (CML) patients develop resistance to tyrosine kinase inhibitors (TKIs) without mutations in the BCR-ABL1 gene, which is typically associated with this resistance.
  • They used a lentiviral shRNA library to target around 5000 cell signaling genes in a CML cell line known for its resistance, identifying key genes that when knocked down, significantly affected cell growth.
  • Their findings highlight RAN and XPO1 as important factors in overcoming TKI resistance, suggesting they could be potential targets for enhancing treatment effectiveness in CML patients with BCR-ABL1 kinase-independent resistance.
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  • Mutations in the BCR-ABL1 kinase domain are known to cause resistance to tyrosine kinase inhibitors (TKIs) in leukemia, but some patients still experience treatment failure without these mutations, a phenomenon known as BCR-ABL1 kinase-independent resistance.
  • Researchers found that the activation of STAT3, either from external influences or internal changes, plays a key role in this type of resistance.
  • They developed a compound called BP-5-087 that effectively inhibits STAT3, restoring sensitivity to TKI therapy in resistant leukemia cells and suggesting its potential as a treatment option for cancers involving STAT3 activation.
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Ponatinib is the only currently approved tyrosine kinase inhibitor (TKI) that suppresses all BCR-ABL1 single mutants in Philadelphia chromosome-positive (Ph(+)) leukemia, including the recalcitrant BCR-ABL1(T315I) mutant. However, emergence of compound mutations in a BCR-ABL1 allele may confer ponatinib resistance. We found that clinically reported BCR-ABL1 compound mutants center on 12 key positions and confer varying resistance to imatinib, nilotinib, dasatinib, ponatinib, rebastinib, and bosutinib.

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AZD9272 and AZD6538 are two novel mGluR5 negative allosteric modulators selected for further clinical development. An initial high-throughput screening revealed leads with promising profiles, which were further optimized by minor, yet indispensable, structural modifications to bring forth these drug candidates. Advantageously, both compounds may be synthesized in as little as one step.

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Design, new synthesis, structure-activity relationship studies and calcium receptor antagonist (calcilytic) properties of novel 3H-pyrimidin-4-ones are described.

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Structure-activity relationship studies, focused on identification of the active pharmacophore fragments in a single high-throughput screening calcilytic hit, resulted in the discovery of potent calcium receptor antagonists, substituted 3H-quinazolin-4-ones.

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