A5042750142- Histone Deacetylase Inhibitors Research
- Cancer Immunotherapy and Biomarkers
- Protein Degradation and Inhibitors
- Ferroptosis and cancer prognosis
- Epigenetics and DNA Methylation
- Peptidase Inhibition and Analysis
- Heat shock proteins research
- Cancer-related gene regulation
- Hedgehog Signaling Pathway Studies
- Cancer, Hypoxia, and Metabolism
- Advanced Breast Cancer Therapies
- SARS-CoV-2 and COVID-19 Research
- Influenza Virus Research Studies
- Colorectal Cancer Treatments and Studies
- Traditional and Medicinal Uses of Annonaceae
- Lymphoma Diagnosis and Treatment
- Nicotinic Acetylcholine Receptors Study
- Lung Cancer Treatments and Mutations
- Animal Virus Infections Studies
- Nanoparticle-Based Drug Delivery
- Immune cells in cancer
- Chronic Myeloid Leukemia Treatments
- Click Chemistry and Applications
- Hair Growth and Disorders
- Indoor Air Quality and Microbial Exposure
Curis (United States)
2005-2023
Millennium Engineering and Integration (United States)
2001
University of Virginia
1998
United States Army Medical Research Institute of Infectious Diseases
1992-1994
Oak Ridge Associated Universities
1991
Abstract Purpose: Given that histone deacetylase (HDAC) inhibitors are known to induce multiple epigenetic modifications affecting signaling networks and act synergistically with phosphatidylinositol 3-kinase (PI3K) inhibitors, we developed a strategy simultaneously inhibit HDACs PI3K in cancer cells. Experimental Design: We constructed dual-acting by incorporating HDAC inhibitory functionality into inhibitor pharmacophore. CUDC-907, development candidate selected from these dual was...
The capacity of targeted anticancer agents to exert immunomodulatory effects provides a strong rationale develop novel suitable for combinatorial regimens with immunotherapy improve clinical outcomes. In this study, we developed dual-targeting PI3K and HDAC inhibitor BEBT-908 that potently inhibits tumor cell growth potentiates anti-PD1 therapy in mice by inducing immunogenic ferroptosis cancer cells. Treatment promoted ferroptotic death cells hyperacetylating p53 facilitating the expression...
By incorporating histone deacetylase (HDAC) inhibitory functionality into the pharmacophore of epidermal growth factor receptor (EGFR) and human 2 (HER2) inhibitors, we synthesized a novel series compounds with potent, multiacting HDAC, EGFR, HER2 inhibition identified 7-(4-(3-ethynylphenylamino)-7-methoxyquinazolin-6-yloxy)-N-hydroxyheptanamide 8 (CUDC-101) as drug candidate, which is now in clinical development. displays potent vitro activity against an IC(50) 4.4, 2.4, 15.7 nM,...
Receptor tyrosine kinase inhibitors have recently become important therapeutics for a variety of cancers. However, due to the heterogeneous and dynamic nature tumors, effectiveness these agents is often hindered by poor response rates acquired drug resistance. To overcome limitations, we created novel small molecule, CUDC-101, which simultaneously inhibits histone deacetylase receptor kinases epidermal growth factor (EGFR) human 2 (HER2) in cancer cells. Because its integrated inhibition,...
Abstract Purpose: We designed and synthesized CUDC-305, an HSP90 inhibitor of the novel imidazopyridine class. Here, we report its unique pharmacologic properties antitumor activities in a variety tumor types. Experimental Design: The potency compound was analyzed by fluorescence polarization competition binding assay. Its antiproliferative were assessed 40 human cancer cell lines. evaluated xenograft models. Results: CUDC-305 shows high affinity for HSP90α/β (IC50, ∼100 nmol/L) complex...
Abstract CUDC-305 is a heat shock protein 90 (HSP90) inhibitor of the novel imidazopyridine class. Here, we report its activities in non–small cell lung cancer (NSCLC) lines with gene deregulations conferring primary or secondary resistance to epidermal growth factor receptor (EGFR) inhibitors. We show that binds strongly HSP90 extracted from erlotinib-resistant NSCLC cells (IC50 70 nmol/L). This result correlates well potent antiproliferative activity 120–700 nmol/L) reported previously....
Abstract Recent evidence indicates that both PI3K-Akt-mTOR signaling pathway and HDAC are validated targets in hematological cancers. In order to overcome primary resistance prevent secondary resulting from compensatory/feedback mechanisms cancer cells, CUDC-907 was designed inhibit all isoforms of Class I PI3K II HDAC, based on previous observations synergistic effects can be achieved by inhibition cells. cell proliferation assays, this compound displays potent anti-proliferation activity...
By incorporating an N-hydroxyurea functionality onto diaryltetrahydrofurans, a novel series of compounds was investigated as dual 5-lipoxygenese (5-LO) inhibitor and platelet-activating factor (PAF) receptor antagonist. These functional were evaluated in vitro for 5-LO inhibition RBL cell extracts human whole blood, PAF antagonism binding assay. PAF-induced hemoconcentration arachidonic acid- TPA-induced ear edema mice used to determine vivo activities. The structure-activity relationship...
EGFR mutation-positive NSCLC tumors are highly heterogeneous, therefore, exploring an agent simultaneously targeting multiple mutations may be valuable for clinical practice. Compared with osimertinib, BEBT-109 shows more sensitive and extensive antitumor activity in mutant NSCLC, while sparing wild-type cell lines. Meanwhile, unlike the metabolite of osimertinib AZ5104, main metabolites found lacking against Preclinical studies demonstrate a unique pharmacokinetic profiles rapid absorption...
Abstract The molecular chaperone heat shock protein 90 (HSP90) is involved in folding and stabilization of a wide range client proteins, including key proteins cancer. Through structure-based design, we synthesized novel imidazopyridine class potent HSP90 inhibitors. synthesis SAR surrounding this compounds will be discussed. extensive study lead optimization resulted the identification development candidate CUDC-305, later renamed Debio 0932. 0932 displays high oral bioavailability (96%...