A5011819247- Lung Cancer Research Studies
- Neuroendocrine Tumor Research Advances
- Cancer therapeutics and mechanisms
- Heat shock proteins research
- PARP inhibition in cancer therapy
- Crystallization and Solubility Studies
- Sirtuins and Resveratrol in Medicine
- X-ray Diffraction in Crystallography
- Radiation Therapy and Dosimetry
- Chemical Synthesis and Analysis
- Marine Toxins and Detection Methods
- Tea Polyphenols and Effects
- Histone Deacetylase Inhibitors Research
- Chemical Reaction Mechanisms
- Synthetic Organic Chemistry Methods
- Peptidase Inhibition and Analysis
- Monoclonal and Polyclonal Antibodies Research
- Glycosylation and Glycoproteins Research
- Nanoparticle-Based Drug Delivery
- Enzyme function and inhibition
- Nanoplatforms for cancer theranostics
- Catalytic Alkyne Reactions
- Phenothiazines and Benzothiazines Synthesis and Activities
- Synthesis and Biological Evaluation
- Cyclopropane Reaction Mechanisms
Enveda Therapeutics (United States)
2017-2020
GlaxoSmithKline (United States)
2015
Tris Pharma (United States)
2015
Oklahoma State University
2009
Boston College
2003-2004
Emory University
2003
Chronic inflammation is a major contributing factor in the pathogenesis of many age-associated diseases. One central protein that regulates NF-κB, activity which modulated by post-translational modifications as well association with co-activator and co-repressor proteins. SIRT1, an NAD(+)-dependent deacetylase, has been shown to suppress NF-κB signaling through deacetylation p65 subunit resulting reduction inflammatory responses mediated this transcription factor. The role SIRT1 regulation...
SIRT1, the founding member of mammalian family seven NAD(+)-dependent sirtuins, is composed 747 amino acids forming a catalytic domain and extended N- C-terminal regions. We report design characterization an engineered human SIRT1 construct (mini-hSIRT1) containing minimal structural elements required for lysine deacetylation activation by small molecule sirtuin-activating compounds (STACs). Using this construct, we solved crystal structure mini-hSIRT1-STAC complex, which revealed...
Small cell lung cancer (SCLC) is an aggressive neuroendocrine carcinoma with a 95% mortality rate no improvement to treatment in decades, and new therapies are desperately needed. PEN-221 miniaturized peptide-drug conjugate (∼2 kDa) designed target SCLC via Somatostatin Receptor 2 (SSTR2)-targeting ligand overcome the high proliferation characteristic of this disease by using potent cytotoxic payload, DM1. SSTR2 ideal for drug conjugate, as it overexpressed limited normal tissue expression....
Somatostatin receptor 2 (SSTR2) is frequently overexpressed on several types of solid tumors, including neuroendocrine tumors and small-cell lung cancer. Peptide agonists SSTR2 are rapidly internalized upon binding to the linking a toxic payload an agonist potential method kill SSTR2-expressing tumor cells. Herein, we describe our efforts towards efficacious SSTR2-targeting cytotoxic conjugate; examination different ligands, conjugation sites, payloads led discovery 22 (PEN-221), conjugate...
Ring-opening/ring-closing metathesis on cyclobutene-containing substrates with angular oxygen functionality provides a stereospecific introduction of 1,5-bis-dienes required for an anion-accelerated oxy-Cope rearrangement. The reaction sequence offers generally stereocontrolled preparation variety medium ring-containing bicyclic ring systems, while rearrangement to the bicyclo[7,3,0]dodecane (9-5) system leads mixture olefin isomers.
Abstract The PI3K pathway is considered a master regulator for cancer due to its frequent activation, making it an attractive target pharmacologic intervention. While substantial efforts have been made develop drugs targeting signaling, few able achieve the inhibition necessary effective tumor control at tolerated doses. HSP90 chaperone protein that overexpressed and activated in many tumors as consequence, small-molecule ligands of are preferentially retained up 20 times longer than normal...
Abstract magnified image A tandem reductive amination‐S N Ar reaction has been applied to the synthesis of (±)‐1,2‐dialkyl‐5‐nitro‐2,3‐dihydro‐1 H ‐indoles. Treatment a series 2‐fluoro‐5‐nitrobenzyl ketones with primary amines and sodium cyanoborohydride in methanol at room temperature provided good yields target heterocycles. The is sensitive steric hindrance proceeds best less hindered ketone substrates using that are unbranched α carbon. J. Heterocyclic Chem., (2009).
Abstract Platinum drugs have proven to be effective in treating cancer, for example >90% of men with testicular cancer are cured a platinum therapeutic. also widely used the adjuvant treatment common cancers such as those lung, colon and ovary. However majority tumor types clinical response rates therapies low, 1 year survival rate lung patients treated therapeutics is ∼30%. The key limitations existing dose limiting toxicities that restrict and/or duration therapy absence...
Abstract The specific targeting of cytotoxic drugs to solid tumors has achieved success with the advent antibody drug conjugates (ADCs). This approach had notable but also met limitations. most common issue limiting ADC effectiveness is believed be low tumor permeation by these large (∼150 kDa) molecules. Attempts address this limitation have been focused on design miniaturized biologic such as those small protein or molecule moieties. However, efforts uniformly result in poor...
Abstract Here we describe the discovery and structure of PEN-221, a somatostatin receptor 2 (SSTR2) targeting peptide conjugated to DM1. PEN-221 is first clinical compound from Tarveda’s Pentarin platform, which utilizes miniaturized drug conjugates that diffuse rapidly deeply into solid tumors. Antibody (ADCs) have garnered significant amount attention in their ability direct cytotoxic drugs cancer cells; however, efficacy ADCs tumors limited by slow diffusion such large molecules through...
Abstract The expression of somatostatin receptor subtype 2 (SSTR2) is increased in up to 80% neuroendocrine tumors (NETs), 20-40% small cell lung cancers (SCLC) and a number other tumor types. As surface receptor, SSTR2 logical target for drug conjugate. However, marginal, or loss of, tissues has potential limit the benefit from such conjugates. Recent published preclinical studies have demonstrated that epigenetic modulators, as HDAC inhibitors, can result with treatment. Given be variable...
Abstract For see ChemInform in Full Text.
<p>Description of BT-984 synthesis and LC-MS/MS sample preparation</p>
<p>Immunohistochemical Analysis of SSTR2 Expression in 35 Small Cell Lung Cancer Patient Samples</p>
<p>In vitro inhibition of proliferation SCLC cells by PEN-221 or DM1</p>
<p>Body weight (BW) and health observations for efficacy studies</p>
<p>Immunohistochemical Analysis of SSTR2 Expression in 44 Small Cell Lung Cancer Patient Samples</p>
<p>Pharmacokinetic analysis of PEN-221 and DM1 in non-tumor bearing mice</p>
<p>SSTR2 expression analysis in xenograft tissue</p>
<p>Supplementary Figure 3 shows the body weights from all efficacy studies discussed in article.</p>
<p>detailed and complete T-2143 synthesis route</p>
<p>Supplementary Figure S1 shows the pharmacokinetic profiles of T-2143 and T-2122</p>
<p>Supplementary figure 2 shows blood glucose levels in mice who have been dosed with a single dose of T-2143 over 24 hour period.</p>
<p>Supplementary figure 4 shows suppression of the PI3K pathway post a single dose T-2143 in LS174T xenograft model.</p>