22 research outputs found
Methylnaltrexone bromide: research update of pharmacokinetics following parenteral administration
No full textAbstract B215: Correlation of PSMA ADC exposure with reduction in tumor growth rate determined using serial PSA measurements from a Phase I clinical trial.
No full text
Abstract 4491: Novel multiplex PI3-kinase inhibitors potently inhibit Ras-mutated tumors via suppression of eIF-4E-mediated protein translation
No full textAbstract
Background: The PI3K pathway is a target of significant interest for cancer drug development due to its prominent role in cancer cell growth and survival. However, PI3K pathway inhibition alone has limited efficacy in the presence of oncogenic Ras mutations, which are found in approximately one-third of all human tumors. In preclinical models, efficacy in Ras-mutated tumors has required the inhibition of both PI3K and other Ras-activated pathways. One key function of these pathways is to regulate eIF-4E, a central factor in cap-dependent translation of critical proteins involved in growth and survival (e.g., c-myc and Mcl-1), and anti-tumor activity has been associated with the selective inhibition of translation of these proteins. Simultaneous inhibition of PI3K and other Ras-activated pathways that converge on eIF-4E-mediated protein translation represents an attractive strategy for oncology drug development.
Methods and Results: Using rational drug design, we identified a novel chemical series of small molecules that possess potent activity against PI3K and additional Ras-regulated kinases implicated in protein translation. The anti-tumor activity of these multiplex PI3K inhibitors was assessed against a panel of 30 human tumor cell lines comprised of various genetic backgrounds and histotypes. Multiplex PI3K inhibitors demonstrated broad and potent anti-proliferative activity in all cell lines tested (EC50: 10 nM - 500 nM) and induced cell death in Ras-mutated cell lines (e.g., PANC-1, HCT116 and A549). Mechanistically, these multiplex PI3K inhibitors induced caspase activity, inhibited the phosphorylation of AKT, 4E-BP1, ribosomal S6 and eIF-4E, and inhibited the expression of c-myc and Mcl-1 proteins. In contrast, PI3K-selective inhibitors were partially cytostatic in Ras-mutated tumor cell lines, inhibiting cell proliferation by at most 60-90%. PI3K-selective inhibitors also failed to induce significant increases in caspase activity, inhibit eIF-4E phosphorylation, or inhibit c-myc and Mcl-1 expression.
Conclusion: We have discovered novel multiplex PI3K inhibitors that demonstrate potent anti-tumor activity in Ras-mutant tumors via inhibition of eIF-4E-mediated protein translation.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4491.</jats:p
Pharmacokinetic and pharmacodynamic profile following oral administration of the phosphodiesterase (PDE)4 inhibitor V11294A in healthy volunteers
No full textAims To assess the pharmacokinetic and pharmacodynamic profile of the novel PDE4 inhibitor V11294A (3-(3-cyclopentyloxy-4-methoxybenzyl)-6-ethylamino-8-isopropyl-3H purine hydrochloride) in healthy male volunteers. Methods This was a double-blind, single dose, randomized crossover study in eight healthy volunteers who received a single oral, fasting dose of V11294A (300 mg) or placebo. Blood samples were taken before and 0.5, 1, 2, 2.5, 3, 4, 6, 9, 12, 18 and 24 h after oral dosing for determination of plasma concentrations of V11294A. Blood samples were also taken before and 3 and 24 h after dosing for the assessment of the effect of V11294A on mononuclear cell proliferation and tumour necrosis factor (TNF) release in whole blood. Results Following a single oral dose of 300 mg V11294A, plasma concentrations of V11294A and its active metabolite V10332 reached C-max (ng ml(-1); mean +/- s.d.; 1398 298, 1000 400, respectively) after 2.63 +/- 0.79 and 5.9 +/- 2.3 h, respectively. For V11294A and V10332, t(1/2) were 9.7 +/- 3.9 and 9.5 +/- 1.7 h, and AUC(0,infinity) were 18100 +/- 6100 and 18600 8500 ng ml(-1) h, respectively. At 3 h dosing, plasma concentrations of V11294A and V10332 (3-(3-cyclopentyloxy-4-methoxy-benzyl)-8-isopropyl-3H-purin-6-ylamine) were 1300 +/- 330 and 860 +/- 300 ng ml(-1), 7 and 3 times their in vitro IC(50)s for inhibition of TNT release and proliferation, respectively. Treatment with V11294A resulted in a significant reduction of lipopolysaccharide (LPS)-induced TNT release at 3 h (P <0.001) and at 24 h (P <0.05) post ingestion. The amount of TNT released (pmol ml(-1)) in response to a submaximal concentration of LPS (4 ng nil 1) was not significantly altered following placebo treatment (before 681 +/- 68 vs 3 h postdose 773 +/- 109, P = 0.27). In contrast, there was a significant reduction in the amount of TNT released following treatment with V11294A (before 778 +/- 87 vs 3 h postdose 566 +/- 72, P = 0.02). Phytohaemagluttinin (PHA) stimulated the incorporation of [H-3]-thymidine in whole blood prior to drug administration. V11294A inhibited the PHA-induced proliferation at 3 h (P <0.05). No adverse reactions were noted following single oral administration of V11294A. Conclusions A single oral 300 mg dose of V11294A administered to healthy volunteers results in plasma concentrations adequate to inhibit activation of inflammatory cells ex vivo, which persists for at least 24 h without any adverse reactions
Anti–HIV‐1 Activity of Weekly or Biweekly Treatment with Subcutaneous PRO 140, a CCR5 Monoclonal Antibody
No full textPhase 2a Study of the CCR5 Monoclonal Antibody PRO 140 Administered Intravenously to HIV-Infected Adults
No full textABSTRACT
The anti-CCR5 antibody PRO 140 has shown potent and prolonged antiretroviral activity in subjects infected with CCR5-tropic (R5) HIV-1. Prior studies have examined single intravenous doses ranging up to 5 mg/kg of body weight or up to three subcutaneous doses ranging up to 324 mg. Here we report the results of a randomized, double-blind, placebo-controlled trial that examined the antiviral activity, tolerability, and pharmacokinetics of single 5-mg/kg and 10-mg/kg intravenous infusions of PRO 140 in 31 treated subjects. Eligibility criteria included HIV-1 RNA levels of >5,000 copies/ml, CD4
+
cell counts of >300/μl, no antiretroviral therapy for ≥12 weeks, and detection of only R5 HIV-1 in the original Trofile assay. Following poststudy testing with an enhanced-sensitivity Trofile assay, one subject treated with 10 mg/kg was reclassified as having dual/mixed-tropic virus at screening, and the data for that subject were censored from efficacy analyses. The mean maximum reduction of the HIV-1 RNA level from the baseline level was 1.8 log
10
units for both the 5-mg/kg and 10-mg/kg doses (
P
< 0.0001 relative to placebo). Viral loads reached their nadir at day 12 posttreatment and remained significantly (
P
< 0.01) reduced through day 29 for both PRO 140 dose groups. Treatment was generally well tolerated, with no dose-limiting toxicity being observed. Peak serum concentrations and overall exposures increased proportionally with dose. In summary, single 5-mg/kg and 10-mg/kg doses of PRO 140 exhibited potent, long-lived antiviral activity and were generally well tolerated. The findings further delineate the safety and antiviral properties of this novel, long-acting antiretroviral agent.
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Novel small-molecule inhibitors of hepatitis C virus entry block viral spread and promote viral clearance in cell culture.
No full textCombinations of direct-acting anti-virals offer the potential to improve the efficacy, tolerability and duration of the current treatment regimen for hepatitis C virus (HCV) infection. Viral entry represents a distinct therapeutic target that has been validated clinically for a number of pathogenic viruses. To discover novel inhibitors of HCV entry, we conducted a high throughput screen of a proprietary small-molecule compound library using HCV pseudoviral particle (HCVpp) technology. We independently discovered and optimized a series of 1,3,5-triazine compounds that are potent, selective and non-cytotoxic inhibitors of HCV entry. Representative compounds fully suppress both cell-free virus and cell-to-cell spread of HCV in vitro. We demonstrate, for the first time, that long term treatment of an HCV cell culture with a potent entry inhibitor promotes sustained viral clearance in vitro. We have confirmed that a single amino acid variant, V719G, in the transmembrane domain of E2 is sufficient to confer resistance to multiple compounds from the triazine series. Resistance studies were extended by evaluating both the fusogenic properties and growth kinetics of drug-induced and natural amino acid variants in the HCVpp and HCV cell culture assays. Our results indicate that amino acid variations at position 719 incur a significant fitness penalty. Introduction of I719 into a genotype 1b envelope sequence did not affect HCV entry; however, the overall level of HCV replication was reduced compared to the parental genotype 1b/2a HCV strain. Consistent with these findings, I719 represents a significant fraction of the naturally occurring genotype 1b sequences. Importantly, I719, the most relevant natural polymorphism, did not significantly alter the susceptibility of HCV to the triazine compounds. The preclinical properties of these triazine compounds support further investigation of entry inhibitors as a potential novel therapy for HCV infection
Phase 1 study of PSMA ADC, an antibody‐drug conjugate targeting prostate‐specific membrane antigen, in chemotherapy‐refractory prostate cancer
No full textSpectrum of activity of representative triazines against envelopes isolated from HCV<sup>+</sup> patient sera.
No full text<p>HCV RNA was isolated and purified from sera obtained from individuals infected with different strains of HCV, representing genotypes 1a, 1b, 2a, 2b. Envelopes representing genotypes 3, 4, and 6 were described in the <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0035351#s2" target="_blank">Materials and Methods</a> and published elsewhere <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0035351#pone.0035351-Lavillette1" target="_blank">[33]</a>. Genotype specific primers were used to amplify sequences encoding the E1/E2 glycoprotein from each of the strains by RT-PCR. Envelope sequences were ligated into expression constructs as described in the <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0035351#s2" target="_blank">Materials and Methods</a>. Unique HCVpp, representing different genotypes, were produced in 293T cells and validated with the anti-CD81 mAb, JS-81. Individual HCVpp were normalized based on total infectivity and added to Hep3B cells in the presence of various concentrations of PRO0371155 (Panel A) or PRO0502797 (Panel B) in 384-well microplates. Luciferase activity was measured 72 hrs post-infection using Bright Glo reagent (Promega). The potency of PRO0371155 and PRO0502797 against each fusogenic envelope was expressed as a mean EC<sub>50</sub>. Each data point represents the average of multiple dose response experiments (n>3). The genotype specific panel consisted of the following strains: genotype 1a (n = 22), genotype 1b (n = 19), genotype 2a (n = 2), genotype 2b (n = 1), genotype 3, (n = 1), genotype 4, n = 1), genotype 6 (n = 1). Actual number of strains tested for each compound is summarized in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0035351#pone-0035351-t001" target="_blank">Table 1</a>. The box extends from the 25<sup>th</sup> to the 75<sup>th</sup> percentile, with a line at the median EC<sub>50</sub>. The whiskers mark the full range from the lowest to the highest EC<sub>50</sub>.</p
