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This disclosure relates to methods of treatment using compound (1) or analogs thereof, and pharmaceutically acceptable salts thereof. Also disclosed are compounds of formula (10): as defined in the specification, and pharmaceutically acceptable salts thereof, as well as pharmaceutical compositions comprising the same. Methods of treatment, such as for cancer, are provided that comprise administering the compounds and their salts to a subject in need of such treatment.

Patel H.H.,University of California at San Diego | Hamuro L.L.,Provid Pharmaceuticals, Inc | Chun B.J.,University of California at San Diego | Kawaraguchi Y.,University of California at San Diego | And 11 more authors.
Journal of Biological Chemistry | Year: 2010

Localization of protein kinase A (PKA) via A-kinase-anchoring proteins (AKAPs) is important for cAMP responsiveness in many cellular systems, and evidence suggests that AKAPs play an important role in cardiac signaling. To test the importance of AKAP-mediated targeting of PKA on cardiac function, we designed a cell-permeable peptide, which we termed trans-activator of transcription (TAT)-AKAD for TAT-conjugated A-kinase-anchoring disruptor, using the PKA binding region of AKAP10 and tested the effects of this peptide in isolated cardiac myocytes and in Langendorff-perfused mouse hearts. We initially validated TAT-AKAD as a PKA localization inhibitor in cardiac myocytes by the use of confocal microscopy and cellular fractionation to show that treatment with the peptide disrupts type I and type II PKA regulatory subunits. Knockdown of PKA activity was demonstrated by decrease in phosphorylation of phospholamban and troponin I after β-adrenergic stimulation in isolated myocytes. Treatment with TAT-AKAD reduced myocyte shortening and rates of contraction and relaxation. Injection of TAT-AKAD (1 μM), but not scrambled control peptide, into the coronary circulation of isolated perfused hearts rapidly (<1 min) and reversibly decreased heart rate and peak left ventricular developed pressure. TAT-AKAD also had a pronounced effect on developed pressure (-dP/dt), consistent with a delayed relaxation of the heart. The effects of TAT-AKAD on heart rate and contractility persisted in hearts pretreated with isoproterenol. Disruption of PKA localization with TAT-AKAD thus had negative effects on chronotropy, inotropy, and lusitropy, thereby indicating a key role for AKAP-targeted PKA in control of heart rate and contractile function.

Ji N.,University of Texas at San Antonio | Somanaboeina A.,University of Texas at San Antonio | Dixit A.,University of Texas at San Antonio | Kawamura K.,University of Texas at San Antonio | And 4 more authors.
Journal of Immunology | Year: 2013

The strong association of HLA-DR2b (DRB1*1501) with multiple sclerosis (MS) suggests this molecule as prime target for specific immunotherapy. Inhibition of HLA-DR2b-restricted myelin-specific T cells has the potential to selectively prevent CNS pathology mediated by these MHC molecules without undesired global immunosuppression. In this study, we report development of a highly selective small molecule inhibitor of peptide binding and presentation by HLA-DR2b. PV-267, the candidate molecule used in these studies, inhibited cytokine production and proliferation of myelin-specific HLA-DR2b-restricted T cells. PV-267 had no significant effect on T cell responses mediated by other MHC class II molecules, including HLA-DR1, -DR4, or-DR9. Importantly, PV-267 did not induce nonspecific immune activation of human PBMC. Lastly, PV-267 showed treatment efficacy both in preventing experimental autoimmune encephalomyelitis and in treating established disease. The results suggest that blocking the MS-associated HLA-DR2b allele with small molecule inhibitors may be a promising therapeutic strategy for the treatment of MS. Copyright © 2013 by The American Association of Immunologists, Inc.

Wagner J.,Pennsylvania State University | Wagner J.,Molecular Therapeutics | Kline C.L.,Pennsylvania State University | Kline C.L.,Molecular Therapeutics | And 8 more authors.
Oncotarget | Year: 2014

We previously identified TRAIL-inducing compound 10 (TIC10), also known as NSC350625 or ONC201, from a NCI chemical library screen as a small molecule that has potent anti-tumor efficacy and a benign safety profile in preclinical cancer models. The chemical structure that was originally published by Stahle, et. al. in the patent literature was described as an imidazo[1,2-a]pyrido[4,3-d]pyrimidine derivative. The NCI and others generally accepted this as the correct structure, which was consistent with the mass spectrometry analysis outlined in the publication by Allen et. al. that first reported the molecule's anticancer properties. A recent publication demonstrated that the chemical structure of ONC201 material from the NCI is an angular [3,4-e] isomer of the originally disclosed, linear [4,3-d] structure. Here we confirm by NMR and X-ray structural analysis of the dihydrochloride salt form that the ONC201 material produced by Oncoceutics is the angular [3,4-e] structure and not the linear structure originally depicted in the patent literature and by the NCI. Similarly, in accordance with our biological evaluation, the previously disclosed anticancer activity is associated with the angular structure and not the linear isomer. Together these studies confirm that ONC201, produced by Oncoceutics or obtained from the NCI, possesses an angular [3,4-e] structure that represents the highly active anti-cancer compound utilized in prior preclinical studies and now entering clinical trials in advanced cancers.

PubMed | University of Houston, Fox Chase Cancer Center, Kuwait University, Oncoceutics and 6 more.
Type: Review | Journal: Oncotarget | Year: 2016

ONC201 is the founding member of a novel class of anti-cancer compounds called imipridones that is currently in Phase II clinical trials in multiple advanced cancers. Since the discovery of ONC201 as a p53-independent inducer of TRAIL gene transcription, preclinical studies have determined that ONC201 has anti-proliferative and pro-apoptotic effects against a broad range of tumor cells but not normal cells. The mechanism of action of ONC201 involves engagement of PERK-independent activation of the integrated stress response, leading to tumor upregulation of DR5 and dual Akt/ERK inactivation, and consequent Foxo3a activation leading to upregulation of the death ligand TRAIL. ONC201 is orally active with infrequent dosing in animals models, causes sustained pharmacodynamic effects, and is not genotoxic. The first-in-human clinical trial of ONC201 in advanced aggressive refractory solid tumors confirmed that ONC201 is exceptionally well-tolerated and established the recommended phase II dose of 625 mg administered orally every three weeks defined by drug exposure comparable to efficacious levels in preclinical models. Clinical trials are evaluating the single agent efficacy of ONC201 in multiple solid tumors and hematological malignancies and exploring alternative dosing regimens. In addition, chemical analogs that have shown promise in other oncology indications are in pre-clinical development. In summary, the imipridone family that comprises ONC201 and its chemical analogs represent a new class of anti-cancer therapy with a unique mechanism of action being translated in ongoing clinical trials.

Rutgers University and Provid Pharmaceuticals, Inc | Date: 2016-03-08

The invention provides compounds of formula Ia, Ib and Ic: and salts thereof, wherein variables are as described in the specification, as well as compositions comprising a compound of formula Ia-Ic, methods of making such compounds, and methods of using such compounds, e.g., as inhibitors of bacterial RNA polymerase and as antibacterial agents.

Rutgers University and Provid Pharmaceuticals, Inc | Date: 2013-06-19

The invention provides compounds of formula la, lb and Ic: [Formula Ia, Ib, and Ic] and salts thereof, wherein variables are as described in the specification, as well as compositions comprising a compound of formula Ia-Ic, methods of making such compounds, and methods of using such compounds, e.g., as inhibitors of bacterial RNA polymerase and as antibacterial agents.

The United States Of America and Provid Pharmaceuticals, Inc | Date: 2012-10-26

A method of treating an Hepatitis C Virus infection in a patient, comprising providing a therapeutically effective amount, to a patient in need thereof, of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, wherein: G_(1 )is a group of the formula or where n is 0, 1, 2, 3, or 4 and Het is a 5- or 6-membered heteroaryl group containing 1 to 4 heteroatoms independently chosen from N, O, and S, which Het is optionally substituted.

Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 175.20K | Year: 2010

DESCRIPTION (provided by applicant): The proposed research is directed toward the discovery of novel peptide inhibitors of platelet adhesion to the inflamed endothelium that would have value in the prevention and treatment of atherosclerosis, thrombosis, stroke, and heart attack. The novel mechanism addressed is inhibition of the F11 receptor (F11R; aka JAM-A), a cell adhesion molecule found on the surface of human platelets and in the vascular endothelium. F11R is critical for the adhesion of platelets to inflamed blood vessels. Two peptide leads (peptides 1 and 4) derived from the F11R sequence have been shown to inhibit F11R activity. The sequences of these peptides are found in close proximity on the F11R protein surface, suggesting that both sequences are involved in the interaction during adhesion. Free peptides 1 and 4 inhibit the association and are thought to interact with F11R to block the cell-adhesion. Extensive work has validated the activity of these peptides in models of platelet activity, however, these leads are long peptides (14 and 23 amino acids), lacking proteolytic stability, and there has been no systematic study of peptide structure-activity relationships and the requirements for biological activity. This project's specific aims are to identify a minimal active sequence within each of the two peptides, to build peptide 1 - peptide 4 hybrids with novel chemistry and via cyclic analogs, to define the structure-activity relationships and to establish efficacy in inhibiting platelet adhesion in vitro. Optimized compounds resulting from these studies are expected to have biological properties suitable for validation of the F11R inhibition strategy in animal models of cardiovascular disease and as leads for the development of new therapeutics. PUBLIC HEALTH RELEVANCE: The proposed research will help define a novel approach to the treatment of cardiovascular diseases such as atherosclerosis, thrombosis, stroke, and heart attack. New compounds that inhibit platelet adhesion to the inflamed endothelium, mediated by the protein F11R found on both platelets and damaged blood vessel walls, will be designed and synthesized. New peptide inhibitors of F11R that may be suitable for use as therapeutic drugs will be developed and characterized in this research.

Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 224.96K | Year: 2014

Project Summary/Abstract TIC10 (ONC201) is a first-in-class antitumor agent and small molecule inducer of the TRAIL gene which was identified in a high-throughput small molecule library screen in the lab of our collaborator, Dr. Wafik El-Deiry at Penn State University and has been shown to have preclinical efficacy in several difficult-to-treat disease settings that include unmet clinical needs such as glioblastoma and triple-negative breast cancer. The motivation for developing the small molecule TIC10 andanalogs is to overcome efficacy-limiting properties of recombinant TRAIL and to optimize advantages TIC10 that have been demonstrated (Allen et al, 2013), including: (i) longer half-life, (ii) prolonged elevation of serum TRAIL, (iii) a bystander effect through normal cell TRAIL production, (iv) stimulation of TRAIL and death receptor expression, and other properties that are only obtained by a small molecule, such as (v) stability, (vi) cost, (vii) oral activity, and (viii) ability to cross the blood-bra

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