Joyant Pharmaceuticals

Dallas, TX, United States

Joyant Pharmaceuticals

Dallas, TX, United States
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Wang G.,University of Texas Southwestern Medical Center | Wang X.,Tianjin University | Yu H.,University of Texas Southwestern Medical Center | Wei S.,University of Texas Southwestern Medical Center | And 11 more authors.
Nature Chemical Biology | Year: 2013

Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) activates apoptosis through the death receptors DR4 and DR5. Because of its superior safety profile and high tumor specificity compared to other TNF family members, recombinant soluble TRAIL and agonistic antibodies against its receptors are actively being developed for clinical cancer therapy. Here, we describe the identification and characterization of the small molecules that directly target DR5 to initiate apoptosis in human cancer cells. The activity was initially discovered through a high-throughput chemical screen for compounds that promote cell death in synergy with a small-molecule mimetic of Smac, the antagonist for inhibitor of apoptosis protein. Structure-activity relationship studies yielded a more potent analog called bioymifi, which can act as a single agent to induce DR5 clustering and aggregation, leading to apoptosis. Thus, this study identified potential lead compounds for the development of small-molecule TRAIL mimics targeting DR5 for cancer therapy. © 2013 Nature America, Inc. All rights reserved.


Ding H.,University of California at Los Angeles | Deroy P.L.,Paraza Pharma Inc. 7171 | Perreault C.,Paraza Pharma Inc. 7171 | Larivee A.,Paraza Pharma Inc. 7171 | And 4 more authors.
Angewandte Chemie - International Edition | Year: 2015

An electrochemical method to synthesize the core macrolactam of diazonamides is described. Large ring-forming dehydrogenation is initiated by anodic oxidation at a graphite surface. The reaction requires no tailoring of the substrate and occurs at ambient temperature in aqueous DMF in an undivided cell open to air. This unique chemistry has enabled a concise, scalable preparation of DZ-2384; a refined analog of diazonamide A slated for clinical development as a cancer therapeutic. Electrifying chemistry! The core macrolactam of diazonamides can be synthesized electrochemically. This large ring forming dehydrogenation has enabled a concise preparation of DZ-2384, a refined analog of diazonamide A slated for clinical development as a cancer therapeutic. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.


Ding H.,University of California at Los Angeles | Deroy P.L.,Paraza Pharma Inc. | Perreault C.,Paraza Pharma Inc. | Larivee A.,Paraza Pharma Inc. | And 4 more authors.
Angewandte Chemie - International Edition | Year: 2015

An electrochemical method to synthesize the core macrolactam of diazonamides is described. Large ring-forming dehydrogenation is initiated by anodic oxidation at a graphite surface. The reaction requires no tailoring of the substrate and occurs at ambient temperature in aqueous DMF in an undivided cell open to air. This unique chemistry has enabled a concise, scalable preparation of DZ-2384; a refined analog of diazonamide A slated for clinical development as a cancer therapeutic. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.


Huang S.,University of Houston | Ren X.,University of Houston | Wang L.,Joyant Pharmaceuticals | Zhang L.,University of Houston | Wu X.,University of Houston
Cancer Prevention Research | Year: 2011

Lung cancer is the leading cause of cancer death in both men and women in the United States, with a low 5-year survival rate despite improved treatment strategies. These data underscore the great need for effective chemoprevention of this cancer. Mutations and activation of KRAS occur frequently in, and are thought to be a primary driver of the development of, non-small cell lung cancers (NSCLC) of the adenocarcinoma subtype. In this study, we developed a new approach for the chemoprevention of NSCLC involving specific targeting of apoptosis in mutant KRAS cells. This approach is based on a synthetic lethal interaction among TNF-related apoptosis-inducing ligand (TRAIL), the second mitochondria-derived activator of caspase Smac/DIABLO (Smac), and KRAS. Mutational activation of KRAS modulated the expression of TRAIL receptors by upregulating death receptors and downregulating decoy receptors. Furthermore, oncogenic KRAS repressed cellular FADD-like interleukin 1β-converting enzyme (FLICE)-like inhibitory protein (c-FLIP) expression through activation of Erk/mitogen-activated protein kinase (MAPK)-mediated activation of c-Myc. Smac overcame KRAS-induced cell-survival signaling by antagonizing X-linked inhibitor of apoptosis protein (XIAP). Therefore, the combination of TRAIL and a small molecule mimic of Smac induced apoptosis specifically in mutant KRAS cells without harming normal cells. We further showed that short-term, intermittent in vivo treatment with TRAIL and Smac mimic induced apoptosis in tumor cells and reduced tumor burden in a murine model of KRAS-induced lung cancer. These results reflect the potential benefit of a selective therapeutic approach for the chemoprevention of NSCLC. ©2011 AACR.


Huerta S.,University of Texas Southwestern Medical Center | Gao X.,University of Texas Southwestern Medical Center | Livingston E.H.,University of Texas Southwestern Medical Center | Kapur P.,University of Texas Southwestern Medical Center | And 2 more authors.
Surgery | Year: 2010

Background: The response to neoadjuvant chemoradiation in rectal cancer is variable and unpredictable. Resistance to chemoradiation has been directly correlated with the levels of the inhibitors of apoptosis (IAPs) in several malignancies. Because smac-DIABLO is a pro-apoptotic gene product that directly inhibits the activity of the IAPs, molecules with similar activity might radiosensitize rectal tumors with phenotypes that express high levels of IAPs. This study was undertaken to assess the radiosensitizing properties of the smac mimetic JP-1201 in radioresistant HT-29 colorectal cancer cells in vitro and established xenografts in SCID mice. Methods: Survival was determined by clonogenic assays. PARP-1, caspase-8 cleavage, and IAP levels were assessed by Western blot analysis. SCID mice bearing HT-29 xenografts were treated with ionizing radiation: 2.0 Gy × 5; (n = 6), JP-1201 (5.0 mg/Kg i.p., n = 5) or combination treatment (n = 7) and compared to control (n = 8). DNA repair mechanisms were interrogated by γH2AX positive foci. Results: Pretreatment of HT-29 cells with JP-1201 (5.0 μM) prior to ionizing radiation (IR) significantly decreased the survival of these cells. SCID mice bearing HT-29 xenografts demonstrated no difference in tumor load in the group receiving exclusively JP-1201 versus control. At the end of the treatment (day 40), a 46% reduction of tumor load was observed in the IR+JP-1201-treated group compared to the IR-only treated group. Radiosensitization was achieved with a substantial elevation of cleaved PARP-1 in JP-1201- treated HT-29 cells versus control cells with a concomitant decrease of XIAP, but not of survivin or cIAP1/2. JP-1201-treated HT-29 cells had a reduced ability to repair double-stranded DNA breaks (DSBs). Conclusion: The smac mimetic JP-1201 decreased the survival of HT-29 cells and tumor growth by an additive effect in apoptosis and a reduction in the level of XIAP and an impairment of DNA repair mechanisms. The pathways leading to this response need to be further investigated. © 2010 Mosby, Inc.

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