Ron de Jong
Takeda Pharmaceutical Company
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Featured researches published by Ron de Jong.
Molecular and Cellular Biology | 2005
Rachael M. Easton; Han Cho; Kristin Roovers; Diana W. Shineman; Moshe Mizrahi; Virginia M.-Y. Lee; Matthias Szabolcs; Ron de Jong; Tilman Oltersdorf; Thomas Ludwig; Argiris Efstratiadis; Morris J. Birnbaum
ABSTRACT Studies of Drosophila and mammals have revealed the importance of insulin signaling through phosphatidylinositol 3-kinase and the serine/threonine kinase Akt/protein kinase B for the regulation of cell, organ, and organismal growth. In mammals, three highly conserved proteins, Akt1, Akt2, and Akt3, comprise the Akt family, of which the first two are required for normal growth and metabolism, respectively. Here we address the function of Akt3. Like Akt1, Akt3 is not required for the maintenance of normal carbohydrate metabolism but is essential for the attainment of normal organ size. However, in contrast to Akt1− / − mice, which display a proportional decrease in the sizes of all organs, Akt3 −/− mice present a selective 20% decrease in brain size. Moreover, although Akt1- and Akt3-deficient brains are reduced in size to approximately the same degree, the absence of Akt1 leads to a reduction in cell number, whereas the lack of Akt3 results in smaller and fewer cells. Finally, mammalian target of rapamycin signaling is attenuated in the brains of Akt3 −/− but not Akt1 −/− mice, suggesting that differential regulation of this pathway contributes to an isoform-specific regulation of cell growth.
Molecular Cancer Therapeutics | 2005
Yan Luo; Alexander R. Shoemaker; Xuesong Liu; Keith W. Woods; Sheela A. Thomas; Ron de Jong; Edward K. Han; Tongmei Li; Vincent S. Stoll; Jessica Powlas; Anatol Oleksijew; Michael J. Mitten; Yan Shi; Ran Guan; Thomas McGonigal; Vered Klinghofer; Eric F. Johnson; Joel D. Leverson; Jennifer J. Bouska; Mulugeta Mamo; Richard Smith; Emily Gramling-Evans; Bradley A. Zinker; Amanda K. Mika; Phong T. Nguyen; Tilman Oltersdorf; Saul H. Rosenberg; Qun Li; Vincent L. Giranda
The Akt kinases are central nodes in signal transduction pathways that are important for cellular transformation and tumor progression. We report the development of a series of potent and selective indazole-pyridine based Akt inhibitors. These compounds, exemplified by A-443654 (Ki = 160 pmol/L versus Akt1), inhibit Akt-dependent signal transduction in cells and in vivo in a dose-responsive manner. In vivo, the Akt inhibitors slow the progression of tumors when used as monotherapy or in combination with paclitaxel or rapamycin. Tumor growth inhibition was observed during the dosing interval, and the tumors regrew when compound administration was ceased. The therapeutic window for these compounds is narrow. Efficacy is achieved at doses ∼2-fold lower than the maximally tolerated doses. Consistent with data from knockout animals, the Akt inhibitors induce an increase in insulin secretion. They also induce a reactive increase in Akt phosphorylation. Other toxicities observed, including malaise and weight loss, are consistent with abnormalities in glucose metabolism. These data show that direct Akt inhibition may be useful in cancer therapy, but significant metabolic toxicities are likely dose limiting.
Bioorganic & Medicinal Chemistry Letters | 2010
Jerome C. Bressi; Andy Jennings; Robert J. Skene; Yiqin Wu; Robert Melkus; Ron de Jong; Shawn O’Connell; Charles E. Grimshaw; Marc Navre; Anthony R. Gangloff
A series of N-(2-amino-5-substituted phenyl)benzamides (3-21) were designed, synthesized and evaluated for their inhibition of HDAC2 and their cytotoxicity in HCT116 cancer cells. Multiple compounds from this series demonstrated time-dependent binding kinetics that is rationalized using a co-complex crystal structure of HDAC2 and N-(4-aminobiphenyl-3-yl)benzamide (6).
Bioorganic & Medicinal Chemistry Letters | 2010
Jerome C. Bressi; Ron de Jong; Yiqin Wu; Andy Jennings; Jason W. Brown; Shawn O’Connell; Leslie W. Tari; Robert J. Skene; Phong H. Vu; Marc Navre; Xiaodong Cao; Anthony R. Gangloff
A series of N-hydroxy-3-[3-(1-substituted-1H-benzoimidazol-2-yl)-phenyl]-acrylamides (5a-5ab) and N-hydroxy-3-[3-(1,4,5-trisubstituted-1H-imidazol-2-yl)-phenyl]-acrylamides (12a-s) were designed, synthesized, and found to be nanomolar inhibitors of human histone deacetylases. Multiple compounds bearing an N1-piperidine demonstrate EC(50)s of 20-100 nM in human A549, HL60, and PC3 cells, in vitro and in vivo hyperacetylation of histones H3 and H4, and induction of p21(waf). Compound 5x displays efficacy in human tumor xenograft models.
Bioorganic & Medicinal Chemistry Letters | 2013
Anthony R. Gangloff; Jason W. Brown; Ron de Jong; Douglas R. Dougan; Charles E. Grimshaw; Mark S. Hixon; Andy Jennings; Ruhi Kamran; Andre A. Kiryanov; Shawn O’Connell; Ewan Taylor; Phong H. Vu
Structure based drug design of a series of novel 1,4-benzoxazin-3-one derived PARP-1 inhibitors are described. The synthesis, enzymatic & cellular activities and pharmacodynamic effects are described. Optimized analogs demonstrated inhibition of poly-ADP-ribosylation in SW620 tumor bearing nude mice through 24h following a single dose.
Molecular Cancer Therapeutics | 2013
Pamela Farrell; Lihong Shi; Jennifer Matuszkiewicz; Deepika Balakrishna; Takashi Hoshino; Lilly Zhang; Sarah Elliott; Robyn Fabrey; Bumsup Lee; Petro Halkowycz; Bi-Ching Sang; Seigo Ishino; Toshiyuki Nomura; Mika Teratani; Yoshikazu Ohta; Charles E. Grimshaw; Bheema R. Paraselli; Takashi Satou; Ron de Jong
Protein kinases Aurora A, B, and C play essential roles during mitosis and cell division, are frequently elevated in cancer, and represent attractive targets for therapeutic intervention. TAK-901 is an investigational, multitargeted Aurora B kinase inhibitor derived from a novel azacarboline kinase hinge-binder chemotype. TAK-901 exhibited time-dependent, tight-binding inhibition of Aurora B, but not Aurora A. Consistent with Aurora B inhibition, TAK-901 suppressed cellular histone H3 phosphorylation and induced polyploidy. In various human cancer cell lines, TAK-901 inhibited cell proliferation with effective concentration values from 40 to 500 nmol/L. Examination of a broad panel of kinases in biochemical assays revealed inhibition of multiple kinases. However, TAK-901 potently inhibited only a few kinases other than Aurora B in intact cells, including FLT3 and FGFR2. In rodent xenografts, TAK-901 exhibited potent activity against multiple human solid tumor types, and complete regression was observed in the ovarian cancer A2780 model. TAK-901 also displayed potent activity against several leukemia models. In vivo biomarker studies showed that TAK-901 induced pharmacodynamic responses consistent with Aurora B inhibition and correlating with retention of TAK-901 in tumor tissue. These preclinical data highlight the therapeutic potential of TAK-901, which has entered phase I clinical trials in patients within a diverse range of cancers. Mol Cancer Ther; 12(4); 460–70. ©2013 AACR.
Bioorganic & Medicinal Chemistry Letters | 2016
Betty Lam; Yasuyoshi Arikawa; Joshua Cramlett; Qing Dong; Ron de Jong; Victoria Feher; Charles E. Grimshaw; Pamela Farrell; Isaac D. Hoffman; Andy Jennings; Benjamin Jones; Jennifer Matuszkiewicz; Joanne Miura; Hiroshi Miyake; Srinivasa Reddy Natala; Lihong Shi; Masashi Takahashi; Ewan Taylor; Corey Wyrick; Jason Yano; Jonathan Zalevsky; Zhe Nie
Spleen Tyrosine Kinase (SYK) is a non-receptor cytoplasmic tyrosine kinase that is primarily expressed in hematopoietic cells. SYK is a key mediator for a variety of inflammatory cells, including B cells, mast cells, macrophages and neutrophils and therefore, an attractive approach for treatment of both inflammatory diseases and oncology indications. Using in house co-crystal structure information, and structure-based drug design, we designed and optimized a novel series of heteroaromatic pyrrolidinone SYK inhibitors resulting in the selection of the development candidate TAK-659. TAK-659 is currently undergoing Phase I clinical trials for advanced solid tumor and lymphoma malignancies, a Phase Ib study in advanced solid tumors in combination with nivolumab, and PhIb/II trials for relapsed/refractory AML.
Bioorganic & Medicinal Chemistry Letters | 2017
Walter Keung; Amogh Boloor; Jason W. Brown; Andre A. Kiryanov; Anthony R. Gangloff; J. David Lawson; Robert J. Skene; Isaac D. Hoffman; Josephine M. Atienza; Jason Kahana; Ron de Jong; Pamela Farrell; Deepika Balakrishna; Petro Halkowycz
Axl has been a target of interest in the oncology field for several years based on its role in various oncogenic processes. To date, no wild-type Axl crystal structure has been reported. Herein, we describe the structure-based optimization of a novel chemotype of Axl inhibitors, 1H-imidazole-2-carboxamide, using a mutated kinase homolog, Mer(I650M), as a crystallographic surrogate. Iterative optimization of the initial lead compound (1) led to compound (21), a selective and potent inhibitor of wild-type Axl. Compound (21) will serve as a useful compound for further in vivo studies.
Journal of Clinical Investigation | 2018
Matthew Riopel; Jong Bae Seo; Gautam Bandyopadhyay; Pingping Li; Joshua Wollam; Heekyung Chung; Seung-Ryoung Jung; Anne N. Murphy; Maria Wilson; Ron de Jong; Sanjay Patel; Deepika Balakrishna; James Bilakovics; Andrea Fanjul; Artur Plonowski; Duk Su Koh; Christopher J. Larson; Jerrold M. Olefsky; Yun Sok Lee
We have previously reported that the fractalkine (FKN)/CX3CR1 system represents a novel regulatory mechanism for insulin secretion and &bgr; cell function. Here, we demonstrate that chronic administration of a long-acting form of FKN, FKN-Fc, can exert durable effects to improve glucose tolerance with increased glucose-stimulated insulin secretion and decreased &bgr; cell apoptosis in obese rodent models. Unexpectedly, chronic FKN-Fc administration also led to decreased &agr; cell glucagon secretion. In islet cells, FKN inhibited ATP-sensitive potassium channel conductance by an ERK-dependent mechanism, which triggered &bgr; cell action potential (AP) firing and decreased &agr; cell AP amplitude. This results in increased glucose-stimulated insulin secretion and decreased glucagon secretion. Beyond its islet effects, FKN-Fc also exerted peripheral effects to enhance hepatic insulin sensitivity due to inhibition of glucagon action. In hepatocytes, FKN treatment reduced glucagon-stimulated cAMP production and CREB phosphorylation in a pertussis toxin–sensitive manner. Together, these results raise the possibility of use of FKN-based therapy to improve type 2 diabetes by increasing both insulin secretion and insulin sensitivity.
Molecular Cancer Therapeutics | 2009
Takashi Satou; Takashi Hoshino; Pamela Farrell; Lilly Zhang; Sarah Elliott; Robyn Fabrey; Bumsup Lee; Bheema R. Paraselli; Seigo Ishino; Toshiyuki Nomura; Mika Teratani; Yoshikazu Ohta; Ron de Jong
Aurora kinases play an essential role in cell division, specifically orchestrating several intricate steps during the mitotic phase of the cell cycle. The human genome encodes for 3 Aurora kinase genes, designated Aurora A, B, and C. Aurora A localizes to centrosomes and spindle poles and is required for mitotic spindle assembly, whereas Aurora B is a chromosome passenger protein required for phosphorylation of histone H3, chromosome segregation, and cytokinesis. Expression levels of Aurora A and B kinases are frequently elevated in human cancers making them attractive targets for therapeutic intervention. TAK‐901 is an Aurora B kinase inhibitor with multi‐targeted inhibitory activity against other kinases important in malignancy. In the present study, we investigated the pharmacodynamic effects and in vivo activity of TAK‐901 in human tumor xenograftmodels. In solid tumor xenograft models, potent dose‐dependent antitumor activity was observed against HCT116 (colon), H460 (large cell lung) and A2780 (ovary) cancer models by twice daily intravenous dosing on 2 consecutive days per week for 3 cycles. TAK‐901 also displayed potent activity against several leukemia models such as subcutaneously implanted MV4‐11 and HL60 (AML). In the A2780, HCT116, and HL60 models, TAK‐901 induced tumor regression at higher dose levels, including complete regression of A2780 tumors at 30 and 45 mg/kg/injection. When dosed in combination with chemotherapeutic agents, such as irinotecan in the HCT116 model or daunorubicin in the HL60 model, TAK‐901 produced additive effects. Following intravenous administration of 20 and 40 mg/kg TAK‐901 in the A2780 xenograft model, histone H3 phosphorylation was completely suppressed for at least 6 hours and in the 40 mg/kg treated tumors did not return to control levels during the 12 hour time course. After multiple doses of TAK‐901, polyploidy was observed in the tumor samples. TAK‐901 drug levels remained constant throughout the time course in tumor tissues whereas plasma levels declined steadily. These in vivo biomarker studies demonstrate that TAK‐901 induces pharmacodynamic responses consistent with Aurora B kinase inhibition, which correlates with effective retention of TAK 901 in tumor tissues. Taken together, these preclinical data emphasize the therapeutic potential of TAK‐ 901 in the treatment of diverse human malignancies. TAK‐901 is currently under investigation in Phase I clinical trials. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):C193.