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Your search keyword '"Raymon, Heather K."' showing total 2 results
Start Over Author "Raymon, Heather K." Topic antineoplastic agents
2 results on '"Raymon, Heather K."'

1. Discovery of mammalian target of rapamycin (mTOR) kinase inhibitor CC-223.

Author

Mortensen DS, Perrin-Ninkovic SM, Shevlin G, Zhao J, Packard G, Bahmanyar S, Correa M, Elsner J, Harris R, Lee BG, Papa P, Parnes JS, Riggs JR, Sapienza J, Tehrani L, Whitefield B, Apuy J, Bisonette RR, Gamez JC, Hickman M, Khambatta G, Leisten J, Peng SX, Richardson SJ, Cathers BE, Canan SS, Moghaddam MF, Raymon HK, Worland P, Narla RK, Fultz KE, and Sankar S

Subjects
Animals, Antineoplastic Agents chemical synthesis, Humans, Male, Models, Molecular, Molecular Structure, Protein Kinase Inhibitors chemical synthesis, Pyrazines chemical synthesis, Rats, Structure-Activity Relationship, Tumor Cells, Cultured, Antineoplastic Agents pharmacology, Drug Discovery, Phosphoinositide-3 Kinase Inhibitors, Prostatic Neoplasms drug therapy, Protein Kinase Inhibitors pharmacology, Pyrazines pharmacology, Signal Transduction drug effects, TOR Serine-Threonine Kinases antagonists & inhibitors
Abstract

We report here the synthesis and structure-activity relationship (SAR) of a novel series of mammalian target of rapamycin (mTOR) kinase inhibitors. A series of 4,6- or 1,7-disubstituted-3,4-dihydropyrazino[2,3-b]pyrazine-2(1H)-ones were optimized for in vivo efficacy. These efforts resulted in the identification of compounds with excellent mTOR kinase inhibitory potency, with exquisite kinase selectivity over the related lipid kinase PI3K. The improved PK properties of this series allowed for exploration of in vivo efficacy and ultimately the selection of CC-223 for clinical development.

Published
2015
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2. 1,1-Diarylalkenes as anticancer agents: dual inhibitors of tubulin polymerization and phosphodiesterase 4.

Author

Ruchelman AL, Man HW, Chen R, Liu W, Lu L, Cedzik D, Zhang L, Leisten J, Collette A, Narla RK, Raymon HK, and Muller GW

Subjects
Alkenes chemical synthesis, Animals, Antineoplastic Agents chemical synthesis, Antineoplastic Agents pharmacology, Benzene Derivatives chemical synthesis, Cell Proliferation drug effects, Colorectal Neoplasms metabolism, Cyclic Nucleotide Phosphodiesterases, Type 4 metabolism, HCT116 Cells, Humans, Inhibitory Concentration 50, Magnetic Resonance Spectroscopy, Mice, Models, Molecular, Molecular Dynamics Simulation, Phosphodiesterase Inhibitors chemical synthesis, Phosphodiesterase Inhibitors pharmacology, Structure-Activity Relationship, Tubulin metabolism, Tubulin Modulators chemical synthesis, Tubulin Modulators pharmacology, Alkenes chemistry, Alkenes pharmacology, Antineoplastic Agents chemistry, Benzene Derivatives chemistry, Benzene Derivatives pharmacology, Colorectal Neoplasms drug therapy, Phosphodiesterase Inhibitors chemistry, Tubulin Modulators chemistry
Abstract

A series of 1,1-diarylalkene derivatives were prepared to optimize the properties of CC-5079 (1), a dual inhibitor of tubulin polymerization and phosphodiesterase 4 (PDE4). By using the 3-ethoxy-4-methoxyphenyl PDE4 pharmacophore as one of the aromatic rings, a significant improvement in PDE4 inhibition was achieved. Compound 28 was identified as a dual inhibitor with potent PDE4 (IC(50)=54 nM) and antitubulin activity (HCT-116 IC(50)=34 nM and tubulin polymerization IC(50) ∼1 μM). While the nitrile group at the alkene terminus was generally required for potent antiproliferative activity, its replacement was tolerated if there was a hydroxyl or amino group on one of the aryl rings. Conveniently, this group could also serve as a handle for amino acid derivatization to improve the compounds' solubility. The glycinamide analog 45 showed significant efficacy in the HCT-116 xenograft model, with 64% inhibition of tumor growth upon dosing at 20 mg/kg qd., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Published
2011
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