Antiangiogenic Activity and in Silico Cereblon Binding Analysis of Novel Thalidomide Analogs
Megan L. Peach,
Shaunna L. Beedie,
Cindy H. Chau,
Matthew K. Collins,
Suzana Markolovic,
Weiming Luo,
David Tweedie,
Christian Steinebach,
Nigel H. Greig,
Michael Gütschow,
Neil Vargesson,
Marc C. Nicklaus,
William D. Figg
Affiliations
Megan L. Peach
Basic Science Program, Chemical Biology Laboratory, Frederick National Laboratory for Cancer Research, National Cancer Institute, Frederick, MD 21701, USA
Shaunna L. Beedie
Molecular Pharmacology Section, Genitourinary Malignancies Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD 20892, USA
Cindy H. Chau
Molecular Pharmacology Section, Genitourinary Malignancies Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD 20892, USA
Matthew K. Collins
Molecular Pharmacology Section, Genitourinary Malignancies Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD 20892, USA
Suzana Markolovic
Molecular Pharmacology Section, Genitourinary Malignancies Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD 20892, USA
Weiming Luo
Drug Design & Development Section, Translational Gerontology Branch, National Institute on Aging, NIH, Baltimore, MD 21224, USA
David Tweedie
Drug Design & Development Section, Translational Gerontology Branch, National Institute on Aging, NIH, Baltimore, MD 21224, USA
Christian Steinebach
Pharmaceutical Institute, University of Bonn, 53121 Bonn, Germany
Nigel H. Greig
Drug Design & Development Section, Translational Gerontology Branch, National Institute on Aging, NIH, Baltimore, MD 21224, USA
Michael Gütschow
Pharmaceutical Institute, University of Bonn, 53121 Bonn, Germany
Neil Vargesson
School of Medicine, Medical Sciences & Nutrition, Institute of Medical Sciences, University of Aberdeen, Aberdeen AB25 2ZD, UK
Marc C. Nicklaus
Chemical Biology Laboratory, Center for Cancer Research, National Cancer Institute, NIH, Frederick, MD 21701, USA
William D. Figg
Molecular Pharmacology Section, Genitourinary Malignancies Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD 20892, USA
Due to its antiangiogenic and anti-immunomodulatory activity, thalidomide continues to be of clinical interest despite its teratogenic actions, and efforts to synthesize safer, clinically active thalidomide analogs are continually underway. In this study, a cohort of 27 chemically diverse thalidomide analogs was evaluated for antiangiogenic activity in an ex vivo rat aorta ring assay. The protein cereblon has been identified as the target for thalidomide, and in silico pharmacophore analysis and molecular docking with a crystal structure of human cereblon were used to investigate the cereblon binding abilities of the thalidomide analogs. The results suggest that not all antiangiogenic thalidomide analogs can bind cereblon, and multiple targets and mechanisms of action may be involved.
