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

doi:10.3390/molecules25235683

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^* (Corresponding Author)

^*Corresponding author for this work

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Abstract

Due to its anti-angiogenic 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 anti-angiogenic 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 anti-angiogenic thalidomide analogs can bind cereblon, and multiple targets and mechanisms of action may be involved.

Original language	English
Article number	5683
Number of pages	18
Journal	Molecules
Volume	25
Issue number	23
DOIs	https://doi.org/10.3390/molecules25235683
Publication status	Published - 2 Dec 2020

Keywords

angiogenesis
thalidomide
SAR
cereblon
docking
structure-activity
relationships
structure–activity relationships

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Cite this

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title = "Antiangiogenic Activity and in Silico Cereblon Binding Analysis of Novel Thalidomide Analogs",

abstract = "Due to its anti-angiogenic 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 anti-angiogenic 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 anti-angiogenic thalidomide analogs can bind cereblon, and multiple targets and mechanisms of action may be involved.",

keywords = "angiogenesis, thalidomide, SAR, cereblon, docking, structure-activity, relationships, structure–activity relationships",

author = "Peach, {Megan L} and Shaunna-L Beedie and Chau, {Cindy H.} and Collins, {Matthew K} and Suzana Markolovic and Weiming Luo and David Tweedie and Christian Steinebach and Greig, {Nigel H} and Michael G{\"u}tschow and Neil Vargesson and Nicklaus, {Marc C.} and Figg, {William D}",

note = "Funding: This research was supported in part by the Intramural Research Program of the Center for Cancer Research, National Cancer Institute (ZIA SC006538); in part with Federal funds from the Frederick National Laboratory for Cancer Research, National Institutes of Health, under contract HHSN261200800001E; the Intramural Research Program of the National Institute on Aging, National Institutes of Health; and a Wellcome Trust-NIH PhD Studentship to SB, WDF, and NV (Grant number 098252/Z/12/Z). Acknowledgments: The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products or organizations imply endorsement by the US Government.",

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doi = "10.3390/molecules25235683",

language = "English",

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AU - Peach, Megan L

AU - Beedie, Shaunna-L

AU - Chau, Cindy H.

AU - Collins, Matthew K

AU - Markolovic, Suzana

AU - Luo, Weiming

AU - Tweedie, David

AU - Steinebach, Christian

AU - Greig, Nigel H

AU - Gütschow, Michael

AU - Vargesson, Neil

AU - Nicklaus, Marc C.

AU - Figg, William D

N1 - Funding: This research was supported in part by the Intramural Research Program of the Center for Cancer Research, National Cancer Institute (ZIA SC006538); in part with Federal funds from the Frederick National Laboratory for Cancer Research, National Institutes of Health, under contract HHSN261200800001E; the Intramural Research Program of the National Institute on Aging, National Institutes of Health; and a Wellcome Trust-NIH PhD Studentship to SB, WDF, and NV (Grant number 098252/Z/12/Z). Acknowledgments: The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products or organizations imply endorsement by the US Government.

PY - 2020/12/2

Y1 - 2020/12/2

N2 - Due to its anti-angiogenic 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 anti-angiogenic 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 anti-angiogenic thalidomide analogs can bind cereblon, and multiple targets and mechanisms of action may be involved.

AB - Due to its anti-angiogenic 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 anti-angiogenic 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 anti-angiogenic thalidomide analogs can bind cereblon, and multiple targets and mechanisms of action may be involved.

KW - angiogenesis

KW - thalidomide

KW - SAR

KW - cereblon

KW - docking

KW - structure-activity

KW - relationships

KW - structure–activity relationships

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U2 - 10.3390/molecules25235683

DO - 10.3390/molecules25235683

M3 - Article

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JO - Molecules

JF - Molecules

SN - 1420-3049

IS - 23

M1 - 5683

ER -

Antiangiogenic Activity and in Silico Cereblon Binding Analysis of Novel Thalidomide Analogs

Abstract

Keywords

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