Application of High-Throughput, Molecular-Targeted Screening to Anticancer Drug Discovery

Shoemaker, Robert H.; Scudiero, Dominic A.; Melillo, Giovanni; Currens, Michael J.; Monks, Anne; Rabow, Alfred A.; Covell, David G.; Sausville, Edward A.

doi:10.2174/1568026023394317

Cited by 88 publications

(42 citation statements)

References 72 publications

(60 reference statements)

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“…Such a HIGH-THROUGHPUT SCREENING (HTS) method can involve many different bioassays [6][7][8][9][10][11] , which monitor the effects of different compounds on specific targets (such as the ability to bind a protein), on specific cellular pathways (for example, the capacity to inhibit the mitogenic pathway of a tumour cell) 12 or on the phenotype of a whole cell or organism. The assays can be generally divided into cell-free, cell-based and organismal assays 13 . Cell-free, universal binding assays -in which several compounds are simultaneously tested for their binding affinity to a wide panel of specific targets -are usually simple, precise, highly automated and modern genomics methodologies.…”

Section: Experimental Chemogenomicsmentioning

confidence: 99%

“…Probably the most extensive HTS attempt for novel anticancer drug and target profiling is the in vitro cell-line screening project (IVCLSP) that has been undertaken by the Developmental Therapeutics Program (DTP) of the National Cancer Institute (NCI). Here, a panel of 60 untreated cancer cell lines -the so-called 'NCI60' -is used for the drug-discovery screening of 140,000 compounds from the NCI chemical library 13,48,49 . The aim is to 'fingerprint' and prioritize compounds for further evaluation.…”

Section: Chemogenomics and Cancer Researchmentioning

confidence: 99%

“…Potential targets are assessed en masse, allowing the activity patterns and DESCRIPTORS of molecular structure to be linked to genomic profiles. Compounds that are deemed to be sufficiently interesting in the screen are subjected to further experimental testing 13,48,49 . Chemogenomics-based anticancer drug discovery faces special challenges.…”

Section: Chemogenomics and Cancer Researchmentioning

confidence: 99%

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Chemogenomics: an emerging strategy for rapid target and drug discovery

2004

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Section: Experimental Chemogenomicsmentioning

confidence: 99%

Section: Chemogenomics and Cancer Researchmentioning

confidence: 99%

Section: Chemogenomics and Cancer Researchmentioning

confidence: 99%

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Chemogenomics: an emerging strategy for rapid target and drug discovery

2004

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“…In order to address this challenge, it is natural to screen subsets of large screening collections. A subset can be selected on the basis of target-specific, 7 gene familyspecific 8 or chemical diversity for wider coverage of chemical series. 9,10 Beginning in 2006, a novel form of subset screening coined plate-based diversity screening (PBDS) was developed and implemented in Pfizer.…”

Section: Introductionmentioning

confidence: 99%

A Heuristic Algorithm for Plate SelectionThat Maximizes Compound Diversity

Zhu¹,

Klug-McLeod²,

Bakken³

2013

Croat. Chem. Acta

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Abstract. A heuristic algorithm was developed to maximize compound diversity within a subset of screening plates used in high throughput screening (HTS) to initiate the drug discovery process. The approach overcame the challenge of combinatorial explosion for selecting plate subsets with maximum compound diversity. The method yielded novel forms of plate-based diversity subsets (PBDS) for HTS screening in lead discovery. The algorithm, its validation and the application to our screening collection are outlined.

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“…One advantage of cell-based HIF-1-targeted HTS is the prospect of discovering small molecules that inhibit unidentified components of the hypoxic cell signaling pathway. However, several extensive mechanistic investigations are frequently required to validate any potential anti HIF-1 compound identified in the primary screen [57]; therefore more experiments are usually expected and routinely performed for the validation purposes.…”

Section: Design and Validation Of A High-throughput Screen System Formentioning

confidence: 99%

Inhibition of Breast Cancer Angiogenesis and Metastasis ay Targeting Hypoxia-Inducible Factor-1α

Madu¹

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DEDICATION"To (God) who is able to do immeasurably more than all we ask or imagine, according to his power that is at work within us"-Ephesians 3:20.And to my family-my wife, Pamela; and my children, Chinua and Elechi. For all you did to sustain my choice. Without you, this will not be.iv ACKNOWLEDGEMENTS I observe this dissertation today not as a completion of a search, but a celebration of success; symbolizing a temporary end as well as a beginning-signifying an achievement as well as triumph.This project culminating into this dissertation would not have been possible if it were not for the contributions and assistance I received from several people. In an attempt to express my appreciation, it will be very difficult to find words that have not already been used over again-a situation where statements will seem no longer sufficient and words inadequate. However I still wish to acknowledge the following persons who stood by me and contributed to make this long-nursed dream a reality.I would like thank my mentor, Dr Yi Lu, for the opportunity to work in his lab, and supervising this project. To my committee members, Dr Wei Li (for providing the compounds used in this project), Dr Leonard Lothstein (for his input, valuable discussions, and accessibility; for listening and reassuring), Dr Ram I Mahato (for his kind words of encouragement and permitting me to use his lab equipment), Dr Andrzej T Slominski (for his wise suggestions). Thank you for accepting to serve as members of this committee, your thoughtful criticism, and involvement during the course of this project. I would like to thank Dr liyuan Li for the lab training. I gratefully acknowledge Dr Pfeffer for his advice, and unending encouragement and support.My mother merits special thanks for her support and sacrifice through the years. So does my father-in-law, Obong Okon Mkpong, for his prayers and encouragement. Sufficient words fail me in expressing my gratitude to my wife, Eno-Obong Pamela, whose love, dedication, and relentless confidence in me was the driving force behind all of this. You are the bedrock upon which the past twelve years of my life have been built. My ambition was great, but your faith in me was greater. I love you dearly! To my children Chinua and Elechi, for their love, and understanding during the long years of my education, and sacrificially spending three summers with me in the lab-I promise, this is it! This project would never have been completed without the encouragement and devotion of all of you, and so many other family members and friends. In the words of President John F. Kennedy, "In your hands, more than mine, rest the final success of (my) course". Thank you! v ABSTRACTThe current clinical chemotherapy agents are not ideal for breast cancer as they are not curative, but only provide a modest extension of survival with sometimes a severely adverse effect on the patient's quality of life. There is, therefore, an urgent need to search for new and more effective anti-breast cancer drugs. However, the existing screening sy...

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Application of High-Throughput, Molecular-Targeted Screening to Anticancer Drug Discovery

Cited by 88 publications

References 72 publications

Chemogenomics: an emerging strategy for rapid target and drug discovery

Chemogenomics: an emerging strategy for rapid target and drug discovery

A Heuristic Algorithm for Plate SelectionThat Maximizes Compound Diversity

Inhibition of Breast Cancer Angiogenesis and Metastasis ay Targeting Hypoxia-Inducible Factor-1α

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