Chemical Proteomics Facilitating Drug Discovery

Apr
11
2018

Analytica Conference > GBM / Room 2 > OMICS Tools for Precision Medicine

11. Apr 2018
12:30-13:00 h  |  ICM - Internationales Congress Center München Room 2

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Subjects: 

Biotechnology & Life Sciences

|

Medicine/public health

|

Pharma & Diagnostics

Speaker: 

Prof. Dr. Roman A. Zubarev 

(Karolinska Institutet)

Type:
Lecture
Speech: English

Traditionally, Chemical proteomics is defined as the use of small molecules to decipher
the role and function of proteins. But with more and more academic researchers
abandoning the studies of the fundamental biological processes and focusing instead
on early stages of drug discovery, this definition was turned upside down. Today,
Chemical proteomics is defined as the use of proteomics methods to identify the target
and the mechanism of action of small-molecule drugs.

Recently, powerful tools of chemical proteomics emerged, such as thermal proteome
profiling (TPP) and functional identification of target by expression proteomics (FITExP
[1]). In TPP, cell lysates, living cells or animals are treated (or not) with a drug, after
which the tissue (in case of animals) is excised, the cells are incubated at different
temperatures, cells are lysed, the thermally unfolded proteins are centrifuged down,
and the remaining soluble proteins are analysed by proteomics. This way, for each of
5,000-8,000 proteins, a “melting curve” is obtained, from which melting temperature Tm
is extracted. The shift in Tm in the presence of drug versus drug absence provides the
degree of stabilization by drug binding. Thus protein list sorted by ΔTm reveals likely
drug target candidates. Alternatively, the temperature is fixed and the drug
concentration is altered. The shift in protein abundance indicates drug engagement by
the protein, thus concentration dependence can help differentiating primary targets
from secondary targets.

TPP is a powerful tool but it has its limitations, not least in terms of specificity. To
increase the specificity of drug target identifications, we have developed FITExP [1]. In
FITExP, a panel (2-5) of cell lines is treated by a panel of drug molecules for 48 h at a
dose that induces 50% cell death, after which the still-alive cells are collected and their
proteomes are analyzed by LC-MS. Bioinformatic analysis of the protein abundances
reveals for each drug in the panel a set of specifically and extraordinarily regulated
proteins, that usually includes the drug target as one of the most prominent members.
FITExP analysis applied to A549 cells and 60 different drugs provided a database of
characteristic proteome responses (TargetMiner) which helps identifying the
mechanism of cancer cell death [2].

Both TPP and FITExP require extensive LC-MS/MS analyses performed using Orbitrap
mass spectrometers.

Literature:

[1] Chernobrovkin AL, Marin Vicente C, Visa N, Zubarev RA, Sci. Rep. 2015, 5, 11176.
[2] Saei A, Zubarev RA, et al. manuscript in preparation.

Speaker
Prof. Dr. Roman A. Zubarev, Karolinska Institutet Show Profile

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Apr
11
2018

Analytica Conference > GBM / Room 2 > OMICS Tools for Precision Medicine

Rapid Analysis of Human Proteomes for Precision Medicine

11. Apr 2018
09:30-10:00 h  |  ICM - Internationales Congress Center München Room 2
Speaker: Prof. Dr. Jesper V. Olsen (University of Copenhagen)

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Apr
10
2018

Analytica Conference > GBM / Room 2 > OMICS Tools for Precision Medicine

Proteogenomics: Redefining the Approach for Precision Cancer Medicine

10. Apr 2018
13:00-13:30 h  |  ICM - Internationales Congress Center München Room 2
Speaker: Prof. Dr. Thomas A. Conrads

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Apr
11
2018

Analytica Conference > GBM / Room 2 > OMICS Tools for Precision Medicine

Development and Delivery of Mass Spectrometry Based Multiplexed Protein Biomarker Assays for Advanced Diagnostic Tests

11. Apr 2018
10:00-10:30 h  |  ICM - Internationales Congress Center München Room 2
Speaker: Prof. Dr. Stephen Pennington

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Apr
11
2018

Analytica Conference > GBM / Room 2 > OMICS Tools for Precision Medicine

OMICS tools to characterize platelet function

11. Apr 2018
13:30-14:00 h  |  ICM - Internationales Congress Center München Room 2
Speaker: Prof. Dr. Albert Sickmann (Leibniz-Institut für Analytische Wissenschaften - ISAS - e.V.)

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Apr
11
2018

Analytica Conference > GBM / Room 2 > OMICS Tools for Precision Medicine

Biomarkers for the detection of idiosyncratic liver injury

11. Apr 2018
14:00-14:30 h  |  ICM - Internationales Congress Center München Room 2
Speaker: Dr. Oliver Pötz (NMI Natural and Medical Sciences Institute / Signatope GmbH)

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