In vivo protein target identification / target deconvolution via chemical proteomics as a facilitating tool for phenotype based drug discovery. www.j-vomacka.com

1. tarGETiDtarget identification strategy

2. The chance of phenotype based drug discovery.
Phenotype based drug discovery offers the opportunity to screen
active compounds directly with complex biological systems. Whole
cells can be used instead of in vitro protein assays.
An increased focus on phenotype based screening will help to
develop innovative first-in-class drugs and will contribute to lower
project attrition rates.
The challenge. Mechanism of action and direkt protein targets of
phenotype based screening hits are initially unknown.
2
1 Swinney, D.C., Phenotypic vs. target-based drug discovery for first-in-class medicines. Clin Pharmacol Ther, 2013. 93(4): p. 299-301.
2 Swinney, D.C. and J. Anthony, How were new medicines discovered? Nat Rev Drug Discov, 2011. 10(7): p. 507-519.
3 Kotz, J., Phenotypic screening, take two. Science–Business eXchange, 2012. 5(15): p. 1-3.

3. 3
How can chemical proteomics help?
By phenotypic screening active compounds with a potentially
unique mode of action (first-in-class) are identified. With chemical
proteomics the relevant protein interaction partner(s) in whole cells
can be determined. After a sucessfull target identification one can
proceed with a regular target based drug development process
(best-in-class).
phenotype based
drug discovery
target based
drug development
1 Swinney, D.C., Phenotypic vs. target-based drug discovery for first-in-class medicines. Clin Pharmacol Ther, 2013. 93(4): p. 299-301.
2 Swinney, D.C. and J. Anthony, How were new medicines discovered? Nat Rev Drug Discov, 2011. 10(7): p. 507-519.
3 Kotz, J., Phenotypic screening, take two. Science–Business eXchange, 2012. 5(15): p. 1-3.

4. 4
The benefits of knowing the protein interaction partners.
• Chemical structure optimization of a screening hit based on
crystal structure-guided rational design.
• New active structures by target-based high throughput screening.
• Better understanding of the toxicology of a candidate.
• Off-target profile for priorization of projects at an early
development stage.

5. 5
Target identification technology.
Starting point. Small molecule causing a desired effect in human
or microbial cell culture.
Design of a chemical probe. A derivative of the active compound
is synthesized: The chemical probe. Changes of the chemical
structure ideally should have only a minimal effect on the
biological activity.
active compound chemical probe

6. 6
Target identification technology.
target protein(s)
interaction partners
of active compound
cell lysis
biotin / avidin enrichment
quantitative MS analysis
covalent bond
formation by
UV irradiation
labeling of
whole cells
chemical probe

7. 7
Target identification technology.
Target identification process. Cells are cultured and incubated with
the chemical probe bearing a photoactivatable moiety. Covalent
binding to the protein targets is then achieved by UV irradiation.
After cell lysis a biotin tag is attached to the probe. Target proteins
are enriched with the help of avidin beads. Quantitative mass
spectrometric analysis of probe treated vs. control samples finally
reveals the targets.

8. 8
Jan Vomacka, a short CV.
Jan Vomacka, geb. 14.01.88

9. 9
Techniche Universität München
10/2008 - 05/2013 Chemistry, B.Sc. and M.Sc.
since 06/2013 Chemistry, PhD student
AVIRU GmbH
01/2013 - 12/2014
Anti-virulence drug development (MRSA).
tarGET iD (seed phase)
01/2015 - 05/2015
Target identification via chemical proteomics.

10. What I offer.
experience with:
• chemical proteomics
• assay development
• target identification (deconvolution) and validation
• phenotype based drug development (anti-infectives, MRSA)
10

11. What I seek.
• challenges with impact on pharmaceutical industry
• teamwork
• project management
• intrapreneurship
• trust-based working hours
• personal responsibility
11

12. Jan Vomacka
www.j-vomacka.com
vomacka@me.com / +49 160 7882820
Gowirichweg 6a / D-85748 Garching