Findings at Onsite Meeting, SLAS 2016

Compound Combinations SIG

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Presenters: Stephan Steigele & Oliver Leven (chair)

SIG’s mission:

The mission of the SLAS Compound Combination Screening SIG is

to create a knowledge-sharing forum for screening practitioners

active in the field of compound combinations. As such, the goal is to

mature the field of compound combination screening, aimed at

better science that accelerates the pace of drug discovery.

– No interest to change mission as of now

Current chair: Oliver Leven, Genedata

Co-chair: Rajarshi Guha, NIH

– Volunteer for chair or co-chair are welcome

Initiating the SIG / Logistics

Online forum to exchange ideas and questions around combination

screening

Currently 65 registered members

Rajashi will post interesting publications – others are welcome to

post as well

https://www.linkedin.com/groups/Compound-Combination-

Screening-SIG-SLAS-8421958/about

Linkedin Group

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Some numbers from an informal query

Total: 35 attendees

Background / interest

– More than 50% research scientists, majority active in the field of

combination screening

– About 10 persons from vendors (pipetting, software)

– About 25% of the attendees have practical experience in the field

– About 25% are interested because they might have to start combination

studios at some point

Meeting Statistics

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1. Typical experimental designs and their applications in different

therapeutic areas

2. Best practices in experimental designs for achieving better results

(i.e., self-cross)

3. Analysis options for the different types of experiments

4. Result quality assurance, standardization and comparability

5. Combination screening panels: systematic analysis of combination

effects across cell lines within one experiment

Agenda for SLAS 2016

Checkerboard / full matrix

– Require a lot of resources

Fixed Ratio / Ray

– Pro: High efficiency: An attendee reported studies showing 98%

accordance in findings for full matrix vs. singe ray experiments

– Con: Risk to miss effects if these are off the diagonal

Mentioned but not discussed

– “Sparse” matrices

– “Curve shift” design

Experimental Designs

Combination screening: look for new, promising combinations

(typically n compounds with know effect vs. m compounds with

assumed activity)

Target validation / chemical genomics: pin point pathways with

known compounds across different cell lines

Investigate compound behavior in combination for mechanistic

studies; to drive SAR (one compound has to be fixed for this)

Application areas

Screening technology

– Most experiments run with simple, stable screening technologies

(luminescence, fluorescence, …)

– HCS – but only single feature. HCS adds additional noise, which makes

the measurement of synergetic effects more difficult

Dispensing technology

– Pipetting (only used by a few)

– Acoustic (significant investment, but needed for any higher throughput)

– Piezo technology (flexible, but only for lower throughput)

Technologies used

Best practices discussed

– Self crosses / sham controls

– Replicates

– Cell line specific controls

A balance between throughput and understanding of replicability has

to be found

– Running self crosses and at least duplicates is recommended, but they

add to the overall effort.

– If run at (very) high throughput to screen for synergetic effects,

combinations without effect can be used to judge error and

reproducibility – so no replicates or self crosses would be needed

(single person’s opinion)

Best practices in experimental

designs for achieving better results

No findings / no discussion

Analysis options for the different

types of experiments

Known issues

– Single Ray designs might miss synergetic effects (if off-diagonal)

– Synergy scores may be dependent of matrix size (depending on the

actual calculation)

– How to compare results from different experimental setups

Result quality assurance,

standardization and comparability