PAINS: Elucidation of mechanisms of action in inhibiting translation

Project type

Honours and/or PhD

Supervisor(s) Division Email

Associate Professor Jonathan Baell

(Primary)		 Chemical Biology .(JavaScript must be enabled to view this email address)

Dr Chris Burns

(Co-supervisor)		 Chemical Biology .(JavaScript must be enabled to view this email address)

 

Details of project

In 2003, the Walter and Eliza Hall Institute was one of the few worldwide to have established a large library of compounds for screening, in our case numbering some 93,212. Over the subsequent years, it became clear that certain classes of compounds frequently appeared as screening hits, but because they did so, were almost certainly non-specifically active. 

These pan assay interference compounds (PAINS) can furnish biological data that makes them appear to be real and selective for the target of interest. As a result, high profile publications mistakenly describing PAINS as progressable compounds are becoming increasingly prevalent. Our 2010 publication describing these classes has been met with intense interest and is currently the second most cited paper in the Journal of Medicinal Chemistry over the last three years. 

Part of the problem in identifying PAINS is that there is simply no knowledge on how these compounds are being so subversive. We have recently identified some compounds that have been suggested as being selective inhibitors of the translation initiation complex eIF4F and thus representing potential anti-cancer agents. The data is convincing and the journal high impact, but currently, we recognise these compounds as PAINS.

The question is, can we also show these compounds to be selective and “real”? If this is the case we may need to refine our definitions of PAINS and, in expanding structure-activity relationships (SAR), could find more potent and drug-like compounds as potential anti-cancer agents. Alternatively, can we find evidence to suggest that they are false and non-specifically active? These are the questions to be answered in this project, which will involve the synthesis of an SAR set of these compounds, investigations into in vitro reactivity, and assessment of their biological behaviour in assays for inhibition of eIF4F.

Project references

  1. Saubern S, Guha R, Baell JB. KNIME workflow to assess PAINS filters in SMARTS format. Comparison of RDKit and Indigo Cheminform libraries. Mol. Inf. 2011 (in print). DOI: 10.1002/minf.201100076.
  2. Lagorce D, Maupetit J, Baell J, Sperandio O, Tuffery P, Miteva MA, Galons G, Villoutreix BO. The FAF-Drugs2 server: a multistep engine to prepare electronic chemical compound libraries. Bioinformat. 2011 27:2018-2020.
  3. Cencic R, Hall DR, Robert F, Du Y, Min J, Li L, Qui M, Lewis L, Kurtkaya, Dingledine R, Fu H, Kozakov D, Vajda S, Pelletier J. Reversing chemoresistance by small molecule inhibition of the translation initiation complex eIF4F. Proc. Natl. Acad. Sci. USA 2011 108:1046-1051.
  4. Baell JB. Observations on screening-based research and some concerning trends in the literature. Future Med. Chem. 2010, 2:1529–1546.
  5. Baell JB, Holloway GA.  New substructure filters for removal of pan assay interference compounds [PAINS] from screening libraries and for their exclusion in bioassays. J. Med. Chem. 2010, 53:2719-2740.

Research interests

The Medicinal Chemistry laboratory, part of the division of Chemical Biology, conducts research aimed at developing new therapeutically useful molecules. Projects in the laboratory currently focus on cancer and parasitic diseases such as malaria, human African trypanosomiasis (sleeping sickness), leishmaniasis, Chagas’ disease and most recently, those arising from fungal infections. Of great relevance to this project, the division as a whole is focused very much on cancer, one of the mechanisms of interest being inhibition of translation.

With our historical database of screening data, we are also very interested in data analysis and looking at compounds that appear to interfere in our assays and to work out how they are doing so. This is of great relevance to this project.

Selected publications

  1. Brady RM, Khakham Y, Lessene G & Baell JB. Benzoylureas as Removable Cis Amide Inducers: Synthesis of Cyclic Amides via Ring Closing Metathesis (RCM). Org. Biomol. Chem. 2011 9:656-658.
  2. Sleebs BE, Czabotar PE, Fairbrother, WJ, Fairlie WD, Flygare, JA, Huang, DCS, Kersten WJA, Koehler MFT, Lessene G, Lowes K, Parisot JP, Smith BJ, Smith ML, Souers AJ, Street IP, Yang H and Baell JB. Quinazoline sulfonamides as dual binders of the proteins B-cell lymphoma 2 (Bcl-2) and B-cell lymphoma extra long (Bcl-xL) with potent pro-apoptotic cell-based activity. J. Med. Chem. 2011 54: 1914-1926.
  3. Ban K, Duffy S, Khakham Y, Avery VM, Hughes AH, Montagnat O, Katneni K, Ryan E & Baell JB. 3-Alkylthio-1,2,4-triazine dimers with potent antimalarial activity. Bioorg. Med. Chem. Lett. 2010, 20:6024-6029.
  4. Sleebs BE, Street IP, Bu X & Baell JB.  De novo synthesis of a potent LIMK1 inhibitor. Synthesis 2010 7:1091-1096.
  5. Holloway GA, Charman WN, Fairlamb AH, Brun R, Kaiser, M Kostewicz E, Novello PM, Parisot JP, Richardson J, Street IP, Watson KG and Baell JB.  Trypanothione reductase high-throughput screening campaign identifies novel classes of inhibitors with anti-parasitic activity. Antimicrob. Agents Chemother. 2009 53:2824-2833.

Research theme

Cancer

Scientific discipline

  • Chemistry
  • Medicinal Chemistry

Keywords

PAINS, Mechanism of Action, Protein Reactivity, Covalent Modifiers

Sponsors

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