The paracaspase MALT1 plays a key role in the activation of lymphocytes and other immune cells, including myeloid cells, mast cells, and NK cells. Enhanced MALT1 activity has been associated with the development of lymphoid malignancies and autoimmune diseases. Recently-developed MALT1 inhibitors have shown promising anti-tumor effects in xenograft models of non-Hodgkin lymphoma.
The race is on to find potent MALT1 inhibitors showing high selectivity, low toxicity, and poor off-target effects. As usual, the main issue is to find a reliable assay that helps dissect complex signaling pathways. It is critical to achieve a reliable assay, effective with human cells, in a high-throughput compatible format.
This article by Adeline Unterreiner and colleagues from Novartis illustrates well how their team optimized a readout for discovering new active compounds on MALT1.
Human cells? Yes. Reference inhibitors were tested on PBMCs, THP-1, and purified non-differentiated human cells, all stimulated with LPS.
High-throughput compatible format? Yes. All experiments were run in 384-well plates.
Selectivity and toxicity assessment? Yes. The team documented a comparison of several compound potencies, including their effects on cell viability.
Lastly, by using a unique readout across all experiments, the most potent receptor linked to MALT1 activity and its downstream signaling pathway was identified.
Learn more about the readout in this article. You might already have guessed which one we’re talking about…
Adeline Unterreiner et al.
Novartis Institutes for BioMedical Research, Basel, Switzerland
Immunology Letters, 2017 Dec; 192:48-51. doi: 10.1016.