A team of iMed.ULisboa researchers published the paper Phenotypic high-throughput screening platform identifies novel chemotypes for necroptosis inhibition, in a collaborative study with BioPharmaceuticals R&D at AstraZeneca.

The paper published in Cell Death Discovery demonstrates the value of academia-industry collaborative efforts to identify new potential therapeutic agents and drug targets. Testing of AstraZeneca compounds through the company’s Open Innovation programme, in a high-throughput phenotypic screen for necroptosis inhibitors at iMed.ULisboa, University of Lisbon has identified novel inhibitors of known necroptosis regulators, including RIPK1 and RIPK3, as well as many compounds acting by novel mechanisms of action.

The deregulation of cell death is widely associated with human disease, and one specific form of inflammatory cell death, termed necroptosis, is known to play key pathogenic roles in the development of a wide range of inflammatory, infectious and degenerative disorders. The underlying mechanisms of necroptosis have been well characterized, with proteins including RIPK1, RIPK3 and MLKL being identified as key regulatory elements. This combination of a contributory role in several diseases and extensive mechanistic knowledge, offers potential therapeutic opportunities through the development of inhibitors, which block necroptosis.

Cecilia Rodrigues from iMed.ULisboa and leader of the study said: “The various modes of cell death represent unique therapeutic avenues for the treatment of inflammatory, neurodegenerative and oncogenic human diseases. A variety of targets and potential inhibitors of necroptosis are being suggested by this study. As these compounds and others become further developed as pharmacologic agents using relevant pre-clinical models of disease, we look forward to future therapeutic opportunities with anticipation.”

David Smith, Principal Scientist in Emerging Innovations, Discovery Sciences, BioPharmaceuticals R&D, AstraZeneca, and co-author of the study, added “This work exemplifies the value of working with academics who are expert in the field combined with AstraZeneca’s excellent compound library, and is a great example of our approach to follow the science.“

The manuscript can be read, here.

Article:

Brito H, Marques V, Afonso MB, Brown DG, Börjesson U, Selmi N, Smith DM, Roberts IO, Fitzek M, Aniceto N, Guedes RC, Moreira R, Rodrigues CMP. 2020. Phenotypic high-throughput screening platform identifies novel chemotypes for necroptosis inhibition. Cell Death Discovery, 6: 6.