The current outlook for acute myeloid leukaemia (AML) patients is poor: a five-year survival rate of approximately 22% and harsh, non-specific treatments that often fail long term (due to disease recurrence), justifying further research towards improving AML therapies. Mouse models implicate ‘Tribbles’ pseudokinase proteins as potential targets for AML therapy, as overexpression of Tribbles 1 (TRIB1) or Tribbles 2 (TRIB2) in blood cells induces and accelerates AML progression. However, the role of each isoform in AML remains ambiguous, as a lack of specific Tribbles targeting compounds limit further research. Therefore, this project aimed to develop isoform specific compounds against TRIB1 and TRIB2.

While there are many FDA approved kinase inhibitors, only one pseudokinase inhibitor has reached the market. As kinase inhibitors typically target the ATP active site, they are less effective against catalytically inactive pseudokinases. Therefore, alternative strategies are required to target the TRIB1 and TRIB2 pseudokinases. As such, this project explored two approaches: engineering nanobody-degraders and generating de novo minibinders with an AI protein design tool, BindCraft.

This seminar will outline the trials and TRIBulations in developing these alternative TRIB1 and TRIB2 targeting compounds and showcase the opportunities AI tools provide to novel binder development.