Naphannop Sereesongsaeng

eLife Assessment This important paper reports the development of proteins and small molecules that induce degradation of a clinically-relevant oncogenic transcription factor, LMO2. The findings provide a proof of concept that PROTAC-type chemicals can be developed against intrinsically disordered proteins. The methods provide a blueprint for rational design of PROTACs starting from intracellular antibody paratopes.

Abstract LMO2 is an intrinsically disordered transcription factor activated in T cell leukaemia that is difficult to target. It forms part of a multiprotein complex that has bipartite DNA binding through heterodimeric bHLH and GATA proteins. To determine if degradation of LMO2 in the context of T-ALL has therapeutic potential, a chimaeric intracellular antibody has been developed fusing an anti-LMO2 single domain variable region with one of three E3 ligases to create biodegraders.

Abstract LMO2 is a transcription factor activated by chromosomal translocations or promoter mutations in T cell leukaemia. It forms part of a multiprotein complex that has bipartite DNA binding through heterodimeric TAL1/SCL-E47 bHLH and GATA proteins. LMO2 is an intrinsically disordered protein and difficult to study in its cellular environment.