Thermal shift analysis of small molecule inhibitors of YTHDC1 and YTHDF1 using Differential Scanning Fluorimetry as a target for treating acute myeloid leukaemia.

Abstract

Acute myeloid leukaemia (AML) is an aggressive haematological malignancy. It is the leading cause of annual leukaemia-related deaths worldwide. Despite current therapeutic approaches, fewer than 30% of AML patients survive more than five years after diagnosis. Recent research has highlighted the significance of RNA modifications, particularly N6-methyladenosine (m6A), in AML pathogenesis. m6A is one of the most abundant and conserved internal co-transcriptional modifications found in eukaryotic messenger RNA (mRNA). This study focused on understanding the role of YTH domain proteins, specifically YTHDC1 and YTHDF1. These proteins recognise and interact with m6A-modified RNA, influencing mRNA fate and cellular processes. The study aimed to identify small-molecule inhibitors targeting human YTHDF1 to promote the development of novel therapeutic agents for AML. It used a series of 17 analogues derived from two previously described compounds. Differential scanning fluorimetry analysis was used to evaluate the thermal stability of these compounds with YTHDC1 and YTHDF1. The study found no significant impact of most compounds on YTHDC1 or YTHDF1, except for one compound.