Structure-based design of ligands of the m6A-RNA reader YTHDC1

Fragment Ligands of the m6A-RNA Reader YTHDF2

“…Thus, we started from the hypothesis that m 6 adenine derivatives and hetero­aromatics with similar spatial arrangements of polar groups would bind to the tryptophan cage of the YTHDF m 6 A-RNA readers. We first evaluated small sets of derivatives of m 6 adenine and of the m 6 adenine-isosteric pyrazolo­pyrimidine scaffold which we had previously identified as a binder of the YTHDC1 reader domain . As expected, m 6 adenine (compound 1 ) shows the same position, orientation, and hydrogen-bonding pattern [Figure A] as the nucleobase of m 6 A-RNA [Figure S2].…”

“…The 17 binders were identified from a pool of about 30 fragments. Ligands 1 – 8 were identified among previously reported 29 and putative YTHDC1 binders, while ligands 9 – 17 originated from structure-based design. Compounds 2 – 4 , 7 , and 8 were synthesized in-house, while the remaining fragments were procured from Chemspace.…”

“…A smaller and more rigid binding pocket is one of the features that makes the YTHDF2 reader, as well as YTHDF1 and YTHDF3, more difficult targets than the YTHDC1 reader, for which 58 ligands have already been disclosed. 26 , 29 , 30 …”

“…The development of inhibitors toward epitranscriptomic targets is at its dawn, and only a few papers have been published in this regard. − Moreover, METTL3 is the only epitranscriptomic target for which high potency and selective inhibitors have been presented. ,, About 60 small-molecule ligands (micromolar affinity) of the YTHDC1 m 6 A reader domain have been reported, ,, while no ligand of the three YTHDF domains has been disclosed as of today. Thus, the novelty of the field and the involvement of YTHDF2 in the regulation of mRNA lifetime and tumorigenesis − ,− make YTHDF2 an exciting and promising target for the design of chemical probes and anticancer drugs.…”

“…Accordingly, the YTHDF2 binding site and binding loop show limited plasticity, and only Y418 and W491 display side-chain flexibility. A smaller and more rigid binding pocket is one of the features that makes the YTHDF2 reader, as well as YTHDF1 and YTHDF3, more difficult targets than the YTHDC1 reader, for which 58 ligands have already been disclosed. ,, …”