ABSTRACT
YEATS-domain-containing MLLT1 is an acetyl/acyl-lysine reader domain, which is structurally distinct from well-studied bromodomains and has been strongly associated in development of cancer. Here, we characterized piperazine-urea derivatives as an acetyl/acyl-lysine mimetic moiety for MLLT1. Crystal structures revealed distinct interaction mechanisms of this chemotype compared to the recently described benzimidazole-amide based inhibitors, exploiting different binding pockets within the protein. Thus, the piperazine-urea scaffold offers an alternative strategy for targeting the YEATS domain family.
ABBREVIATIONS
- YEATS domain
- The Yaf9, ENL, AF9, Taf14, Sas5 (YEATS) domain
- ENL
- eleven-nineteen-leukemia protein
- MLLT1
- mye-loid/lymphoid or mixed-lineage leukemia translocated to, chromosome 1 protein
- AF9
- ALL1-fused gene from chromosome 9 protein
- MLLT3
- myeloid/lymphoid or mixed-lineage leukemia translocated to chromosome 3 protein
Copyright
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
Posted November 09, 2019.
Structural insights into interaction mechanisms of alternative piperazine-urea YEATS domain binders in MLLT1
