title: Sinefungin derivatives as inhibitors and structure probes of protein lysine methyltransferase SETD2.
abstract: Epigenetic regulation is involved in numerous physiological and pathogenic processes. Among the key regulators that orchestrate epigenetic signaling are over 50 human protein lysine methyltransferases (PKMTs). Interrogation of the functions of individual PKMTs can be facilitated by target-specific PKMT inhibitors. Given the emerging need for such small molecules, we envisioned an approach to identify target-specific methyltransferase inhibitors by screening privileged small-molecule scaffolds against diverse methyltransferases. In this work, we demonstrated the feasibility of such an approach by identifying the inhibitors of SETD2. N-propyl sinefungin (Pr-SNF) was shown to interact preferentially with SETD2 by matching the distinct transition-state features of SETD2's catalytically active conformer. With Pr-SNF as a structure probe, we further revealed the dual roles of SETD2's post-SET loop in regulating substrate access through a distinct topological reconfiguration. Privileged sinefungin scaffolds are expected to have broad use as structure and chemical probes of methyltransferases.
authors.affiliation: Molecular Pharmacology and Chemistry Program, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA.
authors.forename: Weihong
authors.initials: W
authors.lastname: Zheng
authors.forename: Glorymar
authors.initials: G
authors.lastname: Ibáñez
authors.forename: Hong
authors.initials: H
authors.lastname: Wu
authors.forename: Gil
authors.initials: G
authors.lastname: Blum
authors.forename: Hong
authors.initials: H
authors.lastname: Zeng
authors.forename: Aiping
authors.initials: A
authors.lastname: Dong
authors.forename: Fengling
authors.initials: F
authors.lastname: Li
authors.forename: Taraneh
authors.initials: T
authors.lastname: Hajian
authors.forename: Abdellah
authors.initials: A
authors.lastname: Allali-Hassani
authors.forename: Maria F
authors.initials: MF
authors.lastname: Amaya
authors.forename: Alena
authors.initials: A
authors.lastname: Siarheyeva
authors.forename: Wenyu
authors.initials: W
authors.lastname: Yu
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Brown
authors.forename: Matthieu
authors.initials: M
authors.lastname: Schapira
authors.forename: Masoud
authors.initials: M
authors.lastname: Vedadi
authors.forename: Jinrong
authors.initials: J
authors.lastname: Min
authors.forename: Minkui
authors.initials: M
authors.lastname: Luo
mesh_terms: D000241:Adenosine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011495:Histone-Lysine N-Methyltransferase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D008958:Models, Molecular; D015335:Molecular Probes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D004791:Enzyme Inhibitors; D015335:Molecular Probes; D011495:Histone-Lysine N-Methyltransferase; C521636:SETD2 protein, human; D000241:Adenosine; C006235:sinefungin