title: Small-molecule inhibitors of SETD8 with cellular activity.
abstract: SETD8/SET8/Pr-SET7/KMT5A is the sole protein lysine methyltransferase (PKMT) known to monomethylate lysine 20 of histone H4 in vivo. SETD8's methyltransferase activity has been implicated in many essential cellular processes including DNA replication, DNA damage response, transcription modulation, and cell cycle regulation. Developing SETD8 inhibitors with cellular activity is a key step toward elucidating the diverse roles of SETD8 via convenient pharmacological perturbation. From the hits of a prior high throughput screen (HTS), SPS8I1-3 (NSC663284, BVT948, and ryuvidine) were validated as potent SETD8 inhibitors. These compounds contain different structural motifs and inhibit SETD8 via distinct modes. More importantly, these compounds show cellular activity by suppressing the H4K20me1 mark of SETD8 and recapitulate characteristic S/G2/M-phase cell cycle defects as observed for RNAi-mediated SETD8 knockdown. The commonality of SPS8I1-3 against SETD8, together with their distinct structures and mechanisms for SETD8 inhibition, argues for the collective application of these compounds as SETD8 inhibitors.
authors.affiliation: Molecular Pharmacology and Chemistry Program, ‡Tri-Institutional Training Program in Chemical Biology, and §HTS Core Facility, Memorial Sloan Kettering Cancer Center , New York, New York 10065, United States.
authors.forename: Gil
authors.initials: G
authors.lastname: Blum
authors.forename: Glorymar
authors.initials: G
authors.lastname: Ibáñez
authors.forename: Xiangjun
authors.initials: X
authors.lastname: Rao
authors.forename: David
authors.initials: D
authors.lastname: Shum
authors.forename: Constantin
authors.initials: C
authors.lastname: Radu
authors.forename: Hakim
authors.initials: H
authors.lastname: Djaballah
authors.forename: Judd C
authors.initials: JC
authors.lastname: Rice
authors.forename: Minkui
authors.initials: M
authors.lastname: Luo
mesh_terms: D057809:HEK293 Cells; D057166:High-Throughput Screening Assays; D011495:Histone-Lysine N-Methyltransferase / Q000037:antagonists & inhibitors*; D006801:Humans
chemical_list: D011495:Histone-Lysine N-Methyltransferase; C470730:KMT5A protein, human