Small-molecule inhibitors of setd8 with cellular activity Journal Article


Authors: Blum, G.; Ibáñez, G.; Rao, X.; Shum, D.; Radu, C.; Djaballah, H.; Rice, J. C.; Luo, M.
Article 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. SETD8s 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.
Keywords: unclassified drug; human cell; dna replication; protein motif; dna damage; cell cycle; cell cycle s phase; rna interference; in vivo study; drug structure; high throughput screening; validation study; methyltransferase; cell cycle g2 phase; cell cycle m phase; cell cycle regulation; cell activity; lysine; protein inhibitor; histone lysine methyltransferase; human; article; bvt 948; histone lysine methyltransferase inhibitor; nsc 663284; ryuvidine; ic50
Journal Title: ACS Chemical Biology
Volume: 9
Issue: 11
ISSN: 1554-8929
Publisher: American Chemical Society  
Date Published: 2014-11-21
Start Page: 2471
End Page: 2478
Language: English
DOI: 10.1021/cb500515r
PROVIDER: scopus
PMCID: PMC4245162
PUBMED: 25137013
DOI/URL:
Notes: Export Date: 2 January 2015 -- Source: Scopus
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MSK Authors
  1. Hakim Djaballah
    101 Djaballah
  2. Constantin Radu
    28 Radu
  3. Minkui Luo
    68 Luo
  4. David Shum
    54 Shum
  5. Gil Blum
    15 Blum