期刊
ACS CHEMICAL BIOLOGY
卷 9, 期 11, 页码 2471-2478出版社
AMER CHEMICAL SOC
DOI: 10.1021/cb500515r
关键词
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资金
- The Commonwealth Foundation for Cancer Research
- The Experimental Therapeutics Center of Memorial Sloan Kettering Cancer Center
- NIGMS [1R01GM096056]
- NIH Director's New Innovator Award Program [1DP2-OD007335]
- NINDS [R21NS071520]
- Starr Cancer Consortium
- Tri-Institutional Training Program in Chemical Biology
- William Randolph Hearst Fund in Experimental Therapeutics
- Lillian S. Wells Foundation
- NIH/NCI Cancer Center Support Grant [5P30 CA008748-44]
- NIH [GM075094]
- ACS [RSG117619]
- NATIONAL CANCER INSTITUTE [P30CA008748] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES [R01GM096056, R01GM120570, R01GM075094] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE [R21NS071520] Funding Source: NIH RePORTER
- OFFICE OF THE DIRECTOR, NATIONAL INSTITUTES OF HEALTH [DP2OD007335] Funding Source: NIH RePORTER
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.
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