Unknown

Dataset Information

0

Structure-activity relationship studies of SETD8 inhibitors.


ABSTRACT: SETD8 (also known as SET8, PR-SET7, or KMT5A (lysine methyltransferase 5A)) is the only known lysine methyltransferase that catalyzes monomethylation of histone H4 lysine 20 (H4K20). In addition to H4K20, SETD8 monomethylates non-histone substrates such as the tumor suppressor p53 and proliferating cell nuclear antigen (PCNA). Because of its role in regulating diverse biological processes, SETD8 has been pursued as a potential therapeutic target. We recently reported the first substrate-competitive SETD8 inhibitor, UNC0379 (1), which is selective for SETD8 over 15 other methyltransferases. We characterized this inhibitor in a battery of biochemical and biophysical assays. Here we describe our comprehensive structure-activity relationship (SAR) studies of this chemical series. In addition to 2- and 4-substituents, we extensively explored 6- and 7-substituents of the quinazoline scaffold. These SAR studies led to the discovery of several new compounds, which displayed similar potencies as compound 1, and interesting SAR trends.

SUBMITTER: Ma A 

PROVIDER: S-EPMC4278651 | biostudies-literature | 2014 Dec

REPOSITORIES: biostudies-literature

altmetric image

Publications

Structure-activity relationship studies of SETD8 inhibitors.

Ma Anqi A   Yu Wenyu W   Xiong Yan Y   Butler Kyle V KV   Brown Peter J PJ   Jin Jian J  

MedChemComm 20141201 12


SETD8 (also known as SET8, PR-SET7, or KMT5A (lysine methyltransferase 5A)) is the only known lysine methyltransferase that catalyzes monomethylation of histone H4 lysine 20 (H4K20). In addition to H4K20, SETD8 monomethylates non-histone substrates such as the tumor suppressor p53 and proliferating cell nuclear antigen (PCNA). Because of its role in regulating diverse biological processes, SETD8 has been pursued as a potential therapeutic target. We recently reported the first substrate-competit  ...[more]

Similar Datasets

| S-EPMC4018115 | biostudies-literature
| S-EPMC5774307 | biostudies-literature
| S-EPMC5562403 | biostudies-literature
| S-EPMC4752335 | biostudies-literature
| S-EPMC8819961 | biostudies-literature
| S-EPMC10531289 | biostudies-literature
| S-EPMC2818328 | biostudies-literature
| S-EPMC4245162 | biostudies-literature
| S-EPMC5909242 | biostudies-literature
| S-EPMC4486254 | biostudies-literature