2021
DOI: 10.1016/j.jbc.2021.100349
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Identification and characterization of second-generation EZH2 inhibitors with extended residence times and improved biological activity

Abstract: The histone methyltransferase EZH2 has been the target of numerous small-molecule inhibitor discovery efforts over the last 10+ years. Emerging clinical data have provided early evidence for single agent activity with acceptable safety profiles for first-generation inhibitors. We have developed kinetic methodologies for studying EZH2-inhibitor-binding kinetics that have allowed us to identify a unique structural modification that results in significant increases in the drug-target residence times of all EZH2 i… Show more

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Cited by 10 publications
(12 citation statements)
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“…Enhanced inhibition of cellular trimethylation could be achieved by compound 21 (TDI-11904), derived from the incorporation of thiomethyl substitution on the key pyridone moiety ( 8 vs 21 ). Although not determined, this may be consistent with reports of improved on target residence time with this substitution on a different scaffold. , Our results demonstrate that this is a general effect that can be applied to different chemical series of EZH2 inhibitors. The improved efflux ratio observed with compound 5 could not be maintained with either further modification on the pyridone or with the change to the 7-membered ring lactam structure.…”
supporting
confidence: 90%
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“…Enhanced inhibition of cellular trimethylation could be achieved by compound 21 (TDI-11904), derived from the incorporation of thiomethyl substitution on the key pyridone moiety ( 8 vs 21 ). Although not determined, this may be consistent with reports of improved on target residence time with this substitution on a different scaffold. , Our results demonstrate that this is a general effect that can be applied to different chemical series of EZH2 inhibitors. The improved efflux ratio observed with compound 5 could not be maintained with either further modification on the pyridone or with the change to the 7-membered ring lactam structure.…”
supporting
confidence: 90%
“…Unfortunately the resulting compound 19 displayed has no obvious advantage in permeability relative to compound 8 and also appeared to have a similar potency. This was surprising since this substitution has been associated with enhanced EZH2 potency through increasing residence time . However, the SAR analysis for high affinity compounds is complicated by the active enzyme concentration of 2 nM resulting in a floor of the assay of 1 nM.…”
mentioning
confidence: 99%
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“…Moreover, it has also been highlighted that some of the EZH2 mutations easily lead to resistance against these drugs [ 23 , 24 ]. Recently, efforts have been made to discover EZH2 inhibitors with novel scaffold [ 25 , 26 , 27 , 28 ]. Thus, available information can provide an advantage in developing the classification or predictive models.…”
Section: Introductionmentioning
confidence: 99%