Londregan AT., Aitmakhanova K., Bennett J., Byrnes LJ., Canterbury DP., Cheng X., Christott T., Clemens J., Coffey SB., Dias JM., Dowling MS., Farnie G., Fedorov O., Fennell KF., Gamble V., Gileadi C., Giroud C., Harris MR., Hollingshead BD., Huber K., Korczynska M., Lapham K., Loria PM., Narayanan A., Owen DR., Raux B., Sahasrabudhe PV., Ruggeri RB., Sáez LD., Stock IA., Thuma BA., Tsai A., Varghese AE.

A series of small-molecule YEATS4 binders have been discovered as part of an ongoing research effort to generate high-quality probe molecules for emerging and/or challenging epigenetic targets. Analogues such as 4d and 4e demonstrate excellent potency and selectivity for YEATS4 binding versus YEATS1,2,3 and exhibit good physical properties and in vitro safety profiles. A new X-ray crystal structure confirms direct binding of this chemical series to YEATS4 at the lysine acetylation recognition site of the YEATS domain. Multiple analogues engage YEATS4 with nanomolar potency in a whole-cell nanoluciferase bioluminescent resonance energy transfer assay. Rodent pharmacokinetic studies demonstrate the competency of several analogues as in vivo-capable binders.

Discovery of High-Affinity Small-Molecule Binders of the Epigenetic Reader YEATS4.

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