Discovery of an H3K36me3-Derived Peptidomimetic Ligand with Enhanced Affinity for Plant Homeodomain Finger Protein 1 (PHF1).

Isabelle A Engelberg, Jiuyang Liu, Jacqueline L Norris-Drouin, Stephanie H Cholensky, Samantha A Ottavi, Stephen V Frye, Tatiana G Kutateladze, Lindsey I James

Journal of medicinal chemistry 2021 Jun 24

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Plant homeodomain finger protein 1 (PHF1) is an accessory component of the gene silencing complex polycomb repressive complex 2 and recognizes the active chromatin mark, trimethylated lysine 36 of histone H3 (H3K36me3). In addition to its role in transcriptional regulation, PHF1 has been implicated as a driver of endometrial stromal sarcoma and fibromyxoid tumors. We report the discovery and characterization of UNC6641, a peptidomimetic antagonist of the PHF1 Tudor domain which was optimized through in silico modeling and incorporation of non-natural amino acids. UNC6641 binds the PHF1 Tudor domain with a Kd value of 0.96 ± 0.03 μM while also binding the related protein PHF19 with similar potency. A crystal structure of PHF1 in complex with UNC6641, along with NMR and site-directed mutagenesis data, provided insight into the binding mechanism and requirements for binding. Additionally, UNC6641 enabled the development of a high-throughput assay to identify small molecule binders of PHF1.

Citation

Isabelle A Engelberg, Jiuyang Liu, Jacqueline L Norris-Drouin, Stephanie H Cholensky, Samantha A Ottavi, Stephen V Frye, Tatiana G Kutateladze, Lindsey I James. Discovery of an H3K36me3-Derived Peptidomimetic Ligand with Enhanced Affinity for Plant Homeodomain Finger Protein 1 (PHF1). Journal of medicinal chemistry. 2021 Jun 24;64(12):8510-8522