Fragment-Based NMR Screening of the BPTF PHD Finger Methyl Lysine Reader Leads to the First Small-Molecule Inhibitors

Caroline R. Buchholz; Molly S. Sneddon; Joseph E. McPherson; Sourav Das; Clifford T. Gee; Michael J. Grillo; Sergio C. Chai; Richard E. Lee; Taosheng Chen; Daniel A. Harki; Anang A. Shelat; William C.K. Pomerantz

doi:10.1021/acsmedchemlett.3c00343

Fragment-Based NMR Screening of the BPTF PHD Finger Methyl Lysine Reader Leads to the First Small-Molecule Inhibitors

Caroline R. Buchholz, Molly S. Sneddon, Joseph E. McPherson, Sourav Das, Clifford T. Gee, Michael J. Grillo, Sergio C. Chai, Richard E. Lee, Taosheng Chen, Daniel A. Harki, Anang A. Shelat, William C.K. Pomerantz

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3 Scopus citations

Abstract

Methyl lysine readers, specifically PHD fingers, are emerging epigenetic targets in human diseases. For example, several PHD finger fusions are implicated in clinical cases of acute myeloid leukemia, highlighting the potential for PHD inhibitors in disease regulation. However, limited chemical matter targeting PHD fingers exists. Here we report the first fragment-based screen against the BPTF PHD to identify several of the first reported BPTF PHD-targeting small-molecule ligands. We used ligand-observed NMR to first screen a fragment library, followed by biophysical validation to prioritize two scaffolds, pyrrolidine- and pyridazine-containing fragments. Structural predictions show that these respective scaffolds may engage two distinct subpockets on the protein. The demonstrated ligandability of the BPTF PHD supports the future development of methyl lysine reader chemical probes to study their oncogenic functions.

Original language	English (US)
Pages (from-to)	1441-1447
Number of pages	7
Journal	ACS Medicinal Chemistry Letters
Volume	14
Issue number	10
DOIs	https://doi.org/10.1021/acsmedchemlett.3c00343
State	Published - Oct 12 2023

Bibliographical note

Publisher Copyright:
© 2023 American Chemical Society.

Keywords

BPTF
Epigenetics
Fragment-based screening
Methyl lysine reader
PHD finger

PubMed: MeSH publication types

Journal Article

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Buchholz, C. R., Sneddon, M. S., McPherson, J. E., Das, S., Gee, C. T., Grillo, M. J., Chai, S. C., Lee, R. E., Chen, T., Harki, D. A., Shelat, A. A., & Pomerantz, W. C. K. (2023). Fragment-Based NMR Screening of the BPTF PHD Finger Methyl Lysine Reader Leads to the First Small-Molecule Inhibitors. ACS Medicinal Chemistry Letters, 14(10), 1441-1447. https://doi.org/10.1021/acsmedchemlett.3c00343

Buchholz, CR, Sneddon, MS, McPherson, JE, Das, S, Gee, CT, Grillo, MJ, Chai, SC, Lee, RE, Chen, T, Harki, DA, Shelat, AA & Pomerantz, WCK 2023, 'Fragment-Based NMR Screening of the BPTF PHD Finger Methyl Lysine Reader Leads to the First Small-Molecule Inhibitors', ACS Medicinal Chemistry Letters, vol. 14, no. 10, pp. 1441-1447. https://doi.org/10.1021/acsmedchemlett.3c00343

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abstract = "Methyl lysine readers, specifically PHD fingers, are emerging epigenetic targets in human diseases. For example, several PHD finger fusions are implicated in clinical cases of acute myeloid leukemia, highlighting the potential for PHD inhibitors in disease regulation. However, limited chemical matter targeting PHD fingers exists. Here we report the first fragment-based screen against the BPTF PHD to identify several of the first reported BPTF PHD-targeting small-molecule ligands. We used ligand-observed NMR to first screen a fragment library, followed by biophysical validation to prioritize two scaffolds, pyrrolidine- and pyridazine-containing fragments. Structural predictions show that these respective scaffolds may engage two distinct subpockets on the protein. The demonstrated ligandability of the BPTF PHD supports the future development of methyl lysine reader chemical probes to study their oncogenic functions.",

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doi = "10.1021/acsmedchemlett.3c00343",

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AU - Sneddon, Molly S.

AU - McPherson, Joseph E.

AU - Das, Sourav

AU - Gee, Clifford T.

AU - Grillo, Michael J.

AU - Chai, Sergio C.

AU - Lee, Richard E.

AU - Chen, Taosheng

AU - Harki, Daniel A.

AU - Shelat, Anang A.

AU - Pomerantz, William C.K.

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N2 - Methyl lysine readers, specifically PHD fingers, are emerging epigenetic targets in human diseases. For example, several PHD finger fusions are implicated in clinical cases of acute myeloid leukemia, highlighting the potential for PHD inhibitors in disease regulation. However, limited chemical matter targeting PHD fingers exists. Here we report the first fragment-based screen against the BPTF PHD to identify several of the first reported BPTF PHD-targeting small-molecule ligands. We used ligand-observed NMR to first screen a fragment library, followed by biophysical validation to prioritize two scaffolds, pyrrolidine- and pyridazine-containing fragments. Structural predictions show that these respective scaffolds may engage two distinct subpockets on the protein. The demonstrated ligandability of the BPTF PHD supports the future development of methyl lysine reader chemical probes to study their oncogenic functions.

AB - Methyl lysine readers, specifically PHD fingers, are emerging epigenetic targets in human diseases. For example, several PHD finger fusions are implicated in clinical cases of acute myeloid leukemia, highlighting the potential for PHD inhibitors in disease regulation. However, limited chemical matter targeting PHD fingers exists. Here we report the first fragment-based screen against the BPTF PHD to identify several of the first reported BPTF PHD-targeting small-molecule ligands. We used ligand-observed NMR to first screen a fragment library, followed by biophysical validation to prioritize two scaffolds, pyrrolidine- and pyridazine-containing fragments. Structural predictions show that these respective scaffolds may engage two distinct subpockets on the protein. The demonstrated ligandability of the BPTF PHD supports the future development of methyl lysine reader chemical probes to study their oncogenic functions.

KW - BPTF

KW - Epigenetics

KW - Fragment-based screening

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KW - PHD finger

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Fragment-Based NMR Screening of the BPTF PHD Finger Methyl Lysine Reader Leads to the First Small-Molecule Inhibitors

Abstract

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Keywords

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UN SDGs

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