Selectivity, ligand deconstruction, and cellular activity analysis of a BPTF bromodomain inhibitor

Steven E. Kirberger, Peter D. Ycas, Jorden A. Johnson, Chen Chen, Michael F. Ciccone, Rinette W.L. Woo, Andrew K. Urick, Huda Zahid, Ke Shi, Hideki Aihara, Sean D. McAllister, Mohammed Kashani-Sabet, Junwei Shi, Alex Dickson, Camila O. Dos Santos, William C.K. Pomerantz

Research output: Contribution to journalArticlepeer-review

15 Scopus citations


Bromodomain and PHD finger containing protein transcription factor (BPTF) is an epigenetic protein involved in chromatin remodelling and is a potential anticancer target. The BPTF bromodomain has one reported small molecule inhibitor (AU1, rac-1). Here, advances made on the structure-activity relationship of a BPTF bromodomain ligand are reported using a combination of experimental and molecular dynamics simulations leading to the active enatiomer (S)-1. Additionally, a ligand deconstruction analysis was conducted to characterize important pharmacophores for engaging the BPTF bromodomain. These studies have been enabled by a protein-based fluorine NMR approach, highlighting the versatility of the method for selectivity, ligand deconstruction, and ligand binding. To enable future analysis of biological activity, cell growth analyses in a panel of cancer cell lines were carried out using CRISPR-Cas9 and (S)-1 to identify cell-based model systems that are sensitive to BPTF inhibition.

Original languageEnglish (US)
Pages (from-to)2020-2027
Number of pages8
JournalOrganic and Biomolecular Chemistry
Issue number7
StatePublished - 2019

Bibliographical note

Funding Information:
Research reported in this publication was supported by the National Institute of General Medical Sciences of the National Institutes under the award numbers (R01GM121414, W.C.K.P, R01GM130794, A.D., R35GM118047 H.A.) the National Cancer Institute (R01CA215755 M.K.) and Rita Allen Scholar grant (C.O.D.S.) and Pershing Square Sohn Prize (C.O.D.S.) J.A.J. was supported by a National Institutes of Health Biotechnology training grant 5T32GM008347-23 A.K.U. was supported by a UMN Doctoral Dissertation Fellowship. Cold Spring Harbor Labs shared resources were supported through the Cancer Center 5P30CA045508 and the cell lines were distributed through the Cold Spring Harbor Tissue Culture Facility. We would like to thank Emily Sherman for early synthetic efforts on rac-1 analogs.

Publisher Copyright:
© The Royal Society of Chemistry 2019.


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