title: Structure-Based Design of an in Vivo Active Selective BRD9 Inhibitor.
abstract: Components of the chromatin remodelling switch/sucrose nonfermentable (SWI/SNF) complex are recurrently mutated in tumors, suggesting that altering the activity of the complex plays a role in oncogenesis. However, the role that the individual subunits play in this process is not clear. We set out to develop an inhibitor compound targeting the bromodomain of BRD9 in order to evaluate its function within the SWI/SNF complex. Here, we present the discovery and development of a potent and selective BRD9 bromodomain inhibitor series based on a new pyridinone-like scaffold. Crystallographic information on the inhibitors bound to BRD9 guided their development with respect to potency for BRD9 and selectivity against BRD4. These compounds modulate BRD9 bromodomain cellular function and display antitumor activity in an AML xenograft model. Two chemical probes, BI-7273 (1) and BI-9564 (2), were identified that should prove to be useful in further exploring BRD9 bromodomain biology in both in vitro and in vivo settings.
authors.affiliation: Boehringer Ingelheim RCV GmbH & Co KG , Vienna 1121, Austria.
authors.forename: Laetitia J
authors.initials: LJ
authors.lastname: Martin
authors.affiliation: Boehringer Ingelheim RCV GmbH & Co KG , Vienna 1121, Austria.
authors.forename: Manfred
authors.initials: M
authors.lastname: Koegl
authors.affiliation: Boehringer Ingelheim RCV GmbH & Co KG , Vienna 1121, Austria.
authors.forename: Gerd
authors.initials: G
authors.lastname: Bader
authors.affiliation: Boehringer Ingelheim RCV GmbH & Co KG , Vienna 1121, Austria.
authors.forename: Xiao-Ling
authors.initials: XL
authors.lastname: Cockcroft
authors.affiliation: SGC, University of Oxford , Oxford OX3 7DQ, United Kingdom.
authors.forename: Oleg
authors.initials: O
authors.lastname: Fedorov
authors.affiliation: Boehringer Ingelheim Pharma GmbH & Co KG , Biberach 88400, Germany.
authors.forename: Dennis
authors.initials: D
authors.lastname: Fiegen
authors.affiliation: Boehringer Ingelheim RCV GmbH & Co KG , Vienna 1121, Austria.
authors.forename: Thomas
authors.initials: T
authors.lastname: Gerstberger
authors.affiliation: Boehringer Ingelheim RCV GmbH & Co KG , Vienna 1121, Austria.
authors.forename: Marco H
authors.initials: MH
authors.lastname: Hofmann
authors.affiliation: Cold Spring Harbor Laboratory , Cold Spring Harbor, New York 11724, United States.
authors.forename: Anja F
authors.initials: AF
authors.lastname: Hohmann
authors.affiliation: Boehringer Ingelheim RCV GmbH & Co KG , Vienna 1121, Austria.
authors.forename: Dirk
authors.initials: D
authors.lastname: Kessler
authors.affiliation: SGC, University of Oxford , Oxford OX3 7DQ, United Kingdom.
authors.forename: Stefan
authors.initials: S
authors.lastname: Knapp
authors.affiliation: Boehringer Ingelheim RCV GmbH & Co KG , Vienna 1121, Austria.
authors.forename: Petr
authors.initials: P
authors.lastname: Knesl
authors.affiliation: Boehringer Ingelheim RCV GmbH & Co KG , Vienna 1121, Austria.
authors.forename: Stefan
authors.initials: S
authors.lastname: Kornigg
authors.affiliation: SGC, University of Oxford , Oxford OX3 7DQ, United Kingdom.
authors.forename: Susanne
authors.initials: S
authors.lastname: Müller
authors.affiliation: Boehringer Ingelheim Pharma GmbH & Co KG , Biberach 88400, Germany.
authors.forename: Herbert
authors.initials: H
authors.lastname: Nar
authors.affiliation: SGC, University of Oxford , Oxford OX3 7DQ, United Kingdom.
authors.forename: Catherine
authors.initials: C
authors.lastname: Rogers
authors.affiliation: Boehringer Ingelheim RCV GmbH & Co KG , Vienna 1121, Austria.
authors.forename: Klaus
authors.initials: K
authors.lastname: Rumpel
authors.affiliation: Boehringer Ingelheim RCV GmbH & Co KG , Vienna 1121, Austria.
authors.forename: Otmar
authors.initials: O
authors.lastname: Schaaf
authors.affiliation: Boehringer Ingelheim RCV GmbH & Co KG , Vienna 1121, Austria.
authors.forename: Steffen
authors.initials: S
authors.lastname: Steurer
authors.affiliation: SGC, University of Oxford , Oxford OX3 7DQ, United Kingdom.
authors.forename: Cynthia
authors.initials: C
authors.lastname: Tallant
authors.affiliation: Cold Spring Harbor Laboratory , Cold Spring Harbor, New York 11724, United States.
authors.forename: Christopher R
authors.initials: CR
authors.lastname: Vakoc
authors.affiliation: Boehringer Ingelheim Pharma GmbH & Co KG , Biberach 88400, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Zeeb
authors.affiliation: Boehringer Ingelheim RCV GmbH & Co KG , Vienna 1121, Austria.
authors.forename: Andreas
authors.initials: A
authors.lastname: Zoephel
authors.affiliation: Boehringer Ingelheim RCV GmbH & Co KG , Vienna 1121, Austria.
authors.forename: Mark
authors.initials: M
authors.lastname: Pearson
authors.affiliation: Boehringer Ingelheim RCV GmbH & Co KG , Vienna 1121, Austria.
authors.forename: Guido
authors.initials: G
authors.lastname: Boehmelt
authors.affiliation: Boehringer Ingelheim RCV GmbH & Co KG , Vienna 1121, Austria.
authors.forename: Darryl
authors.initials: D
authors.lastname: McConnell
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D018360:Crystallography, X-Ray; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D006801:Humans; D051379:Mice; D008958:Models, Molecular; D015394:Molecular Structure; D009374:Neoplasms, Experimental / Q000188:drug therapy / Q000473:pathology; D011728:Pyridones / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014157:Transcription Factors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays; D000092468:Bromodomain Containing Proteins
chemical_list: D000970:Antineoplastic Agents; D011728:Pyridones; D014157:Transcription Factors; C587454:BRD9 protein, human; D000092468:Bromodomain Containing Proteins