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In-Depth Characterization and Validation in BRG1-Mutant Lung Cancers Define Novel Catalytic Inhibitors of SWI/SNF Chromatin Remodeling

Zainab Jagani, Gregg Chenail, Kay Xiang, Geoffrey Bushold, Hyo-Eun C. Bhang, Ailing Li, GiNell Elliott, Jiang Zhu, Anthony Vattay, Tamara Gilbert, Anka Bric, Rie Kikkawa, Valérie Dubost, Rémi Terranova, John Cantwell, Catherine Luu, Serena Silver, Matt Shirley, Francois Huet, Rob Maher, John Reece-Hoyes, David Ruddy, Daniel Rakiec, Joshua Korn, Carsten Russ, Vera Ruda, Julia Dooley, Emily Costa, Isabel Park, Henrik Moebitz, Katsumasa Nakajima, Christopher D. Adair, Simon Mathieu, Rukundo Ntaganda, Troy Smith, David Farley, Daniel King, Xiaoling Xie, Raviraj Kulathila, Tiancen Hu, Xuewen Pan, Qicheng Ma, Katarina Vulic, Florencia Rago, Scott Clarkson, Robin Ge, Frederic Sigoillot, Gwynn Pardee, Linda Bagdasarian, Margaret McLaughlin, Kristy Haas, Jan Weiler, Steve Kovats, Mariela Jaskelioff, Marie Apolline-Gerard, Johanna Beil, Ulrike Naumann, Pascal Fortin, Frank P. Stegmeier, Michael G. Acker, Juliet Williams, Matthew Meyer, James E. Bradner, Nicholas Keen, William R. Sellers, Francesco Hofmann, Jeffrey A. Engelman, Darrin Stuart, Julien P.N. Papillon
doi: https://doi.org/10.1101/812628
Zainab Jagani
1Novartis Institutes for BioMedical Research (NIBR), 250 Massachusetts Avenue, Cambridge MA 02139 USA
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  • For correspondence: zainab.jagani@novartis.com
Gregg Chenail
1Novartis Institutes for BioMedical Research (NIBR), 250 Massachusetts Avenue, Cambridge MA 02139 USA
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Kay Xiang
1Novartis Institutes for BioMedical Research (NIBR), 250 Massachusetts Avenue, Cambridge MA 02139 USA
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Geoffrey Bushold
1Novartis Institutes for BioMedical Research (NIBR), 250 Massachusetts Avenue, Cambridge MA 02139 USA
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Hyo-Eun C. Bhang
1Novartis Institutes for BioMedical Research (NIBR), 250 Massachusetts Avenue, Cambridge MA 02139 USA
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Ailing Li
1Novartis Institutes for BioMedical Research (NIBR), 250 Massachusetts Avenue, Cambridge MA 02139 USA
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GiNell Elliott
1Novartis Institutes for BioMedical Research (NIBR), 250 Massachusetts Avenue, Cambridge MA 02139 USA
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Jiang Zhu
1Novartis Institutes for BioMedical Research (NIBR), 250 Massachusetts Avenue, Cambridge MA 02139 USA
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Anthony Vattay
1Novartis Institutes for BioMedical Research (NIBR), 250 Massachusetts Avenue, Cambridge MA 02139 USA
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Tamara Gilbert
1Novartis Institutes for BioMedical Research (NIBR), 250 Massachusetts Avenue, Cambridge MA 02139 USA
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Anka Bric
1Novartis Institutes for BioMedical Research (NIBR), 250 Massachusetts Avenue, Cambridge MA 02139 USA
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Rie Kikkawa
4NIBR, One Health Plaza, East Hanover NJ 07936 USA
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Valérie Dubost
2NIBR, Basel, Switzerland
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Rémi Terranova
2NIBR, Basel, Switzerland
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John Cantwell
3NIBR, 5300 Chiron Way, Emeryville, California, 94608 USA
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Catherine Luu
3NIBR, 5300 Chiron Way, Emeryville, California, 94608 USA
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Serena Silver
1Novartis Institutes for BioMedical Research (NIBR), 250 Massachusetts Avenue, Cambridge MA 02139 USA
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Matt Shirley
1Novartis Institutes for BioMedical Research (NIBR), 250 Massachusetts Avenue, Cambridge MA 02139 USA
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Francois Huet
1Novartis Institutes for BioMedical Research (NIBR), 250 Massachusetts Avenue, Cambridge MA 02139 USA
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Rob Maher
1Novartis Institutes for BioMedical Research (NIBR), 250 Massachusetts Avenue, Cambridge MA 02139 USA
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John Reece-Hoyes
1Novartis Institutes for BioMedical Research (NIBR), 250 Massachusetts Avenue, Cambridge MA 02139 USA
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David Ruddy
1Novartis Institutes for BioMedical Research (NIBR), 250 Massachusetts Avenue, Cambridge MA 02139 USA
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Daniel Rakiec
1Novartis Institutes for BioMedical Research (NIBR), 250 Massachusetts Avenue, Cambridge MA 02139 USA
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Joshua Korn
1Novartis Institutes for BioMedical Research (NIBR), 250 Massachusetts Avenue, Cambridge MA 02139 USA
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Carsten Russ
1Novartis Institutes for BioMedical Research (NIBR), 250 Massachusetts Avenue, Cambridge MA 02139 USA
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Vera Ruda
1Novartis Institutes for BioMedical Research (NIBR), 250 Massachusetts Avenue, Cambridge MA 02139 USA
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Julia Dooley
1Novartis Institutes for BioMedical Research (NIBR), 250 Massachusetts Avenue, Cambridge MA 02139 USA
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Emily Costa
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Isabel Park
1Novartis Institutes for BioMedical Research (NIBR), 250 Massachusetts Avenue, Cambridge MA 02139 USA
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Henrik Moebitz
2NIBR, Basel, Switzerland
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Katsumasa Nakajima
1Novartis Institutes for BioMedical Research (NIBR), 250 Massachusetts Avenue, Cambridge MA 02139 USA
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Christopher D. Adair
1Novartis Institutes for BioMedical Research (NIBR), 250 Massachusetts Avenue, Cambridge MA 02139 USA
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Simon Mathieu
1Novartis Institutes for BioMedical Research (NIBR), 250 Massachusetts Avenue, Cambridge MA 02139 USA
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Rukundo Ntaganda
1Novartis Institutes for BioMedical Research (NIBR), 250 Massachusetts Avenue, Cambridge MA 02139 USA
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Troy Smith
1Novartis Institutes for BioMedical Research (NIBR), 250 Massachusetts Avenue, Cambridge MA 02139 USA
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David Farley
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Daniel King
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Xiaoling Xie
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Raviraj Kulathila
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Tiancen Hu
1Novartis Institutes for BioMedical Research (NIBR), 250 Massachusetts Avenue, Cambridge MA 02139 USA
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Xuewen Pan
1Novartis Institutes for BioMedical Research (NIBR), 250 Massachusetts Avenue, Cambridge MA 02139 USA
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Qicheng Ma
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Katarina Vulic
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Florencia Rago
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Scott Clarkson
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Robin Ge
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Frederic Sigoillot
1Novartis Institutes for BioMedical Research (NIBR), 250 Massachusetts Avenue, Cambridge MA 02139 USA
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Gwynn Pardee
3NIBR, 5300 Chiron Way, Emeryville, California, 94608 USA
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Linda Bagdasarian
1Novartis Institutes for BioMedical Research (NIBR), 250 Massachusetts Avenue, Cambridge MA 02139 USA
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Margaret McLaughlin
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Kristy Haas
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Jan Weiler
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Steve Kovats
1Novartis Institutes for BioMedical Research (NIBR), 250 Massachusetts Avenue, Cambridge MA 02139 USA
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Mariela Jaskelioff
1Novartis Institutes for BioMedical Research (NIBR), 250 Massachusetts Avenue, Cambridge MA 02139 USA
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Marie Apolline-Gerard
2NIBR, Basel, Switzerland
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Johanna Beil
2NIBR, Basel, Switzerland
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Ulrike Naumann
2NIBR, Basel, Switzerland
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Pascal Fortin
1Novartis Institutes for BioMedical Research (NIBR), 250 Massachusetts Avenue, Cambridge MA 02139 USA
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Frank P. Stegmeier
1Novartis Institutes for BioMedical Research (NIBR), 250 Massachusetts Avenue, Cambridge MA 02139 USA
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Michael G. Acker
1Novartis Institutes for BioMedical Research (NIBR), 250 Massachusetts Avenue, Cambridge MA 02139 USA
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Juliet Williams
1Novartis Institutes for BioMedical Research (NIBR), 250 Massachusetts Avenue, Cambridge MA 02139 USA
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Matthew Meyer
1Novartis Institutes for BioMedical Research (NIBR), 250 Massachusetts Avenue, Cambridge MA 02139 USA
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James E. Bradner
1Novartis Institutes for BioMedical Research (NIBR), 250 Massachusetts Avenue, Cambridge MA 02139 USA
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Nicholas Keen
1Novartis Institutes for BioMedical Research (NIBR), 250 Massachusetts Avenue, Cambridge MA 02139 USA
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William R. Sellers
1Novartis Institutes for BioMedical Research (NIBR), 250 Massachusetts Avenue, Cambridge MA 02139 USA
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Francesco Hofmann
2NIBR, Basel, Switzerland
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Jeffrey A. Engelman
1Novartis Institutes for BioMedical Research (NIBR), 250 Massachusetts Avenue, Cambridge MA 02139 USA
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Darrin Stuart
1Novartis Institutes for BioMedical Research (NIBR), 250 Massachusetts Avenue, Cambridge MA 02139 USA
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Julien P.N. Papillon
1Novartis Institutes for BioMedical Research (NIBR), 250 Massachusetts Avenue, Cambridge MA 02139 USA
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  • Abstract
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Abstract

Members of the ATP-dependent SWI/SNF chromatin remodeling complexes are among the most frequently mutated genes in cancer, suggesting their dysregulation plays a critical role. The synthetic lethality between SWI/SNF catalytic subunits BRM/SMARCA2 and BRG1/SMARCA4 has instigated great interest in targeting BRM. Here we have performed a critical and in-depth investigation of novel dual inhibitors (BRM011 and BRM014) of BRM and BRG1 in order to validate their utility as chemical probes of SWI/SNF catalytic function, while obtaining insights into the therapeutic potential of SWI/SNF inhibition. In corroboration of on-target activity, we discovered compound resistant mutations through pooled screening of BRM variants in BRG1-mut cancer cells. Strikingly, genome-wide transcriptional and chromatin profiling (ATAC-Seq) provided further evidence of pharmacological perturbation of SWI/SNF chromatin remodeling as BRM011 treatment induced specific changes in chromatin accessibility and gene expression similar to genetic depletion of BRM. Finally, these compounds have the capacity to inhibit the growth of tumor-xenografts, yielding important insights into the feasibility of developing BRM/BRG1 ATPase inhibitors for the treatment of BRG1-mut lung cancers. Overall, our studies not only establish the feasibility of inhibiting SWI/SNF catalytic function, providing a framework for SWI/SNF therapeutic targeting, but have also yielded successful elucidation of small-molecule inhibitors that will be of importance in probing SWI/SNF function in various disease contexts.

Footnotes

  • ↵† Oncology

  • ↵◊ Global Discovery Chemistry

  • ↵# Chemical Biology and Therapeutics

  • ↵‡ Preclinical Safety

  • ↵± Scientific Data Analytics

  • ↵∞ Analytical Sciences

  • ↵§ debauwicat{at}gmail.com; ankabric{at}gmail.com; emcosta221{at}gmail.com; xpan{at}tangotx.com; qichengm{at}bu.edu; simon{at}kallyope.com; serenajsilver{at}gmail.com; jaskelioff.mariela{at}gmail.com; Christopher.adair{at}canopygrowth.com; pafortin{at}gmail.com; matthew.meyer{at}bms.com; fstegmeier{at}ksqtx.com; nicholas.keen{at}bicycletherapeutics.com; wsellers{at}broadinstitute.org

  • Conflict of Interest Disclosure Statement: All authors performed the work herein as employees of the Novartis Institutes for BioMedical Research Inc.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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In-Depth Characterization and Validation in BRG1-Mutant Lung Cancers Define Novel Catalytic Inhibitors of SWI/SNF Chromatin Remodeling
Zainab Jagani, Gregg Chenail, Kay Xiang, Geoffrey Bushold, Hyo-Eun C. Bhang, Ailing Li, GiNell Elliott, Jiang Zhu, Anthony Vattay, Tamara Gilbert, Anka Bric, Rie Kikkawa, Valérie Dubost, Rémi Terranova, John Cantwell, Catherine Luu, Serena Silver, Matt Shirley, Francois Huet, Rob Maher, John Reece-Hoyes, David Ruddy, Daniel Rakiec, Joshua Korn, Carsten Russ, Vera Ruda, Julia Dooley, Emily Costa, Isabel Park, Henrik Moebitz, Katsumasa Nakajima, Christopher D. Adair, Simon Mathieu, Rukundo Ntaganda, Troy Smith, David Farley, Daniel King, Xiaoling Xie, Raviraj Kulathila, Tiancen Hu, Xuewen Pan, Qicheng Ma, Katarina Vulic, Florencia Rago, Scott Clarkson, Robin Ge, Frederic Sigoillot, Gwynn Pardee, Linda Bagdasarian, Margaret McLaughlin, Kristy Haas, Jan Weiler, Steve Kovats, Mariela Jaskelioff, Marie Apolline-Gerard, Johanna Beil, Ulrike Naumann, Pascal Fortin, Frank P. Stegmeier, Michael G. Acker, Juliet Williams, Matthew Meyer, James E. Bradner, Nicholas Keen, William R. Sellers, Francesco Hofmann, Jeffrey A. Engelman, Darrin Stuart, Julien P.N. Papillon
bioRxiv 812628; doi: https://doi.org/10.1101/812628
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In-Depth Characterization and Validation in BRG1-Mutant Lung Cancers Define Novel Catalytic Inhibitors of SWI/SNF Chromatin Remodeling
Zainab Jagani, Gregg Chenail, Kay Xiang, Geoffrey Bushold, Hyo-Eun C. Bhang, Ailing Li, GiNell Elliott, Jiang Zhu, Anthony Vattay, Tamara Gilbert, Anka Bric, Rie Kikkawa, Valérie Dubost, Rémi Terranova, John Cantwell, Catherine Luu, Serena Silver, Matt Shirley, Francois Huet, Rob Maher, John Reece-Hoyes, David Ruddy, Daniel Rakiec, Joshua Korn, Carsten Russ, Vera Ruda, Julia Dooley, Emily Costa, Isabel Park, Henrik Moebitz, Katsumasa Nakajima, Christopher D. Adair, Simon Mathieu, Rukundo Ntaganda, Troy Smith, David Farley, Daniel King, Xiaoling Xie, Raviraj Kulathila, Tiancen Hu, Xuewen Pan, Qicheng Ma, Katarina Vulic, Florencia Rago, Scott Clarkson, Robin Ge, Frederic Sigoillot, Gwynn Pardee, Linda Bagdasarian, Margaret McLaughlin, Kristy Haas, Jan Weiler, Steve Kovats, Mariela Jaskelioff, Marie Apolline-Gerard, Johanna Beil, Ulrike Naumann, Pascal Fortin, Frank P. Stegmeier, Michael G. Acker, Juliet Williams, Matthew Meyer, James E. Bradner, Nicholas Keen, William R. Sellers, Francesco Hofmann, Jeffrey A. Engelman, Darrin Stuart, Julien P.N. Papillon
bioRxiv 812628; doi: https://doi.org/10.1101/812628

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