Exploiting a water network to achieve enthalpy-driven, bromodomain-selective BET inhibitors

William R. Shadrick; Peter J. Slavish; Sergio C. Chai; Brett Waddell; Michele Connelly; Jonathan A. Low; Cynthia Tallant; Brandon M. Young; Nagakumar Bharatham; Stefan Knapp; Vincent A. Boyd; Marie Morfouace; Martine F. Roussel; Taosheng Chen; Richard E. Lee; R. Kiplin Guy; Anang A. Shelat; Philip M. Potter

doi:10.1016/j.bmc.2017.10.042

Exploiting a water network to achieve enthalpy-driven, bromodomain-selective BET inhibitors

William R. Shadrick
, Peter J. Slavish
, Sergio C. Chai
, Brett Waddell
, Michele Connelly
, Jonathan A. Low
, Cynthia Tallant
, Brandon M. Young
, Nagakumar Bharatham
, Stefan Knapp
, Vincent A. Boyd
, Marie Morfouace
, Martine F. Roussel
, Taosheng Chen
, Richard E. Lee
, R. Kiplin Guy
, Anang A. Shelat
, Philip M. Potter

Research output: Contribution to journal › Article › peer-review

28 Scopus citations

Abstract

Within the last decade, the Bromodomain and Extra-Terminal domain family (BET) of proteins have emerged as promising drug targets in diverse clinical indications including oncology, auto-immune disease, heart failure, and male contraception. The BET family consists of four isoforms (BRD2, BRD3, BRD4, and BRDT/BRDT6) which are distinguished by the presence of two tandem bromodomains (BD1 and BD2) that independently recognize acetylated-lysine (KAc) residues and appear to have distinct biological roles. BET BD1 and BD2 bromodomains differ at five positions near the substrate binding pocket: the variation in the ZA channel induces different water networks nearby. We designed a set of congeneric 2- and 3-heteroaryl substituted tetrahydroquinolines (THQ) to differentially engage bound waters in the ZA channel with the goal of achieving bromodomain selectivity. SJ830599 (9) showed modest, but consistent, selectivity for BRD2-BD2. Using isothermal titration calorimetry, we showed that the binding of all THQ analogs in our study to either of the two bromodomains was enthalpy driven. Remarkably, the binding of 9 to BRD2-BD2 was marked by negative entropy and was entirely driven by enthalpy, consistent with significant restriction of conformational flexibility and/or engagement with bound waters. Co-crystallography studies confirmed that 9 did indeed stabilize a water-mediated hydrogen bond network. Finally, we report that 9 retained cytotoxicity against several pediatric cancer cell lines with EC₅₀ values comparable to BET inhibitor (BETi) clinical candidates.

Original language	English
Pages (from-to)	25-36
Number of pages	12
Journal	Bioorganic and Medicinal Chemistry
Volume	26
Issue number	1
DOIs	https://doi.org/10.1016/j.bmc.2017.10.042
State	Published - Jan 1 2018

Bibliographical note

Publisher Copyright:
© 2017 Elsevier Ltd

Funding

This work was supported in part by NIH grant CA-096832 (MFR), a Cancer Center Core grant CA21765 , and by the American Lebanese Syrian Associated Charities (ALSAC). SK and CT are grateful for support by the SGC, a registered charity that receives funds from AbbVie, Bayer Pharma AG, Boehringer Ingelheim, Canada Foundation for Innovation, Eshelman Institute for Innovation, Genome Canada through Ontario Genomics Institute, IMI [115766], Wellcome Trust, Janssen, Merck & Co., Novartis Pharma AG, Ontario Ministry of Economic Development and Innovation, Pfizer, São Paulo Research Foundation-FAPESP, and Takeda and the Centre of Excellence Macromolecular complexes (CEF) at Frankfurt University.

Funders	Funder number
National Childhood Cancer Registry – National Cancer Institute	P30CA021765, P01CA096832
Seventh Framework Programme	115766

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

ASJC Scopus subject areas

Biochemistry
Molecular Medicine
Molecular Biology
Pharmaceutical Science
Drug Discovery
Clinical Biochemistry
Organic Chemistry

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10.1016/j.bmc.2017.10.042

Cite this

Shadrick, W. R., Slavish, P. J., Chai, S. C., Waddell, B., Connelly, M., Low, J. A., Tallant, C., Young, B. M., Bharatham, N., Knapp, S., Boyd, V. A., Morfouace, M., Roussel, M. F., Chen, T., Lee, R. E., Kiplin Guy, R., Shelat, A. A., & Potter, P. M. (2018). Exploiting a water network to achieve enthalpy-driven, bromodomain-selective BET inhibitors. Bioorganic and Medicinal Chemistry, 26(1), 25-36. https://doi.org/10.1016/j.bmc.2017.10.042

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title = "Exploiting a water network to achieve enthalpy-driven, bromodomain-selective BET inhibitors",

abstract = "Within the last decade, the Bromodomain and Extra-Terminal domain family (BET) of proteins have emerged as promising drug targets in diverse clinical indications including oncology, auto-immune disease, heart failure, and male contraception. The BET family consists of four isoforms (BRD2, BRD3, BRD4, and BRDT/BRDT6) which are distinguished by the presence of two tandem bromodomains (BD1 and BD2) that independently recognize acetylated-lysine (KAc) residues and appear to have distinct biological roles. BET BD1 and BD2 bromodomains differ at five positions near the substrate binding pocket: the variation in the ZA channel induces different water networks nearby. We designed a set of congeneric 2- and 3-heteroaryl substituted tetrahydroquinolines (THQ) to differentially engage bound waters in the ZA channel with the goal of achieving bromodomain selectivity. SJ830599 (9) showed modest, but consistent, selectivity for BRD2-BD2. Using isothermal titration calorimetry, we showed that the binding of all THQ analogs in our study to either of the two bromodomains was enthalpy driven. Remarkably, the binding of 9 to BRD2-BD2 was marked by negative entropy and was entirely driven by enthalpy, consistent with significant restriction of conformational flexibility and/or engagement with bound waters. Co-crystallography studies confirmed that 9 did indeed stabilize a water-mediated hydrogen bond network. Finally, we report that 9 retained cytotoxicity against several pediatric cancer cell lines with EC50 values comparable to BET inhibitor (BETi) clinical candidates.",

author = "Shadrick, \{William R.\} and Slavish, \{Peter J.\} and Chai, \{Sergio C.\} and Brett Waddell and Michele Connelly and Low, \{Jonathan A.\} and Cynthia Tallant and Young, \{Brandon M.\} and Nagakumar Bharatham and Stefan Knapp and Boyd, \{Vincent A.\} and Marie Morfouace and Roussel, \{Martine F.\} and Taosheng Chen and Lee, \{Richard E.\} and \{Kiplin Guy\}, R. and Shelat, \{Anang A.\} and Potter, \{Philip M.\}",

note = "Publisher Copyright: {\textcopyright} 2017 Elsevier Ltd",

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Shadrick, WR, Slavish, PJ, Chai, SC, Waddell, B, Connelly, M, Low, JA, Tallant, C, Young, BM, Bharatham, N, Knapp, S, Boyd, VA, Morfouace, M, Roussel, MF, Chen, T, Lee, RE, Kiplin Guy, R, Shelat, AA & Potter, PM 2018, 'Exploiting a water network to achieve enthalpy-driven, bromodomain-selective BET inhibitors', Bioorganic and Medicinal Chemistry, vol. 26, no. 1, pp. 25-36. https://doi.org/10.1016/j.bmc.2017.10.042

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T1 - Exploiting a water network to achieve enthalpy-driven, bromodomain-selective BET inhibitors

AU - Shadrick, William R.

AU - Slavish, Peter J.

AU - Chai, Sergio C.

AU - Waddell, Brett

AU - Connelly, Michele

AU - Low, Jonathan A.

AU - Tallant, Cynthia

AU - Young, Brandon M.

AU - Bharatham, Nagakumar

AU - Knapp, Stefan

AU - Boyd, Vincent A.

AU - Morfouace, Marie

AU - Roussel, Martine F.

AU - Chen, Taosheng

AU - Lee, Richard E.

AU - Kiplin Guy, R.

AU - Shelat, Anang A.

AU - Potter, Philip M.

PY - 2018/1/1

Y1 - 2018/1/1

N2 - Within the last decade, the Bromodomain and Extra-Terminal domain family (BET) of proteins have emerged as promising drug targets in diverse clinical indications including oncology, auto-immune disease, heart failure, and male contraception. The BET family consists of four isoforms (BRD2, BRD3, BRD4, and BRDT/BRDT6) which are distinguished by the presence of two tandem bromodomains (BD1 and BD2) that independently recognize acetylated-lysine (KAc) residues and appear to have distinct biological roles. BET BD1 and BD2 bromodomains differ at five positions near the substrate binding pocket: the variation in the ZA channel induces different water networks nearby. We designed a set of congeneric 2- and 3-heteroaryl substituted tetrahydroquinolines (THQ) to differentially engage bound waters in the ZA channel with the goal of achieving bromodomain selectivity. SJ830599 (9) showed modest, but consistent, selectivity for BRD2-BD2. Using isothermal titration calorimetry, we showed that the binding of all THQ analogs in our study to either of the two bromodomains was enthalpy driven. Remarkably, the binding of 9 to BRD2-BD2 was marked by negative entropy and was entirely driven by enthalpy, consistent with significant restriction of conformational flexibility and/or engagement with bound waters. Co-crystallography studies confirmed that 9 did indeed stabilize a water-mediated hydrogen bond network. Finally, we report that 9 retained cytotoxicity against several pediatric cancer cell lines with EC50 values comparable to BET inhibitor (BETi) clinical candidates.

AB - Within the last decade, the Bromodomain and Extra-Terminal domain family (BET) of proteins have emerged as promising drug targets in diverse clinical indications including oncology, auto-immune disease, heart failure, and male contraception. The BET family consists of four isoforms (BRD2, BRD3, BRD4, and BRDT/BRDT6) which are distinguished by the presence of two tandem bromodomains (BD1 and BD2) that independently recognize acetylated-lysine (KAc) residues and appear to have distinct biological roles. BET BD1 and BD2 bromodomains differ at five positions near the substrate binding pocket: the variation in the ZA channel induces different water networks nearby. We designed a set of congeneric 2- and 3-heteroaryl substituted tetrahydroquinolines (THQ) to differentially engage bound waters in the ZA channel with the goal of achieving bromodomain selectivity. SJ830599 (9) showed modest, but consistent, selectivity for BRD2-BD2. Using isothermal titration calorimetry, we showed that the binding of all THQ analogs in our study to either of the two bromodomains was enthalpy driven. Remarkably, the binding of 9 to BRD2-BD2 was marked by negative entropy and was entirely driven by enthalpy, consistent with significant restriction of conformational flexibility and/or engagement with bound waters. Co-crystallography studies confirmed that 9 did indeed stabilize a water-mediated hydrogen bond network. Finally, we report that 9 retained cytotoxicity against several pediatric cancer cell lines with EC50 values comparable to BET inhibitor (BETi) clinical candidates.

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IS - 1

ER -

Exploiting a water network to achieve enthalpy-driven, bromodomain-selective BET inhibitors

Abstract

Bibliographical note

Funding

UN SDGs

ASJC Scopus subject areas

Access to Document

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