De-novo designed library of benzoylureas as inhibitors of BCL-XL: Synthesis, structural and biochemical characterization

Ryan Brady, Amelia Vom, Michael J Roy, Nathan Toovey, Brian J Smith, Rebecca M Moss, Effie Hatzis, David CS Huang, John P Parisot, Hong Yang, Ian Philip Street, Peter M Colman, Peter Edward Czabotar, Jonathan Bayldon Baell, Guillaume Lessene

Research output: Contribution to journalArticleResearchpeer-review

Abstract

The prosurvival BCL-2 proteins are attractive yet challenging targets for medicinal chemists. Their involvement in the initiation and progression of many, if not all, tumors makes them prime targets for developing new anticancer therapies. We present our approach based on de novo structure-based drug design. Using known structural information from complexes engaging opposing members of the BCL-2 family of proteins, we designed peptidomimetic compounds using a benzoylurea scaffold to reproduce key interactions between these proteins. A library stemming from the initial de novo designed scaffold led to the discovery of ligands with low micromolar potency (KD = 4 ?M) and selectivity for BCL-XL. These compounds bind in the canonical BH3 binding groove in a binding mode distinct from previously known BCL-2 inhibitors. The results of our study provide insight into the design of a new class of antagonists targeting a challenging class of protein-protein interactions.
Original languageEnglish
Pages (from-to)1323 - 1343
Number of pages21
JournalJournal of Medicinal Chemistry
Volume57
Issue number4
DOIs
Publication statusPublished - 2014
Externally publishedYes

Cite this

Brady, Ryan ; Vom, Amelia ; Roy, Michael J ; Toovey, Nathan ; Smith, Brian J ; Moss, Rebecca M ; Hatzis, Effie ; Huang, David CS ; Parisot, John P ; Yang, Hong ; Street, Ian Philip ; Colman, Peter M ; Czabotar, Peter Edward ; Baell, Jonathan Bayldon ; Lessene, Guillaume. / De-novo designed library of benzoylureas as inhibitors of BCL-XL: Synthesis, structural and biochemical characterization. In: Journal of Medicinal Chemistry. 2014 ; Vol. 57, No. 4. pp. 1323 - 1343.
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abstract = "The prosurvival BCL-2 proteins are attractive yet challenging targets for medicinal chemists. Their involvement in the initiation and progression of many, if not all, tumors makes them prime targets for developing new anticancer therapies. We present our approach based on de novo structure-based drug design. Using known structural information from complexes engaging opposing members of the BCL-2 family of proteins, we designed peptidomimetic compounds using a benzoylurea scaffold to reproduce key interactions between these proteins. A library stemming from the initial de novo designed scaffold led to the discovery of ligands with low micromolar potency (KD = 4 ?M) and selectivity for BCL-XL. These compounds bind in the canonical BH3 binding groove in a binding mode distinct from previously known BCL-2 inhibitors. The results of our study provide insight into the design of a new class of antagonists targeting a challenging class of protein-protein interactions.",
author = "Ryan Brady and Amelia Vom and Roy, {Michael J} and Nathan Toovey and Smith, {Brian J} and Moss, {Rebecca M} and Effie Hatzis and Huang, {David CS} and Parisot, {John P} and Hong Yang and Street, {Ian Philip} and Colman, {Peter M} and Czabotar, {Peter Edward} and Baell, {Jonathan Bayldon} and Guillaume Lessene",
year = "2014",
doi = "10.1021/jm401948b",
language = "English",
volume = "57",
pages = "1323 -- 1343",
journal = "Journal of Medicinal Chemistry",
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Brady, R, Vom, A, Roy, MJ, Toovey, N, Smith, BJ, Moss, RM, Hatzis, E, Huang, DCS, Parisot, JP, Yang, H, Street, IP, Colman, PM, Czabotar, PE, Baell, JB & Lessene, G 2014, 'De-novo designed library of benzoylureas as inhibitors of BCL-XL: Synthesis, structural and biochemical characterization' Journal of Medicinal Chemistry, vol. 57, no. 4, pp. 1323 - 1343. https://doi.org/10.1021/jm401948b

De-novo designed library of benzoylureas as inhibitors of BCL-XL: Synthesis, structural and biochemical characterization. / Brady, Ryan; Vom, Amelia; Roy, Michael J; Toovey, Nathan; Smith, Brian J; Moss, Rebecca M; Hatzis, Effie; Huang, David CS; Parisot, John P; Yang, Hong; Street, Ian Philip; Colman, Peter M; Czabotar, Peter Edward; Baell, Jonathan Bayldon; Lessene, Guillaume.

In: Journal of Medicinal Chemistry, Vol. 57, No. 4, 2014, p. 1323 - 1343.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - De-novo designed library of benzoylureas as inhibitors of BCL-XL: Synthesis, structural and biochemical characterization

AU - Brady, Ryan

AU - Vom, Amelia

AU - Roy, Michael J

AU - Toovey, Nathan

AU - Smith, Brian J

AU - Moss, Rebecca M

AU - Hatzis, Effie

AU - Huang, David CS

AU - Parisot, John P

AU - Yang, Hong

AU - Street, Ian Philip

AU - Colman, Peter M

AU - Czabotar, Peter Edward

AU - Baell, Jonathan Bayldon

AU - Lessene, Guillaume

PY - 2014

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AB - The prosurvival BCL-2 proteins are attractive yet challenging targets for medicinal chemists. Their involvement in the initiation and progression of many, if not all, tumors makes them prime targets for developing new anticancer therapies. We present our approach based on de novo structure-based drug design. Using known structural information from complexes engaging opposing members of the BCL-2 family of proteins, we designed peptidomimetic compounds using a benzoylurea scaffold to reproduce key interactions between these proteins. A library stemming from the initial de novo designed scaffold led to the discovery of ligands with low micromolar potency (KD = 4 ?M) and selectivity for BCL-XL. These compounds bind in the canonical BH3 binding groove in a binding mode distinct from previously known BCL-2 inhibitors. The results of our study provide insight into the design of a new class of antagonists targeting a challenging class of protein-protein interactions.

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