Structure-guided design of a selective BCL-XL inhibitor

Guillaume Lessene, Peter Edward Czabotar, Brad Sleebs, Kerry Zobel, Kym Lowes, Jerry M Adams, Jonathan Bayldon Baell, Peter M Colman, Kurt Deshayes, Wayne J Fairbrother, John A Flygare, Paul Gibbons, Wilhelmus J A Kersten, Sanjitha Kulasegaram, Rebecca M Moss, John P Parisot, Brian J Smith, Ian Philip Street, Hong Yang, David CS Huang & 1 others Keith Geoffrey Watson

Research output: Contribution to journalArticleResearchpeer-review

Abstract

The prosurvival BCL-2 family protein BCL-X-L is often overexpressed in solid tumors and renders malignant tumor cells resistant to anticancer therapeutics. Enhancing apoptotic responses by inhibiting BCL-X-L will most likely have widespread utility in cancer treatment and, instead of inhibiting multiple prosurvival BCL-2 family members, a BCL-X-L-selective inhibitor would be expected to minimize the toxicity to normal tissues. We describe the use of a high-throughput screen to discover a new series of small molecules targeting BCL-X-L and their structure-guided development by medicinal chemistry. The optimized compound, WEHI-539 (7), has high affinity (subnanomolar) and selectivity for BCL-X-L and potently kills cells by selectively antagonizing its prosurvival activity. WEHI-539 will be an invaluable tool for distinguishing the roles of BCL-X-L from those of its prosurvival relatives, both in normal cells and notably in malignant tumor cells, many of which may prove to rely upon BCL-X-L for their sustained growth.
Original languageEnglish
Pages (from-to)390 - 400
Number of pages11
JournalNature Chemical Biology
Volume9
Issue number6
DOIs
Publication statusPublished - 2013
Externally publishedYes

Cite this

Lessene, G., Czabotar, P. E., Sleebs, B., Zobel, K., Lowes, K., Adams, J. M., ... Watson, K. G. (2013). Structure-guided design of a selective BCL-XL inhibitor. Nature Chemical Biology, 9(6), 390 - 400. https://doi.org/10.1038/NCHEMBIO.1246
Lessene, Guillaume ; Czabotar, Peter Edward ; Sleebs, Brad ; Zobel, Kerry ; Lowes, Kym ; Adams, Jerry M ; Baell, Jonathan Bayldon ; Colman, Peter M ; Deshayes, Kurt ; Fairbrother, Wayne J ; Flygare, John A ; Gibbons, Paul ; Kersten, Wilhelmus J A ; Kulasegaram, Sanjitha ; Moss, Rebecca M ; Parisot, John P ; Smith, Brian J ; Street, Ian Philip ; Yang, Hong ; Huang, David CS ; Watson, Keith Geoffrey. / Structure-guided design of a selective BCL-XL inhibitor. In: Nature Chemical Biology. 2013 ; Vol. 9, No. 6. pp. 390 - 400.
@article{c4288eef54cc4e0eab7f4ca39a843026,
title = "Structure-guided design of a selective BCL-XL inhibitor",
abstract = "The prosurvival BCL-2 family protein BCL-X-L is often overexpressed in solid tumors and renders malignant tumor cells resistant to anticancer therapeutics. Enhancing apoptotic responses by inhibiting BCL-X-L will most likely have widespread utility in cancer treatment and, instead of inhibiting multiple prosurvival BCL-2 family members, a BCL-X-L-selective inhibitor would be expected to minimize the toxicity to normal tissues. We describe the use of a high-throughput screen to discover a new series of small molecules targeting BCL-X-L and their structure-guided development by medicinal chemistry. The optimized compound, WEHI-539 (7), has high affinity (subnanomolar) and selectivity for BCL-X-L and potently kills cells by selectively antagonizing its prosurvival activity. WEHI-539 will be an invaluable tool for distinguishing the roles of BCL-X-L from those of its prosurvival relatives, both in normal cells and notably in malignant tumor cells, many of which may prove to rely upon BCL-X-L for their sustained growth.",
author = "Guillaume Lessene and Czabotar, {Peter Edward} and Brad Sleebs and Kerry Zobel and Kym Lowes and Adams, {Jerry M} and Baell, {Jonathan Bayldon} and Colman, {Peter M} and Kurt Deshayes and Fairbrother, {Wayne J} and Flygare, {John A} and Paul Gibbons and Kersten, {Wilhelmus J A} and Sanjitha Kulasegaram and Moss, {Rebecca M} and Parisot, {John P} and Smith, {Brian J} and Street, {Ian Philip} and Hong Yang and Huang, {David CS} and Watson, {Keith Geoffrey}",
year = "2013",
doi = "10.1038/NCHEMBIO.1246",
language = "English",
volume = "9",
pages = "390 -- 400",
journal = "Nature Chemical Biology",
issn = "1552-4450",
publisher = "Nature Publishing Group",
number = "6",

}

Lessene, G, Czabotar, PE, Sleebs, B, Zobel, K, Lowes, K, Adams, JM, Baell, JB, Colman, PM, Deshayes, K, Fairbrother, WJ, Flygare, JA, Gibbons, P, Kersten, WJA, Kulasegaram, S, Moss, RM, Parisot, JP, Smith, BJ, Street, IP, Yang, H, Huang, DCS & Watson, KG 2013, 'Structure-guided design of a selective BCL-XL inhibitor' Nature Chemical Biology, vol. 9, no. 6, pp. 390 - 400. https://doi.org/10.1038/NCHEMBIO.1246

Structure-guided design of a selective BCL-XL inhibitor. / Lessene, Guillaume; Czabotar, Peter Edward; Sleebs, Brad; Zobel, Kerry; Lowes, Kym; Adams, Jerry M; Baell, Jonathan Bayldon; Colman, Peter M; Deshayes, Kurt; Fairbrother, Wayne J; Flygare, John A; Gibbons, Paul; Kersten, Wilhelmus J A; Kulasegaram, Sanjitha; Moss, Rebecca M; Parisot, John P; Smith, Brian J; Street, Ian Philip; Yang, Hong; Huang, David CS; Watson, Keith Geoffrey.

In: Nature Chemical Biology, Vol. 9, No. 6, 2013, p. 390 - 400.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Structure-guided design of a selective BCL-XL inhibitor

AU - Lessene, Guillaume

AU - Czabotar, Peter Edward

AU - Sleebs, Brad

AU - Zobel, Kerry

AU - Lowes, Kym

AU - Adams, Jerry M

AU - Baell, Jonathan Bayldon

AU - Colman, Peter M

AU - Deshayes, Kurt

AU - Fairbrother, Wayne J

AU - Flygare, John A

AU - Gibbons, Paul

AU - Kersten, Wilhelmus J A

AU - Kulasegaram, Sanjitha

AU - Moss, Rebecca M

AU - Parisot, John P

AU - Smith, Brian J

AU - Street, Ian Philip

AU - Yang, Hong

AU - Huang, David CS

AU - Watson, Keith Geoffrey

PY - 2013

Y1 - 2013

N2 - The prosurvival BCL-2 family protein BCL-X-L is often overexpressed in solid tumors and renders malignant tumor cells resistant to anticancer therapeutics. Enhancing apoptotic responses by inhibiting BCL-X-L will most likely have widespread utility in cancer treatment and, instead of inhibiting multiple prosurvival BCL-2 family members, a BCL-X-L-selective inhibitor would be expected to minimize the toxicity to normal tissues. We describe the use of a high-throughput screen to discover a new series of small molecules targeting BCL-X-L and their structure-guided development by medicinal chemistry. The optimized compound, WEHI-539 (7), has high affinity (subnanomolar) and selectivity for BCL-X-L and potently kills cells by selectively antagonizing its prosurvival activity. WEHI-539 will be an invaluable tool for distinguishing the roles of BCL-X-L from those of its prosurvival relatives, both in normal cells and notably in malignant tumor cells, many of which may prove to rely upon BCL-X-L for their sustained growth.

AB - The prosurvival BCL-2 family protein BCL-X-L is often overexpressed in solid tumors and renders malignant tumor cells resistant to anticancer therapeutics. Enhancing apoptotic responses by inhibiting BCL-X-L will most likely have widespread utility in cancer treatment and, instead of inhibiting multiple prosurvival BCL-2 family members, a BCL-X-L-selective inhibitor would be expected to minimize the toxicity to normal tissues. We describe the use of a high-throughput screen to discover a new series of small molecules targeting BCL-X-L and their structure-guided development by medicinal chemistry. The optimized compound, WEHI-539 (7), has high affinity (subnanomolar) and selectivity for BCL-X-L and potently kills cells by selectively antagonizing its prosurvival activity. WEHI-539 will be an invaluable tool for distinguishing the roles of BCL-X-L from those of its prosurvival relatives, both in normal cells and notably in malignant tumor cells, many of which may prove to rely upon BCL-X-L for their sustained growth.

UR - http://www.nature.com/nchembio/journal/v9/n6/full/nchembio.1246.html

U2 - 10.1038/NCHEMBIO.1246

DO - 10.1038/NCHEMBIO.1246

M3 - Article

VL - 9

SP - 390

EP - 400

JO - Nature Chemical Biology

JF - Nature Chemical Biology

SN - 1552-4450

IS - 6

ER -

Lessene G, Czabotar PE, Sleebs B, Zobel K, Lowes K, Adams JM et al. Structure-guided design of a selective BCL-XL inhibitor. Nature Chemical Biology. 2013;9(6):390 - 400. https://doi.org/10.1038/NCHEMBIO.1246