Discovery of potent and selective benzothiazole hydrazone inhibitors of Bcl-XL

Brad Sleebs, Wilhelmus J A Kersten, Sanjitha Kulasegaram, George Nikolakopoulos, Effie Hatzis, Rebecca M Moss, John P Parisot, Hong Yang, Peter Edward Czabotar, W Douglas Fairlie, Erinna F Lee, Jerry M Adams, Lin Chen, Mark F van Delft, Kym N Lowes, Andrew Wei, David CS Huang, Peter M Colman, Ian Philip Street, Jonathan Bayldon Baell & 2 others Keith Geoffrey Watson, Guillaume Lessene

Research output: Contribution to journalArticleResearchpeer-review

Abstract

Developing potent molecules that inhibit Bcl-2 family mediated apoptosis affords opportunities to treat cancers via reactivation of the cell death machinery. We describe the hit-to-lead development of selective Bcl-X-L inhibitors originating from a high-throughput screening campaign. Small structural changes to the hit compound increased binding affinity more than 300-fold (to IC50 <20 nM). This molecular series exhibits drug-like characteristics, low molecular weights (M-w <450) and unprecedented selectivity for Bcl-X-L. Surface plasmon resonance experiments afford strong evidence of binding affinity within the hydrophobic groove of Bcl-X-L. Biological experiments using engineered Mcl-1 deficient mouse embryonic fibroblasts (MEFs, reliant only on Bcl-X-L, for survival) and Bax/Bak deficient MEFs (insensitive to selective activation of Bcl-2-driven apoptosis) support a mechanism-based induction of apoptosis. This manuscript describes the first series of selective small-molecule inhibitors of Bcl-X-L and provides promising leads for the development of efficacious therapeutics against solid tumors and chemoresistant cancer cell lines.
Original languageEnglish
Pages (from-to)5514 - 5540
Number of pages27
JournalJournal of Medicinal Chemistry
Volume56
Issue number13
DOIs
Publication statusPublished - 2013

Cite this

Sleebs, B., Kersten, W. J. A., Kulasegaram, S., Nikolakopoulos, G., Hatzis, E., Moss, R. M., ... Lessene, G. (2013). Discovery of potent and selective benzothiazole hydrazone inhibitors of Bcl-XL. Journal of Medicinal Chemistry, 56(13), 5514 - 5540. https://doi.org/10.1021/jm400556w
Sleebs, Brad ; Kersten, Wilhelmus J A ; Kulasegaram, Sanjitha ; Nikolakopoulos, George ; Hatzis, Effie ; Moss, Rebecca M ; Parisot, John P ; Yang, Hong ; Czabotar, Peter Edward ; Fairlie, W Douglas ; Lee, Erinna F ; Adams, Jerry M ; Chen, Lin ; van Delft, Mark F ; Lowes, Kym N ; Wei, Andrew ; Huang, David CS ; Colman, Peter M ; Street, Ian Philip ; Baell, Jonathan Bayldon ; Watson, Keith Geoffrey ; Lessene, Guillaume. / Discovery of potent and selective benzothiazole hydrazone inhibitors of Bcl-XL. In: Journal of Medicinal Chemistry. 2013 ; Vol. 56, No. 13. pp. 5514 - 5540.
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title = "Discovery of potent and selective benzothiazole hydrazone inhibitors of Bcl-XL",
abstract = "Developing potent molecules that inhibit Bcl-2 family mediated apoptosis affords opportunities to treat cancers via reactivation of the cell death machinery. We describe the hit-to-lead development of selective Bcl-X-L inhibitors originating from a high-throughput screening campaign. Small structural changes to the hit compound increased binding affinity more than 300-fold (to IC50 <20 nM). This molecular series exhibits drug-like characteristics, low molecular weights (M-w <450) and unprecedented selectivity for Bcl-X-L. Surface plasmon resonance experiments afford strong evidence of binding affinity within the hydrophobic groove of Bcl-X-L. Biological experiments using engineered Mcl-1 deficient mouse embryonic fibroblasts (MEFs, reliant only on Bcl-X-L, for survival) and Bax/Bak deficient MEFs (insensitive to selective activation of Bcl-2-driven apoptosis) support a mechanism-based induction of apoptosis. This manuscript describes the first series of selective small-molecule inhibitors of Bcl-X-L and provides promising leads for the development of efficacious therapeutics against solid tumors and chemoresistant cancer cell lines.",
author = "Brad Sleebs and Kersten, {Wilhelmus J A} and Sanjitha Kulasegaram and George Nikolakopoulos and Effie Hatzis and Moss, {Rebecca M} and Parisot, {John P} and Hong Yang and Czabotar, {Peter Edward} and Fairlie, {W Douglas} and Lee, {Erinna F} and Adams, {Jerry M} and Lin Chen and {van Delft}, {Mark F} and Lowes, {Kym N} and Andrew Wei and Huang, {David CS} and Colman, {Peter M} and Street, {Ian Philip} and Baell, {Jonathan Bayldon} and Watson, {Keith Geoffrey} and Guillaume Lessene",
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language = "English",
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Sleebs, B, Kersten, WJA, Kulasegaram, S, Nikolakopoulos, G, Hatzis, E, Moss, RM, Parisot, JP, Yang, H, Czabotar, PE, Fairlie, WD, Lee, EF, Adams, JM, Chen, L, van Delft, MF, Lowes, KN, Wei, A, Huang, DCS, Colman, PM, Street, IP, Baell, JB, Watson, KG & Lessene, G 2013, 'Discovery of potent and selective benzothiazole hydrazone inhibitors of Bcl-XL', Journal of Medicinal Chemistry, vol. 56, no. 13, pp. 5514 - 5540. https://doi.org/10.1021/jm400556w

Discovery of potent and selective benzothiazole hydrazone inhibitors of Bcl-XL. / Sleebs, Brad; Kersten, Wilhelmus J A; Kulasegaram, Sanjitha; Nikolakopoulos, George; Hatzis, Effie; Moss, Rebecca M; Parisot, John P; Yang, Hong; Czabotar, Peter Edward; Fairlie, W Douglas; Lee, Erinna F; Adams, Jerry M; Chen, Lin; van Delft, Mark F; Lowes, Kym N; Wei, Andrew; Huang, David CS; Colman, Peter M; Street, Ian Philip; Baell, Jonathan Bayldon; Watson, Keith Geoffrey; Lessene, Guillaume.

In: Journal of Medicinal Chemistry, Vol. 56, No. 13, 2013, p. 5514 - 5540.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Discovery of potent and selective benzothiazole hydrazone inhibitors of Bcl-XL

AU - Sleebs, Brad

AU - Kersten, Wilhelmus J A

AU - Kulasegaram, Sanjitha

AU - Nikolakopoulos, George

AU - Hatzis, Effie

AU - Moss, Rebecca M

AU - Parisot, John P

AU - Yang, Hong

AU - Czabotar, Peter Edward

AU - Fairlie, W Douglas

AU - Lee, Erinna F

AU - Adams, Jerry M

AU - Chen, Lin

AU - van Delft, Mark F

AU - Lowes, Kym N

AU - Wei, Andrew

AU - Huang, David CS

AU - Colman, Peter M

AU - Street, Ian Philip

AU - Baell, Jonathan Bayldon

AU - Watson, Keith Geoffrey

AU - Lessene, Guillaume

PY - 2013

Y1 - 2013

N2 - Developing potent molecules that inhibit Bcl-2 family mediated apoptosis affords opportunities to treat cancers via reactivation of the cell death machinery. We describe the hit-to-lead development of selective Bcl-X-L inhibitors originating from a high-throughput screening campaign. Small structural changes to the hit compound increased binding affinity more than 300-fold (to IC50 <20 nM). This molecular series exhibits drug-like characteristics, low molecular weights (M-w <450) and unprecedented selectivity for Bcl-X-L. Surface plasmon resonance experiments afford strong evidence of binding affinity within the hydrophobic groove of Bcl-X-L. Biological experiments using engineered Mcl-1 deficient mouse embryonic fibroblasts (MEFs, reliant only on Bcl-X-L, for survival) and Bax/Bak deficient MEFs (insensitive to selective activation of Bcl-2-driven apoptosis) support a mechanism-based induction of apoptosis. This manuscript describes the first series of selective small-molecule inhibitors of Bcl-X-L and provides promising leads for the development of efficacious therapeutics against solid tumors and chemoresistant cancer cell lines.

AB - Developing potent molecules that inhibit Bcl-2 family mediated apoptosis affords opportunities to treat cancers via reactivation of the cell death machinery. We describe the hit-to-lead development of selective Bcl-X-L inhibitors originating from a high-throughput screening campaign. Small structural changes to the hit compound increased binding affinity more than 300-fold (to IC50 <20 nM). This molecular series exhibits drug-like characteristics, low molecular weights (M-w <450) and unprecedented selectivity for Bcl-X-L. Surface plasmon resonance experiments afford strong evidence of binding affinity within the hydrophobic groove of Bcl-X-L. Biological experiments using engineered Mcl-1 deficient mouse embryonic fibroblasts (MEFs, reliant only on Bcl-X-L, for survival) and Bax/Bak deficient MEFs (insensitive to selective activation of Bcl-2-driven apoptosis) support a mechanism-based induction of apoptosis. This manuscript describes the first series of selective small-molecule inhibitors of Bcl-X-L and provides promising leads for the development of efficacious therapeutics against solid tumors and chemoresistant cancer cell lines.

UR - http://pubs.acs.org/doi/ipdf/10.1021/jm400556w

U2 - 10.1021/jm400556w

DO - 10.1021/jm400556w

M3 - Article

VL - 56

SP - 5514

EP - 5540

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

SN - 0022-2623

IS - 13

ER -

Sleebs B, Kersten WJA, Kulasegaram S, Nikolakopoulos G, Hatzis E, Moss RM et al. Discovery of potent and selective benzothiazole hydrazone inhibitors of Bcl-XL. Journal of Medicinal Chemistry. 2013;56(13):5514 - 5540. https://doi.org/10.1021/jm400556w