Relaxation of the rigid backbone of an oligoamide-foldamer-based α-helix mimetic: identification of potent Bcl-xL inhibitors

Jeremy L. Yap; Xiaobo Cao; Kenno Vanommeslaeghe; Kwan-Young Jung; Chander Peddaboina; Paul T. Wilder; Anjan Nan; Alexander D. MacKerell; W. Roy Smythe; Steven Fletcher

doi:10.1039/C2OB07125H

Relaxation of the rigid backbone of an oligoamide-foldamer-based α-helix mimetic: identification of potent Bcl-x_L inhibitors†

Jeremy L. Yap,^a Xiaobo Cao,^b Kenno Vanommeslaeghe,^a Kwan-Young Jung,^a Chander Peddaboina,^b Paul T. Wilder,^c Anjan Nan,^a Alexander D. MacKerell, Jr,^ad W. Roy Smythe^b and Steven Fletcher*^ad

Author affiliations

* Corresponding authors

^a Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, 20 N Pine St, Baltimore, USA
E-mail: sfletche@rx.umaryland.edu
Fax: +1 410 706 5017
Tel: +1 410 706 6361

^b Scott & White Memorial Hospital, 702 SW HK Dodgen Loop Room 219, Temple, TX 76504, USA

^c Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, 108 N Greene St, Baltimore, USA

^d University of Maryland Marlene and Stewart Greenebaum Cancer Center, 22 S Greene St, Baltimore, MD 21201, USA

Abstract

By conducting a structure–activity relationship study of the backbone of a series of oligoamide-foldamer-based α-helix mimetics of the Bak BH3 helix, we have identified especially potent inhibitors of Bcl-x_L. The most potent compound has a K_i value of 94 nM in vitro, and single-digit micromolar IC₅₀ values against the proliferation of several Bcl-x_L-overexpressing cancer cell lines.

Organic & Biomolecular Chemistry

Relaxation of the rigid backbone of an oligoamide-foldamer-based α-helix mimetic: identification of potent Bcl-x_L inhibitors†

Abstract

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Relaxation of the rigid backbone of an oligoamide-foldamer-based α-helix mimetic: identification of potent Bcl-x_L inhibitors

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Organic & Biomolecular Chemistry

Relaxation of the rigid backbone of an oligoamide-foldamer-based α-helix mimetic: identification of potent Bcl-xL inhibitors†

Abstract

Supplementary files

Article information

Download Citation

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Relaxation of the rigid backbone of an oligoamide-foldamer-based α-helix mimetic: identification of potent Bcl-xL inhibitors

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Relaxation of the rigid backbone of an oligoamide-foldamer-based α-helix mimetic: identification of potent Bcl-x_L inhibitors†

Relaxation of the rigid backbone of an oligoamide-foldamer-based α-helix mimetic: identification of potent Bcl-x_L inhibitors