Strategic Design of Catalytic Lysine-Targeting Reversible Covalent BCR-ABL Inhibitors**. Quach, D., Tang, G., Anantharajan, J., Baburajendran, N., Poulsen, A., Wee, J. L. K., Retna, P., Li, R., Liu, B., Tee, D. H. Y., Kwek, P. Z., Joy, J. K., Yang, W., Zhang, C., Foo, K., Keller, T. H., & Yao, S. Q. Angewandte Chemie International Edition, 60(31):17131–17137, 2021. _eprint: https://onlinelibrary.wiley.com/doi/pdf/10.1002/anie.202105383![Strategic Design of Catalytic Lysine-Targeting Reversible Covalent BCR-ABL Inhibitors** [link]](https://bibbase.org/img/filetypes/link.svg "link")
Paper doi abstract bibtex Targeted covalent inhibitors have re-emerged as validated drugs to overcome acquired resistance in cancer treatment. Herein, by using a carbonyl boronic acid (CBA) warhead, we report the structure-based design of BCR-ABL inhibitors via reversible covalent targeting of the catalytic lysine with improved potency against both wild-type and mutant ABL kinases, especially ABLT315I bearing the gatekeeper residue mutation. We show the evolutionarily conserved lysine can be targeted selectively, and the selectivity depends largely on molecular recognition of the non-covalent pharmacophore in this class of inhibitors, probably due to the moderate reactivity of the warhead. We report the first co-crystal structures of covalent inhibitor-ABL kinase domain complexes, providing insights into the interaction of this warhead with the catalytic lysine. We also employed label-free mass spectrometry to evaluate off-targets of our compounds at proteome-wide level in different mammalian cells.
@article{quach_strategic_2021,
title = {Strategic {Design} of {Catalytic} {Lysine}-{Targeting} {Reversible} {Covalent} {BCR}-{ABL} {Inhibitors}**},
volume = {60},
issn = {1521-3773},
url = {https://onlinelibrary.wiley.com/doi/abs/10.1002/anie.202105383},
doi = {10.1002/anie.202105383},
abstract = {Targeted covalent inhibitors have re-emerged as validated drugs to overcome acquired resistance in cancer treatment. Herein, by using a carbonyl boronic acid (CBA) warhead, we report the structure-based design of BCR-ABL inhibitors via reversible covalent targeting of the catalytic lysine with improved potency against both wild-type and mutant ABL kinases, especially ABLT315I bearing the gatekeeper residue mutation. We show the evolutionarily conserved lysine can be targeted selectively, and the selectivity depends largely on molecular recognition of the non-covalent pharmacophore in this class of inhibitors, probably due to the moderate reactivity of the warhead. We report the first co-crystal structures of covalent inhibitor-ABL kinase domain complexes, providing insights into the interaction of this warhead with the catalytic lysine. We also employed label-free mass spectrometry to evaluate off-targets of our compounds at proteome-wide level in different mammalian cells.},
language = {en},
number = {31},
urldate = {2023-02-23},
journal = {Angewandte Chemie International Edition},
author = {Quach, David and Tang, Guanghui and Anantharajan, Jothi and Baburajendran, Nithya and Poulsen, Anders and Wee, John L. K. and Retna, Priya and Li, Rong and Liu, Boping and Tee, Doris H. Y. and Kwek, Perlyn Z. and Joy, Joma K. and Yang, Wan-Qi and Zhang, Chong-Jing and Foo, Klement and Keller, Thomas H. and Yao, Shao Q.},
year = {2021},
note = {\_eprint: https://onlinelibrary.wiley.com/doi/pdf/10.1002/anie.202105383},
keywords = {cancer, covalent inhibitors, lysine, proteomics, reversibility},
pages = {17131--17137},
}
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