Therapeutic targeting of oncogenic K-ras by a covalent catalytic site inhibitor

Sang Min Lim; Kenneth D. Westover; Scott B. Ficarro; Rane A. Harrison; Hwan Geun Choi; Michael E. Pacold; Martin Carrasco; John Hunter; Nam Doo Kim; Ting Xie; Taebo Sim; Pasi A. Jänne; Matthew Meyerson; Jarrod A. Marto; John R. Engen; Nathanael S. Gray

doi:10.1002/anie.201307387

Therapeutic targeting of oncogenic K-ras by a covalent catalytic site inhibitor

Sang Min Lim, Kenneth D. Westover, Scott B. Ficarro, Rane A. Harrison, Hwan Geun Choi, Michael E. Pacold, Martin Carrasco, John Hunter, Nam Doo Kim, Ting Xie, Taebo Sim, Pasi A. Jänne, Matthew Meyerson, Jarrod A. Marto, John R. Engen, Nathanael S. Gray

Research output: Contribution to journal › Article › peer-review

267 Citations (Scopus)

Abstract

We report the synthesis of a GDP analogue, SML-8-73-1, and a prodrug derivative, SML-10-70-1, which are selective, direct-acting covalent inhibitors of the K-Ras G12C mutant relative to wild-type Ras. Biochemical and biophysical measurements suggest that modification of K-Ras with SML-8-73-1 renders the protein in an inactive state. These first-in-class covalent K-Ras inhibitors demonstrate that irreversible targeting of the K-Ras guanine-nucleotide binding site is potentially a viable therapeutic strategy for inhibition of Ras signaling. Putting a stop to Ras: Two new selective, direct-acting covalent inhibitors of the K-Ras G12C mutant are reported. Studies suggest that the modification of K-Ras with SML-8-73-1 renders the protein inactive. These novel covalent inhibitors demonstrate that irreversible targeting of the K-Ras guanine-nucleotide binding site is potentially a viable therapeutic strategy for inhibition of Ras signaling.

Original language	English
Pages (from-to)	199-204
Number of pages	6
Journal	Angewandte Chemie - International Edition
Volume	53
Issue number	1
DOIs	https://doi.org/10.1002/anie.201307387
Publication status	Published - 2014 Jan 3

Keywords

K-Ras
cancer
covalent inhibitors
drug design

ASJC Scopus subject areas

Catalysis
General Chemistry

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1002/anie.201307387

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Lim, S. M., Westover, K. D., Ficarro, S. B., Harrison, R. A., Choi, H. G., Pacold, M. E., Carrasco, M., Hunter, J., Kim, N. D., Xie, T., Sim, T., Jänne, P. A., Meyerson, M., Marto, J. A., Engen, J. R., & Gray, N. S. (2014). Therapeutic targeting of oncogenic K-ras by a covalent catalytic site inhibitor. Angewandte Chemie - International Edition, 53(1), 199-204. https://doi.org/10.1002/anie.201307387

Lim, SM, Westover, KD, Ficarro, SB, Harrison, RA, Choi, HG, Pacold, ME, Carrasco, M, Hunter, J, Kim, ND, Xie, T, Sim, T, Jänne, PA, Meyerson, M, Marto, JA, Engen, JR & Gray, NS 2014, 'Therapeutic targeting of oncogenic K-ras by a covalent catalytic site inhibitor', Angewandte Chemie - International Edition, vol. 53, no. 1, pp. 199-204. https://doi.org/10.1002/anie.201307387

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title = "Therapeutic targeting of oncogenic K-ras by a covalent catalytic site inhibitor",

abstract = "We report the synthesis of a GDP analogue, SML-8-73-1, and a prodrug derivative, SML-10-70-1, which are selective, direct-acting covalent inhibitors of the K-Ras G12C mutant relative to wild-type Ras. Biochemical and biophysical measurements suggest that modification of K-Ras with SML-8-73-1 renders the protein in an inactive state. These first-in-class covalent K-Ras inhibitors demonstrate that irreversible targeting of the K-Ras guanine-nucleotide binding site is potentially a viable therapeutic strategy for inhibition of Ras signaling. Putting a stop to Ras: Two new selective, direct-acting covalent inhibitors of the K-Ras G12C mutant are reported. Studies suggest that the modification of K-Ras with SML-8-73-1 renders the protein inactive. These novel covalent inhibitors demonstrate that irreversible targeting of the K-Ras guanine-nucleotide binding site is potentially a viable therapeutic strategy for inhibition of Ras signaling.",

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AU - Choi, Hwan Geun

AU - Pacold, Michael E.

AU - Carrasco, Martin

AU - Hunter, John

AU - Kim, Nam Doo

AU - Xie, Ting

AU - Sim, Taebo

AU - Jänne, Pasi A.

AU - Meyerson, Matthew

AU - Marto, Jarrod A.

AU - Engen, John R.

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AB - We report the synthesis of a GDP analogue, SML-8-73-1, and a prodrug derivative, SML-10-70-1, which are selective, direct-acting covalent inhibitors of the K-Ras G12C mutant relative to wild-type Ras. Biochemical and biophysical measurements suggest that modification of K-Ras with SML-8-73-1 renders the protein in an inactive state. These first-in-class covalent K-Ras inhibitors demonstrate that irreversible targeting of the K-Ras guanine-nucleotide binding site is potentially a viable therapeutic strategy for inhibition of Ras signaling. Putting a stop to Ras: Two new selective, direct-acting covalent inhibitors of the K-Ras G12C mutant are reported. Studies suggest that the modification of K-Ras with SML-8-73-1 renders the protein inactive. These novel covalent inhibitors demonstrate that irreversible targeting of the K-Ras guanine-nucleotide binding site is potentially a viable therapeutic strategy for inhibition of Ras signaling.

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Therapeutic targeting of oncogenic K-ras by a covalent catalytic site inhibitor

Abstract

Keywords

ASJC Scopus subject areas

UN SDGs

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