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 journalArticle

165 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 languageEnglish (US)
Pages (from-to)199-204
Number of pages6
JournalAngewandte Chemie - International Edition
Volume53
Issue number1
DOIs
StatePublished - Jan 3 2014

Fingerprint

Binding sites
Nucleotides
Guanine Nucleotides
Proteins
Binding Sites
Prodrugs
Derivatives
SML-8-73-1

Keywords

  • cancer
  • covalent inhibitors
  • drug design
  • K-Ras

ASJC Scopus subject areas

  • Chemistry(all)
  • Catalysis

Cite this

Lim, S. M., Westover, K. D., Ficarro, S. B., Harrison, R. A., Choi, H. G., Pacold, M. E., ... 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

Therapeutic targeting of oncogenic K-ras by a covalent catalytic site inhibitor. / Lim, Sang Min; Westover, Kenneth D.; Ficarro, Scott B.; Harrison, Rane A.; Choi, Hwan Geun; Pacold, Michael E.; Carrasco, Martin; Hunter, John; Kim, Nam Doo; Xie, Ting; Sim, Taebo; Jänne, Pasi A.; Meyerson, Matthew; Marto, Jarrod A.; Engen, John R.; Gray, Nathanael S.

In: Angewandte Chemie - International Edition, Vol. 53, No. 1, 03.01.2014, p. 199-204.

Research output: Contribution to journalArticle

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
Lim, Sang Min ; Westover, Kenneth D. ; Ficarro, Scott B. ; Harrison, Rane A. ; Choi, Hwan Geun ; Pacold, Michael E. ; Carrasco, Martin ; Hunter, John ; Kim, Nam Doo ; Xie, Ting ; Sim, Taebo ; Jänne, Pasi A. ; Meyerson, Matthew ; Marto, Jarrod A. ; Engen, John R. ; Gray, Nathanael S. / Therapeutic targeting of oncogenic K-ras by a covalent catalytic site inhibitor. In: Angewandte Chemie - International Edition. 2014 ; Vol. 53, No. 1. pp. 199-204.
@article{67c4e8100e7a472fbac2e5ad451f76d0,
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.",
keywords = "cancer, covalent inhibitors, drug design, K-Ras",
author = "Lim, {Sang Min} and Westover, {Kenneth D.} and Ficarro, {Scott B.} and Harrison, {Rane A.} and Choi, {Hwan Geun} and Pacold, {Michael E.} and Martin Carrasco and John Hunter and Kim, {Nam Doo} and Ting Xie and Taebo Sim and J{\"a}nne, {Pasi A.} and Matthew Meyerson and Marto, {Jarrod A.} and Engen, {John R.} and Gray, {Nathanael S.}",
year = "2014",
month = "1",
day = "3",
doi = "10.1002/anie.201307387",
language = "English (US)",
volume = "53",
pages = "199--204",
journal = "Angewandte Chemie - International Edition",
issn = "1433-7851",
publisher = "John Wiley and Sons Ltd",
number = "1",

}

TY - JOUR

T1 - Therapeutic targeting of oncogenic K-ras by a covalent catalytic site inhibitor

AU - Lim, Sang Min

AU - Westover, Kenneth D.

AU - Ficarro, Scott B.

AU - Harrison, Rane A.

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.

AU - Gray, Nathanael S.

PY - 2014/1/3

Y1 - 2014/1/3

N2 - 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.

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.

KW - cancer

KW - covalent inhibitors

KW - drug design

KW - K-Ras

UR - http://www.scopus.com/inward/record.url?scp=84890947640&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84890947640&partnerID=8YFLogxK

U2 - 10.1002/anie.201307387

DO - 10.1002/anie.201307387

M3 - Article

C2 - 24259466

AN - SCOPUS:84890947640

VL - 53

SP - 199

EP - 204

JO - Angewandte Chemie - International Edition

JF - Angewandte Chemie - International Edition

SN - 1433-7851

IS - 1

ER -