Potent and Selective Covalent Quinazoline Inhibitors of KRAS G12C

Mei Zeng; Jia Lu; Lianbo Li; Frederic Feru; Chunshan Quan; Thomas W. Gero; Scott B. Ficarro; Yuan Xiong; Chiara Ambrogio; Raymond M. Paranal; Marco Catalano; Jay Shao; Kwok Kin Wong; Jarrod A. Marto; Eric S. Fischer; Pasi A. Jänne; David A. Scott; Kenneth D. Westover; Nathanael S. Gray

doi:10.1016/j.chembiol.2017.06.017

Potent and Selective Covalent Quinazoline Inhibitors of KRAS G12C

Mei Zeng, Jia Lu, Lianbo Li, Frederic Feru, Chunshan Quan, Thomas W. Gero, Scott B. Ficarro, Yuan Xiong, Chiara Ambrogio, Raymond M. Paranal, Marco Catalano, Jay Shao, Kwok Kin Wong, Jarrod A. Marto, Eric S. Fischer, Pasi A. Jänne, David A. Scott, Kenneth D. Westover, Nathanael S. Gray

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

104 Scopus citations

Abstract

Targeted covalent small molecules have shown promise for cancers driven by KRAS G12C. Allosteric compounds that access an inducible pocket formed by movement of a dynamic structural element in KRAS, switch II, have been reported, but these compounds require further optimization to enable their advancement into clinical development. We demonstrate that covalent quinazoline-based switch II pocket (SIIP) compounds effectively suppress GTP loading of KRAS G12C, MAPK phosphorylation, and the growth of cancer cells harboring G12C. Notably we find that adding an amide substituent to the quinazoline scaffold allows additional interactions with KRAS G12C, and remarkably increases the labeling efficiency, potency, and selectivity of KRAS G12C inhibitors. Structural studies using X-ray crystallography reveal a new conformation of SIIP and key interactions made by substituents located at the quinazoline 2-, 4-, and 7-positions. Optimized lead compounds in the quinazoline series selectively inhibit KRAS G12C-dependent signaling and cancer cell growth at sub-micromolar concentrations.

Original language	English (US)
Pages (from-to)	1005-1016.e3
Journal	Cell Chemical Biology
Volume	24
Issue number	8
DOIs	https://doi.org/10.1016/j.chembiol.2017.06.017
State	Published - Aug 17 2017

Keywords

KRAS
covalent inhibitor
drug discovery
protein dynamics

ASJC Scopus subject areas

Biochemistry
Molecular Medicine
Molecular Biology
Pharmacology
Drug Discovery
Clinical Biochemistry

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10.1016/j.chembiol.2017.06.017

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Zeng, M., Lu, J., Li, L., Feru, F., Quan, C., Gero, T. W., Ficarro, S. B., Xiong, Y., Ambrogio, C., Paranal, R. M., Catalano, M., Shao, J., Wong, K. K., Marto, J. A., Fischer, E. S., Jänne, P. A., Scott, D. A., Westover, K. D., & Gray, N. S. (2017). Potent and Selective Covalent Quinazoline Inhibitors of KRAS G12C. Cell Chemical Biology, 24(8), 1005-1016.e3. https://doi.org/10.1016/j.chembiol.2017.06.017

Zeng, M, Lu, J, Li, L, Feru, F, Quan, C, Gero, TW, Ficarro, SB, Xiong, Y, Ambrogio, C, Paranal, RM, Catalano, M, Shao, J, Wong, KK, Marto, JA, Fischer, ES, Jänne, PA, Scott, DA, Westover, KD & Gray, NS 2017, 'Potent and Selective Covalent Quinazoline Inhibitors of KRAS G12C', Cell Chemical Biology, vol. 24, no. 8, pp. 1005-1016.e3. https://doi.org/10.1016/j.chembiol.2017.06.017

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title = "Potent and Selective Covalent Quinazoline Inhibitors of KRAS G12C",

abstract = "Targeted covalent small molecules have shown promise for cancers driven by KRAS G12C. Allosteric compounds that access an inducible pocket formed by movement of a dynamic structural element in KRAS, switch II, have been reported, but these compounds require further optimization to enable their advancement into clinical development. We demonstrate that covalent quinazoline-based switch II pocket (SIIP) compounds effectively suppress GTP loading of KRAS G12C, MAPK phosphorylation, and the growth of cancer cells harboring G12C. Notably we find that adding an amide substituent to the quinazoline scaffold allows additional interactions with KRAS G12C, and remarkably increases the labeling efficiency, potency, and selectivity of KRAS G12C inhibitors. Structural studies using X-ray crystallography reveal a new conformation of SIIP and key interactions made by substituents located at the quinazoline 2-, 4-, and 7-positions. Optimized lead compounds in the quinazoline series selectively inhibit KRAS G12C-dependent signaling and cancer cell growth at sub-micromolar concentrations.",

keywords = "KRAS, covalent inhibitor, drug discovery, protein dynamics",

author = "Mei Zeng and Jia Lu and Lianbo Li and Frederic Feru and Chunshan Quan and Gero, {Thomas W.} and Ficarro, {Scott B.} and Yuan Xiong and Chiara Ambrogio and Paranal, {Raymond M.} and Marco Catalano and Jay Shao and Wong, {Kwok Kin} and Marto, {Jarrod A.} and Fischer, {Eric S.} and J{\"a}nne, {Pasi A.} and Scott, {David A.} and Westover, {Kenneth D.} and Gray, {Nathanael S.}",

note = "Funding Information: We acknowledge the funding from Astellas Pharma (to K.D.W., P.A.J., and N.S.G.), DOD W81XWH-16-1-0106 (to K.D.W.), and Jimmy V Foundation (to K.D.W.). We thank the staff of the UT Southwestern Medical Center structural biology laboratory and beamline 19ID of Advanced Photon Source for assistance with X-ray data collection and processing. Results shown in this report are derived from work performed at Argonne National Laboratory, Structural Biology Center at the Advanced Photon Source. Argonne is operated by UChicago Argonne, LLC, for the US Department of Energy, Office of Biological and Environmental Research under contract DE-AC02-06CH11357. Publisher Copyright: {\textcopyright} 2017 Elsevier Ltd",

year = "2017",

month = aug,

day = "17",

doi = "10.1016/j.chembiol.2017.06.017",

language = "English (US)",

volume = "24",

pages = "1005--1016.e3",

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TY - JOUR

T1 - Potent and Selective Covalent Quinazoline Inhibitors of KRAS G12C

AU - Zeng, Mei

AU - Lu, Jia

AU - Li, Lianbo

AU - Feru, Frederic

AU - Quan, Chunshan

AU - Gero, Thomas W.

AU - Ficarro, Scott B.

AU - Xiong, Yuan

AU - Ambrogio, Chiara

AU - Paranal, Raymond M.

AU - Catalano, Marco

AU - Shao, Jay

AU - Wong, Kwok Kin

AU - Marto, Jarrod A.

AU - Fischer, Eric S.

AU - Jänne, Pasi A.

AU - Scott, David A.

AU - Westover, Kenneth D.

AU - Gray, Nathanael S.

N1 - Funding Information: We acknowledge the funding from Astellas Pharma (to K.D.W., P.A.J., and N.S.G.), DOD W81XWH-16-1-0106 (to K.D.W.), and Jimmy V Foundation (to K.D.W.). We thank the staff of the UT Southwestern Medical Center structural biology laboratory and beamline 19ID of Advanced Photon Source for assistance with X-ray data collection and processing. Results shown in this report are derived from work performed at Argonne National Laboratory, Structural Biology Center at the Advanced Photon Source. Argonne is operated by UChicago Argonne, LLC, for the US Department of Energy, Office of Biological and Environmental Research under contract DE-AC02-06CH11357. Publisher Copyright: © 2017 Elsevier Ltd

PY - 2017/8/17

Y1 - 2017/8/17

N2 - Targeted covalent small molecules have shown promise for cancers driven by KRAS G12C. Allosteric compounds that access an inducible pocket formed by movement of a dynamic structural element in KRAS, switch II, have been reported, but these compounds require further optimization to enable their advancement into clinical development. We demonstrate that covalent quinazoline-based switch II pocket (SIIP) compounds effectively suppress GTP loading of KRAS G12C, MAPK phosphorylation, and the growth of cancer cells harboring G12C. Notably we find that adding an amide substituent to the quinazoline scaffold allows additional interactions with KRAS G12C, and remarkably increases the labeling efficiency, potency, and selectivity of KRAS G12C inhibitors. Structural studies using X-ray crystallography reveal a new conformation of SIIP and key interactions made by substituents located at the quinazoline 2-, 4-, and 7-positions. Optimized lead compounds in the quinazoline series selectively inhibit KRAS G12C-dependent signaling and cancer cell growth at sub-micromolar concentrations.

AB - Targeted covalent small molecules have shown promise for cancers driven by KRAS G12C. Allosteric compounds that access an inducible pocket formed by movement of a dynamic structural element in KRAS, switch II, have been reported, but these compounds require further optimization to enable their advancement into clinical development. We demonstrate that covalent quinazoline-based switch II pocket (SIIP) compounds effectively suppress GTP loading of KRAS G12C, MAPK phosphorylation, and the growth of cancer cells harboring G12C. Notably we find that adding an amide substituent to the quinazoline scaffold allows additional interactions with KRAS G12C, and remarkably increases the labeling efficiency, potency, and selectivity of KRAS G12C inhibitors. Structural studies using X-ray crystallography reveal a new conformation of SIIP and key interactions made by substituents located at the quinazoline 2-, 4-, and 7-positions. Optimized lead compounds in the quinazoline series selectively inhibit KRAS G12C-dependent signaling and cancer cell growth at sub-micromolar concentrations.

KW - KRAS

KW - covalent inhibitor

KW - drug discovery

KW - protein dynamics

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DO - 10.1016/j.chembiol.2017.06.017

M3 - Article

C2 - 28781124

AN - SCOPUS:85027461830

SN - 2451-9456

VL - 24

SP - 1005-1016.e3

JO - Cell Chemical Biology

JF - Cell Chemical Biology

IS - 8

ER -

Potent and Selective Covalent Quinazoline Inhibitors of KRAS G12C

Abstract

Keywords

ASJC Scopus subject areas

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