Exploring Targeted Degradation Strategy for Oncogenic KRASG12C

Mei Zeng; Yuan Xiong; Nozhat Safaee; Radosław P Nowak; Katherine A Donovan; Christine J Yuan; Behnam Nabet; Thomas W Gero; Frederic Feru; Lianbo Li; Sudershan Gondi; Lincoln J Ombelets; Chunshan Quan; Pasi A Jänne; Milka Kostic; David A Scott; Kenneth D Westover; Eric S Fischer; Nathanael S Gray

doi:10.1016/j.chembiol.2019.12.006

Exploring Targeted Degradation Strategy for Oncogenic KRAS^G12C

Cell Chem Biol. 2020 Jan 16;27(1):19-31.e6. doi: 10.1016/j.chembiol.2019.12.006. Epub 2019 Dec 26.

Authors

Mei Zeng¹, Yuan Xiong¹, Nozhat Safaee¹, Radosław P Nowak¹, Katherine A Donovan¹, Christine J Yuan¹, Behnam Nabet¹, Thomas W Gero¹, Frederic Feru¹, Lianbo Li², Sudershan Gondi², Lincoln J Ombelets¹, Chunshan Quan¹, Pasi A Jänne³, Milka Kostic¹, David A Scott¹, Kenneth D Westover⁴, Eric S Fischer⁵, Nathanael S Gray⁶

Affiliations

¹ Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02115, USA; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA.
² Departments of Biochemistry and Radiation Oncology, The University of Texas Southwestern Medical Center at Dallas, Dallas, TX 75390, USA.
³ Lowe Center for Thoracic Oncology and the Belfer Center for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
⁴ Departments of Biochemistry and Radiation Oncology, The University of Texas Southwestern Medical Center at Dallas, Dallas, TX 75390, USA. Electronic address: kenneth.westover@utsouthwestern.edu.
⁵ Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02115, USA; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA. Electronic address: eric_fischer@dfci.harvard.edu.
⁶ Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02115, USA; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA. Electronic address: nathanael_gray@dfci.harvard.edu.

PMID: 31883964
DOI: 10.1016/j.chembiol.2019.12.006

Abstract

KRAS is the most frequently mutated oncogene found in pancreatic, colorectal, and lung cancers. Although it has been challenging to identify targeted therapies for cancers harboring KRAS mutations, KRAS^G12C can be targeted by small-molecule inhibitors that form covalent bonds with cysteine 12 (C12). Here, we designed a library of C12-directed covalent degrader molecules (PROTACs) and subjected them to a rigorous evaluation process to rapidly identify a lead compound. Our lead degrader successfully engaged CRBN in cells, bound KRAS^G12Cin vitro, induced CRBN/KRAS^G12C dimerization, and degraded GFP-KRAS^G12C in reporter cells in a CRBN-dependent manner. However, it failed to degrade endogenous KRAS^G12C in pancreatic and lung cancer cells. Our data suggest that inability of the lead degrader to effectively poly-ubiquitinate endogenous KRAS^G12C underlies the lack of activity. We discuss challenges for achieving targeted KRAS^G12C degradation and proposed several possible solutions which may lead to efficient degradation of endogenous KRAS^G12C.

Keywords: CRBN; KRAS(G12C); PROTAC; caner; degrader; targeted protein degradation; ubiquitination.

Publication types

Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Cell Line, Tumor
Drug Design
Humans
Molecular Structure
Protein Kinase Inhibitors / chemistry
Protein Kinase Inhibitors / pharmacology*
Proteolysis / drug effects*
Proto-Oncogene Proteins p21(ras) / antagonists & inhibitors*
Proto-Oncogene Proteins p21(ras) / genetics
Proto-Oncogene Proteins p21(ras) / metabolism

Substances

Antineoplastic Agents
KRAS protein, human
Protein Kinase Inhibitors
Proto-Oncogene Proteins p21(ras)