Selective and noncovalent targeting of RAS mutants for inhibition and degradation

Kai Wen Teng, Steven T. Tsai, Takamitsu Hattori, Carmine Fedele, Akiko Koide, Chao Yang, Xuben Hou, Yingkai Zhang, Benjamin G. Neel, John P. O’Bryan and Shohei Koide ()
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Kai Wen Teng: Perlmutter Cancer Center, New York University Langone Health
Steven T. Tsai: Perlmutter Cancer Center, New York University Langone Health
Takamitsu Hattori: Perlmutter Cancer Center, New York University Langone Health
Carmine Fedele: Perlmutter Cancer Center, New York University Langone Health
Akiko Koide: Perlmutter Cancer Center, New York University Langone Health
Chao Yang: New York University
Xuben Hou: New York University
Yingkai Zhang: New York University
Benjamin G. Neel: Perlmutter Cancer Center, New York University Langone Health
John P. O’Bryan: Medical University of South Carolina
Shohei Koide: Perlmutter Cancer Center, New York University Langone Health

Nature Communications, 2021, vol. 12, issue 1, 1-13

Abstract: Abstract Activating mutants of RAS are commonly found in human cancers, but to date selective targeting of RAS in the clinic has been limited to KRAS(G12C) through covalent inhibitors. Here, we report a monobody, termed 12VC1, that recognizes the active state of both KRAS(G12V) and KRAS(G12C) up to 400-times more tightly than wild-type KRAS. The crystal structures reveal that 12VC1 recognizes the mutations through a shallow pocket, and 12VC1 competes against RAS-effector interaction. When expressed intracellularly, 12VC1 potently inhibits ERK activation and the proliferation of RAS-driven cancer cell lines in vitro and in mouse xenograft models. 12VC1 fused to VHL selectively degrades the KRAS mutants and provides more extended suppression of mutant RAS activity than inhibition by 12VC1 alone. These results demonstrate the feasibility of selective targeting and degradation of KRAS mutants in the active state with noncovalent reagents and provide a starting point for designing noncovalent therapeutics against oncogenic RAS mutants.

Date: 2021
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DOI: 10.1038/s41467-021-22969-5

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