Discovery of BBO-8520, a First-In-Class Direct and Covalent Dual Inhibitor of GTP-Bound (ON) and GDP-Bound (OFF) KRASG12C

Approved inhibitors of KRASG12C prevent oncogenic activation by sequestering the inactive, GDP-bound (OFF) form rather than directly binding and inhibiting the active, GTP-bound (ON) form. This approach provides no direct target coverage of the active protein. Expectedly, adaptive resistance to KRASG12C (OFF)-only inhibitors is observed in association with increased expression and activity of KRASG12C(ON). To provide optimal KRASG12C target coverage, we have developed BBO-8520, a first-in-class, direct dual inhibitor of KRASG12C(ON) and (OFF) forms. BBO-8520 binds in the Switch-II/Helix3 pocket, covalently modifies the target cysteine, and disables effector binding to KRASG12C(ON). BBO-8520 exhibits potent signaling inhibition in growth factor-activated states, in which current (OFF)-only inhibitors demonstrate little measurable activity. In vivo, BBO-8520 demonstrates rapid target engagement and inhibition of signaling, resulting in durable tumor regression in multiple models, including those resistant to KRASG12C(OFF)-only inhibitors. BBO-8520 is in phase 1 clinical trials in patients with KRASG12C non-small cell lung cancer. Significance: BBO-8520 is a first-in-class direct, small molecule covalent dual inhibitor that engages KRASG12C in the active (ON) and inactive (OFF) conformations. BBO-8520 represents a novel mechanism of action that allows for optimal target coverage and delays the emergence of adaptive resistance seen with (OFF)-only inhibitors in the clinic. See related commentary by Zhou and Westover, p. 455.

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Publication Details

Journal
Cancer Discovery
Published
2024-12-06
DOI
https://doi.org/10.1158/2159-8290.cd-24-0840
Citations
35
Primary Topic
Protein Kinase Regulation and GTPase Signaling
Type
article
Field-Weighted Citation Impact
8.18

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article

Discovery of BBO-8520, a First-In-Class Direct and Covalent Dual Inhibitor of GTP-Bound (ON) and GDP-Bound (OFF) KRASG12C

Patrick Alexander, Marcin D. Dyba, Kwok‐Kin Wong, Pedro J. Beltran et al.
35 citations
Cancer Discovery
Protein Kinase Regulation and GTPase Signaling
8.18
article

Discovery of BBO-8520, a First-In-Class Direct and Covalent Dual Inhibitor of GTP-Bound (ON) and GDP-Bound (OFF) KRASG12C

Patrick Alexander, Marcin D. Dyba, Kwok‐Kin Wong, Pedro J. Beltran, Felice C. Lightstone, Keshi Wang, David M. Turner, Dhirendra K. Simanshu, John-Paul Denson, Mary Meynardie, James P. Stice, Michela Ranieri, Jin Hyun Ju, Dwight V. Nissley, Yue Yang, Zuhui Zhang, Dana Rabara, Devansh Singh, Andrew G. Stephen, Dominic Esposito, Erik K. Larsen, Kerstin W. Sinkevicius, Rui Xu, Frank P. McCormick, Albert H. Chan, Saman Setoodeh, Bin Wang, Alok K. Sharma, Kenneth Lin, Maria Abreu Blanco, Bryan D. Smith, Sadaf Mehdizadeh, Eli Wallace, Anna E. Maciag, Stevan Jeknic
article en
35 citations

Abstract

Approved inhibitors of KRASG12C prevent oncogenic activation by sequestering the inactive, GDP-bound (OFF) form rather than directly binding and inhibiting the active, GTP-bound (ON) form. This approach provides no direct target coverage of the active protein. Expectedly, adaptive resistance to KRASG12C (OFF)-only inhibitors is observed in association with increased expression and activity of KRASG12C(ON). To provide optimal KRASG12C target coverage, we have developed BBO-8520, a first-in-class, direct dual inhibitor of KRASG12C(ON) and (OFF) forms. BBO-8520 binds in the Switch-II/Helix3 pocket, covalently modifies the target cysteine, and disables effector binding to KRASG12C(ON). BBO-8520 exhibits potent signaling inhibition in growth factor-activated states, in which current (OFF)-only inhibitors demonstrate little measurable activity. In vivo, BBO-8520 demonstrates rapid target engagement and inhibition of signaling, resulting in durable tumor regression in multiple models, including those resistant to KRASG12C(OFF)-only inhibitors. BBO-8520 is in phase 1 clinical trials in patients with KRASG12C non-small cell lung cancer. Significance: BBO-8520 is a first-in-class direct, small molecule covalent dual inhibitor that engages KRASG12C in the active (ON) and inactive (OFF) conformations. BBO-8520 represents a novel mechanism of action that allows for optimal target coverage and delays the emergence of adaptive resistance seen with (OFF)-only inhibitors in the clinic. See related commentary by Zhou and Westover, p. 455.

Cancer DiscoveryVol. 15(3)
Leidos (United States) (US), Lawrence Livermore National Laboratory (US), University of California, San Francisco (US), NYU Langone Health (US), Frederick National Laboratory for Cancer Research (US), BridgeBio (United States) (US), National Cancer Institute (US), Io Therapeutics (United States) (US), UCSF Helen Diller Family Comprehensive Cancer Center (US), Leidos Biomedical Research Inc. (United States), New York University (US)
National Cancer Institute
Decent work and economic growth
Openalex Percentile: Top 2%
Protein Kinase Regulation and GTPase Signaling
8.18
DOIOpen Access PDFOpenAlex
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