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.

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©2024 The Authors; Published by the American Association for Cancer Research
2024
American Association for Cancer Research
This open access article is distributed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0) license.
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Supplementary data

Supplementary Material and Methods

Supplementary Material and Methods

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Supplementary Table S1

Supplementary Table S1 summarizes the crystallography data for BBO-8520 bound to GMPPNP- and GDP-bound KRAS G12C

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Supplementary Table S2

Supplementary Table S2 summarizes the potency of BBO-8520, sotorasib, adagrasib and RMC-6291 on pERK and viability in a panel of KRAS mutant, wild type and BRAF V600E mutant cell lines

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Supplementary Figure S1

Supplementary Figure S1 shows the Kinact/KI values for BBO-8520, sotorasib and adagrasib in biochemical and cell-based assays

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Supplementary Figure S2

Supplementary Figure S2 shows the electron density map for BBO-8520 bound to KRAS G12C in the GDP and GppNHp states

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Supplementary Figure S3

Supplementary Figure S3 shows the activity of BBO-8520, sotorasib, and adagrasib on Ba/F3 cells with KRAS G12C mutations with altered states of GTP hydrolysis

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Supplementary Figure S4

Supplementary Figure S4 summarizes cysteine profiling, RNA-seq and kinomescan studies demonstrating that BBO-8520 is selective for KRAS G12C and MAPK inhibition.

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Supplementary Figure S5

Supplementary Figure S5 shows that BBO-8520 demonstrates in vivo pERK inhibition, KRAS G12C target engagement and is well tolerated

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Supplementary Figure S6

Supplementary Figure S6 shows that BBO-8520 shows anti-tumor activity in NCI-H358 CDX sotorasib-resistant tumors

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