Anna E. Maciag
A5115027149- Nitric Oxide and Endothelin Effects
- Cancer, Hypoxia, and Metabolism
- Mechanisms of cancer metastasis
- Metabolism, Diabetes, and Cancer
- Receptor Mechanisms and Signaling
- Amino Acid Enzymes and Metabolism
- Protein Kinase Regulation and GTPase Signaling
- Enzyme Structure and Function
- Enzyme function and inhibition
Frederick National Laboratory for Cancer Research
2024-2025
<div>Abstract<p>Approved inhibitors of KRAS<sup>G12C</sup> prevent oncogenic activation by sequestering the inactive, GDP-bound (OFF) form rather than directly binding and inhibiting active, GTP-bound (ON) form. This approach provides no direct target coverage active protein. Expectedly, adaptive resistance to (OFF)-only is observed in association with increased expression activity KRAS<sup>G12C</sup>(ON). To provide optimal coverage, we have developed...
<p>Supplementary Figure S2 shows the electron density map for BBO-8520 bound to KRAS G12C in GDP and GppNHp states</p>
<p>Supplementary Figure S6 shows that BBO-8520 anti-tumor activity in NCI-H358 CDX sotorasib-resistant tumors</p>
<p>Supplementary Figure S1 shows the Kinact/KI values for BBO-8520, sotorasib and adagrasib in biochemical cell-based assays</p>
<p>Supplementary Material and Methods</p>
<p>Supplementary Figure S5 shows that BBO-8520 demonstrates in vivo pERK inhibition, KRAS G12C target engagement and is well tolerated</p>
<p>Supplementary Figure S3 shows the activity of BBO-8520, sotorasib, and adagrasib on Ba/F3 cells with KRAS G12C mutations altered states GTP hydrolysis</p>
<p>Supplementary Figure S4 summarizes cysteine profiling, RNA-seq and kinomescan studies demonstrating that BBO-8520 is selective for KRAS G12C MAPK inhibition.</p>
Abstract Sotorasib and adagrasib, allele-specific KRASG12C covalent inhibitors that only target in the inactive GDP-bound (OFF) state, have been approved for patients with locally advanced or metastatic non-small cell lung cancer (NSCLC). While these improved treatment paradigm tumors harboring mutations, they are limited their depth duration of response. The suboptimal efficacy (OFF)-only is likely driven by adaptation through increasing population drug-insensitive bound to GTP (ON)....
Approved inhibitors of KRASG12C prevent oncogenic activation by sequestering the inactive, GDP-bound (OFF) form rather than directly binding and inhibiting active, GTP-bound (ON) form. This approach provides no direct target coverage active protein. Expectedly, adaptive resistance to (OFF)-only is observed in association with increased expression activity KRASG12C(ON). To provide optimal coverage, we have developed BBO-8520, a first-in-class, dual inhibitor KRASG12C(ON) forms. BBO-8520 binds...