Download MendeleyDiscovery of BBO-8520, a first-in-class direct and covalent dual inhibitor of GTP-bound (ON) and GDP-bound (OFF) KRASG12C.
Maciag, A.E., Stice, J.P., Wang, B., Sharma, A.K., Chan, A.H., Lin, K., Singh, D., Dyba, M., Yang, Y., Setoodeh, S., Smith, B.P., Ju, J.H., Jeknic, S., Rabara, D., Zhang, Z., Larsen, E.K., Esposito, D., Denson, J.P., Ranieri, M., Meynardie, M., Mehdizadeh, S., Alexander, P.A., Abreu Blanco, M., Turner, D.M., Xu, R., Lightstone, F.C., Wong, K.K., Stephen, A.G., Wang, K., Simanshu, D.K., Sinkevicius, K.W., Nissley, D.V., Wallace, E., McCormick, F., Beltran, P.J.(2024) Cancer Discov
- PubMed: 39642212
- DOI: https://doi.org/10.1158/2159-8290.CD-24-0840
- Primary Citation of Related Structures:
8V39, 8V3A - PubMed 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 where 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 (NSCLC).
Organizational Affiliation:
Frederick National Laboratory for Cancer Research, Frederick, MD, United States.
