Sotorasib is a First-in-Class, Orally Active, and Selective KRAS G12C Inhibitor

The KRAS oncoprotein is a GTPase and an essential mediator of intracellular signaling pathways. They are involved in tumor cell growth and survival. Somatic, activating mutations in KRAS are a hallmark of cancer. Furthermore, they prevent the association of GTPase-activating proteins, thus stabilizing effector binding and enhancing KRAS signaling. KRAS G12C is present in approximately 13% of lung adenocarcinoma, 3% of colorectal cancer and 2% of other solid tumors. It is present in the inactive GDP-bound form of KRAS. There are some inhibitors of several MAPK pathway proteins for a subset of tumor types, but has no selective for KRAS-mutant tumors. Moreover, several MAPK-pathway-targeting therapies are contra-indicated for the treatment of KRAS-mutant tumors owing to a lack of clinical efficacy. Sotorasib is a first-in-class, orally bioavailable, and selective KRAS G12C covalent inhibitor. It is the first KRAS G12C inhibitor in clinical development.

Sotorasib is a first-in-class and selective KRAS G12C covalent inhibitor and the first one in clinical development.

Sotorasib irreversibly inhibits KRAS G12C by locking it in an inactive GDP-bound state. Moreover, it leads to the regression of KRAS G12C tumors. In two KRAS G12C cell lines, NCI-H358 and MIA PaCa-2, Sotorasib almost completely inhibited p-ERK (IC₅₀≈0.03 μM) after a 2-hour treatment. Sotorasib also potently impaired cellular viability in both NCI-H358 and MIA PaCa-2 (IC₅₀≈0.006 μM and 0.009 μM respectively. In cell-viability assays, Sotorasib impaired the growth of all KRAS G12C cell lines, except SW1573, with IC₅₀ values ranging from 0.004 μM to 0.032 μM.

In three KRAS G12C tumor models, Sotorasib inhibited p-ERK in a dose-dependent manner 2 h after treatment. Moreover, the maximal inhibition doses range from 30-100 mg/kg. In mice with xenografts of human tumor cells, Sotorasib significantly inhibited the growth of MIA PaCa-2 T2 and NCI-H358 tumors at all doses (30-100 mg/kg). Moreover, higher doses lead to the regression of tumors.

Sotorasib, a first-in-class oral KRAS G12C inhibitor. Preclinically, Sotorasib selectively targeted KRAS G12C tumors. Thus, Sotorasib might be an effective anti-tumor agent even in settings in which KRAS G12C expression is heterogenous.

Reference:

Canon J, et al.  Nature. 2019 Nov;575(7781):217-223.