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. Author manuscript; available in PMC: 2023 Jun 1.
Published in final edited form as: Trends Pharmacol Sci. 2022 Apr 21;43(6):536–537. doi: 10.1016/j.tips.2022.03.011

Sotorasib, a KRASG12C inhibitor for non-small cell lung cancer

Arghya Ganguly 1, Euna Yoo 1,*
PMCID: PMC9106916  NIHMSID: NIHMS1800304  PMID: 35461718

STRUCTURE:

Sotorasib is an acrylamide-derived covalent inhibitor of KRAS that reacts with cysteine-12 present in mutated KRAS. Sotorasib contains a pyrido[2,3-d]pyrimidin-2(1H)-one core substituted by 4-methyl-2-(propan-2-yl)pyridin-3-yl, (2S)-2-methyl-4-(prop-2-enoyl)piperazin-1-yl, fluoro, and 2-fluoro-6-hydroxyphenyl groups at positions 1, 4, 6 and 7, respectively. Its molecular formula is C30H30F2N6O3 and molecular weight is 560.6 g/mol. The (2,6)-dialkyl substitution of pyridine ring restricts biaryl C-N bond rotation and affords a stable atropisomer.

graphic file with name nihms-1800304-f0001.jpg

MECHANISM OF ACTION:

KRAS is a guanosine triphosphatase (GTPase) protein essential for intracellular signaling pathways that are involved in cell differentiation, proliferation and survival. In normal healthy cells, KRAS acts as a molecular switch between GTP-bound active form and GDP-bound inactive form. The combined interactions of SHP2 and SOS1 transition the GDP-bound state of KRAS to the GTP-bound state, rendering the protein active. The active KRAS promotes binding of effector proteins to transmit signals in MAPK pathway. A single point mutation of glycine to cysteine at codon 12 (KRAS p.G12C) is present in approximately 12–15% of non-small cell lung cancers, 2% of other solid tumors and 3% of colorectal cancers. The KRAS G12C mutation results in abnormally high concentrations of GTP-bound active form of KRAS, leading to hyperactivation of downstream oncogenic pathways and uncontrolled cell growth. Sotorasib binds to a pocket of the switch II region that is present only in the inactive GDP-bound state through a covalent reaction between the cysteine residue and the acrylamide group of the molecule. Bis-ortho substituted pyridine ring engages additional protein-ligand interactions with a proximal cryptic pocket. This specific and irreversible binding of sotorasib results in trapping KRASG12C in the inactive state and inhibiting KRAS oncogenic signaling. Sotorasib inhibits KRASG12C in vitro and in vivo with no inhibitory effect to the wild-type KRAS and leads to the regression of KRASG12C tumors and improves the anti-tumor efficacy of other chemotherapy and immunotherapy.

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NAME:

Sotorasib (also known as AMG 510), brand name is Lumakras.

DRUG CLASS:

Sotorasib is a first-in-class orally available, small molucule targeted therapy for tumors with KRAS mutation. It selectively and irreversibly inhibits KRASG12C.

CLINICAL USE:

Lumakras is indicated to treat adult patients with KRASG12C-mutated locally advanced or metastatic non-small cell lung cancer, who have received at least one prior systemic therapy. The FDA recommended dosage is 960 mg (8 tablets, each 120 mg) to be taken orally once daily.

DEVELOPED BY:

AMGEN Inc.

ADVERSE EFFECTS:

During clinical trials, serious adverse reactions occurred in 50% of patients receiving sotorasib, with diarrhea (2%), hepatotoxicity (3%) and pneumonia (8%) reported most frequently. The most common adverse effects are musculoskeletal pain (35%), diarrhea (42%), nausea (26%), fatigue (26%), cough (20%), and hepatotoxicity (25%). The most common (≥30%) laboratory abnormalities are increased aspartate/alanine aminotransferase and alkaline phosphatase, decreased lymphocytes and hemoglobin, and decreased calcium.

TIMELINE:.

2018-present: Phase 1/2 trials, CodeBreaK 100 (NCT03600883), CodeBreak 101 (NCT04185883), CodeBreaK201 (NCT04933695), NCT04625647 2020-present: Phase 3 trial with Docetaxel, CodeBreak 200 (NCT04303780) December, 2020: New drug application (NDA) by Amgen May 28, 2021: FDA approval for Lumakras (Sotorasib)

Acknowledgments

This work was supported by the Intramural Research Program of the NIH, National Cancer Institute, The Center for Cancer Research (ZIA BC011961).

Footnotes

Declaration of interests

The authors declare no conflict of interest.

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