Sotorasib
[CAS# 2296729-00-3]

Identification

• Classification: Pharmaceutical intermediate >> Heterocyclic compound intermediate >> Pyridine compound
• Name: Sotorasib
• Synonyms: 6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(4-methyl-2-propan-2-ylpyridin-3-yl)-4-[(2S)-2-methyl-4-prop-2-enoylpiperazin-1-yl]pyrido[2,3-d]pyrimidin-2-one
• Molecular Formula: C₃₀H₃₀F₂N₆O₃
• Molecular Weight: 560.59
• CAS Registry Number: 2296729-00-3
• EC Number: 853-474-3
• SMILES: C[C@H]1CN(CCN1C2=NC(=O)N(C3=NC(=C(C=C32)F)C4=C(C=CC=C4F)O)C5=C(C=CN=C5C(C)C)C)C(=O)C=C

Properties

• Density: 1.4±0.1 g/cm³, Calc.^*
• Index of Refraction: 1.651, Calc.^*
• Boiling Point: 730.5±70.0 ºC (760 mmHg), Calc.^*
• Flash Point: 395.6±35.7 ºC, Calc.^*

^* Calculated using Advanced Chemistry Development (ACD/Labs) Software.

Safety Data

• Hazard Symbols: GHS07 Warning
• Hazard Statements: H302-H315-H319-H335
• Precautionary Statements: P261-P305+P351+P338

Discovory and Applicatios

Sotorasib is a small molecule drug that acts as an inhibitor of the KRAS G12C mutation, which is a common genetic alteration found in various cancers. The KRAS gene encodes a protein that is involved in regulating cell signaling pathways that control cell growth, differentiation, and survival. The G12C mutation in KRAS results in a constitutively active form of the protein, leading to uncontrolled cell growth and cancer development.

The discovery of sotorasib came from the need to target KRAS mutations, which were previously considered "undruggable." KRAS has long been a difficult target for drug development due to its high affinity for GTP and its conformational flexibility. However, advances in understanding the structural biology of KRAS, particularly the discovery of the specific G12C mutation, allowed for the development of inhibitors that can bind selectively to the mutant form of the protein, blocking its activity.

Sotorasib was developed by Amgen and is a selective inhibitor that covalently binds to the cysteine residue in the KRAS G12C protein. By binding to this specific site, sotorasib locks KRAS in an inactive state, preventing its signaling activity and thereby inhibiting the growth and survival of cancer cells harboring the G12C mutation. It is designed to selectively target tumors with this specific mutation while minimizing effects on normal cells, making it a more targeted treatment compared to traditional chemotherapy or non-specific kinase inhibitors.

Sotorasib received approval from the U.S. Food and Drug Administration (FDA) in May 2021 under the brand name Lumakras for the treatment of patients with non-small cell lung cancer (NSCLC) that has a KRAS G12C mutation and has progressed on or after prior systemic therapy. This approval marked a significant milestone in the treatment of cancers driven by KRAS mutations, as it was the first drug to specifically target and inhibit the KRAS G12C mutation. Since then, sotorasib has also been explored in clinical trials for other cancers with KRAS G12C mutations, including colorectal cancer and pancreatic cancer.

Sotorasib is administered orally and is typically prescribed to patients who have advanced or metastatic cancer with a KRAS G12C mutation. It is taken once daily and offers a more convenient route of administration compared to intravenous chemotherapy regimens. Clinical studies have demonstrated that sotorasib can lead to tumor shrinkage in some patients with KRAS G12C-driven cancers, and it has shown a manageable side-effect profile.

Common side effects of sotorasib include diarrhea, fatigue, nausea, and liver enzyme abnormalities. While generally well tolerated, patients on sotorasib require regular monitoring for potential liver toxicity and other adverse effects. Given its selective mechanism of action, sotorasib has fewer off-target effects compared to conventional chemotherapy, offering a more targeted therapeutic approach.

Research into the combination of sotorasib with other treatments, such as immune checkpoint inhibitors and targeted therapies, is ongoing. The goal of these combination studies is to enhance the efficacy of sotorasib, particularly in patients who may not respond to monotherapy. Additionally, clinical trials are exploring the use of sotorasib in other cancer types that may harbor KRAS G12C mutations, expanding its potential clinical applications.

In conclusion, sotorasib represents a breakthrough in cancer therapy, specifically for patients with KRAS G12C mutations, which were once considered a challenging target in cancer treatment. By directly inhibiting this mutation, sotorasib offers a novel and promising treatment option for individuals with certain types of lung cancer and potentially other KRAS-driven cancers. However, continued research is necessary to fully understand its long-term efficacy, optimal use in combination therapies, and broader applications in oncology.

References

2019. Discovery of a Covalent Inhibitor of KRASG12C (AMG 510) for the Treatment of Solid Tumors. Journal of Medicinal Chemistry, 63(1).
DOI: 10.1021/acs.jmedchem.9b01180

2024. Sotorasib for Vascular Malformations Associated with KRAS G12C Mutation. The New England Journal of Medicine, 391(4).
DOI: 10.1056/nejmoa2309160

2024. Sotorasib (960 mg or 240 mg) once daily in patients with previously treated KRAS G12C-mutated advanced NSCLC. European Journal of Cancer, 207.
DOI: 10.1016/j.ejca.2024.114204