Inhibitors of the GTPase KRAS^G12C in cancer: a patent review (2019-2021)

ABSTRACT

Introduction

KRAS is one of the most important oncology proteins, which can activate multiple downstream signaling pathways. Despite the prevalence of KRAS mutations in approximately 30% of human cancers, it has long been considered to be ‘undruggable’ due to the lack of recognizable binding pockets.

Areas covered

This review covers the recent patents (2019–2021) on KRAS^G12C inhibitors, which are mostly highlighted in terms of chemical structures, molecular mechanisms of action, pharmacokinetic properties, and potential clinical applications.

Expert opinion

The last 3 years have seen a significant breakthrough in the development of KRAS inhibitors. So far, ten compounds entered the clinical trials with AMG510 being approved by FDA in May 2021 for the treatment of lung cancer. Moreover, MRTX849 also holds the promise of becoming the next approved drug targeting KRAS^G12C. However, it is noteworthy that acquired resistance is expected to arise inevitably. With a potentially effective treatment on the horizon, combination strategies could further enhance the efficacy of KRAS-targeted inhibition. Whatever their strengths or limitations, emerging KRAS^G12C inhibitors will undoubtedly enrich our understanding of KRAS biology and KRAS-targeted therapy, which will shed light on the development of inhibitors targeting other KRAS mutations.

KEYWORDS:

• KRAS^G12C
• covalent inhibitor
• anticancer agent
• drug design

Article highlights

• KRAS is one of the most frequently mutated oncogenes in human cancer and has challenged the development of clinical anticancer therapeutics in the last 40 years.

• KRAS inhibitors patented from 2019 to 2021 were collected and classified according to the type of inhibition and chemical structure.

• Identification of new KRAS inhibitors provided an interesting insight into new chemotypes.

• Some of these compounds were able to inhibit KRAS^G12C selectively and showed potent anti-cancer activity both in vitro and in vivo.

• Many drug design strategies such as conformational restriction have been used in the development of novel KRAS^G12C inhibitors.

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Declaration of interests

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This work was supported by Natural Science Foundation of Shandong Province (Grant No. ZR2018QH007), Key Research and Development Program of Shandong Province (2017CXGC1401), Young Scholars Program of Shandong University (YSPSDU, 2016WLJH33).