Inhibition of GTPase KRAS^G12D: a review of patent literature

ABSTRACT

Introduction

KRAS is a critical oncogenic protein intricately involved in tumor progression, and the difficulty in targeting KRAS has led it to be classified as an ‘undruggable target.’ Among the various KRAS mutations, KRAS^G12D is highly prevalent and represents a promising therapeutic target, yet there are currently no approved inhibitors for it.

Area covered

This review summarizes numerous patents and literature featuring inhibitors or degraders of KRAS^G12D through searching relevant information in PubMed, SciFinder and Web of Science databases from 2021 to February 2024, providing an overview of the research progress on inhibiting KRAS^G12D in terms of design strategies, chemical structures, biological activities, and clinical advancements.

Expert opinion

Since the approval of AMG510 (Sotorasib), there has been an increasing focus on the inhibition of KRAS^G12D, leading to numerous reports of related inhibitors and degraders. Among them, MRTX1133, as the first KRAS^G12D inhibitor to enter clinical trials, has demonstrated excellent tumor suppression in various KRAS^G12D-bearing human tumor xenograft models. It is important to note, however, that understanding the mechanisms of acquired resistance caused by KRAS inhibition and developing additional combination therapies is crucial. Moreover, seeking covalent inhibition of KRAS^G12D also holds significant potential.

KEYWORDS:

• KRAS^G12D
• inhibitor
• degrader
• drug design
• anticancer

Article highlights

• KRAS^G12D is one of the most commonly occurring KRAS mutations, frequently found in multiple types of tumors, but is also considered one of the undruggable targets.

• In comparison to KRAS^G12C, KRAS^G12D and other KRAS mutants lack the cysteine required for covalent binding. Many patents are focused on overcoming this obstacle to achieve inhibition of KRAS^G12D and other mutants. This review uncovers their design strategies for KRAS^G12D inhibitors.

• With the advancement of targeted protein degradation technology, this review similarly also focuses on the PROTACs designed for KRAS^G12D or pan-KRAS degrader.

• This work lists representative selective KRAS^G12D inhibitors as well as pan-KRAS inhibitors according to their chemical structures, some of which exhibit significant in vivo anti-tumor activity and pharmacokinetic properties.

Declaration of interest

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.

Author contributions

Yuhang Li reviewed and summarized patents and literature, and carried out the writing and revision of the paper. Le Yang and Xiaoran Li conducted a review of patents and literature. Xiaojin Zhang proposed the overall framework of the paper and supervised the writing and revision. All authors have edited and approved the final version of the manuscript.

Data availability statement

The data that support the findings of this study are openly available on the Web of Science at https://www.webofscience.com/wos and Scifinder at https://scifinder.cas.org, reference number [1]–[105].

Additional information

Funding

This work was supported by grants from the National Natural Science Foundation of China (Grants 82322062), Jiangsu Province Funds for Distinguished Young Scientists (Grant BK20211527), and China Pharmaceutical University.