Covalent inhibitors of the GTPase KRAS^G12C: a review of the patent literature

ABSTRACT

Introduction: KRAS is one of the most important oncology drug targets, playing a pivotal role in the initiation and progression of many human tumors. It has long been held undruggable due to many previously failed attempts to both directly and indirectly target this challenging GTPase protein family.

Areas covered: This review covers patent applications claiming inhibitors of the mutant GTPase KRAS^G12C that act via covalent modification of cysteine at codon 12 in the period of 2014 to the present. A total of 37 PCT applications from 9 applicants are evaluated, with the discussion organized alphabetically by assignee name.

Expert opinion: The last 5 years have seen an explosion in interest around this important target with many companies aiming to capitalize on the breakthrough discovery of covalent allosteric inhibitors of the glycine to cysteine mutant form of the enzyme. The first agents from this effort have now entered clinical trials and preliminary data are encouraging with responses seen in both lung adenocarcinoma and colorectal cancer patients.

KEYWORDS:

• KRAS
• G12C
• inhibitor
• lung adenocarcinoma
• colorectal cancer

Article highlights

• The frequently mutated GTPase KRAS may be viewed as the archetypal high value, yet intractable oncology drug target. Despite elucidation of its importance in promoting cellular growth, differentiation, and proliferation several decades ago, it remains un-drugged, despite numerous direct and indirect approaches.

• A glycine to cysteine mutation at codon 12 in KRAS, prevalent in lung adenocarcinoma and other tumors, has recently been recognized as an ‘Achilles heel’ amenable to intervention using covalent allosteric small molecule inhibitors that bind to the GDP-bound form of KRAS and prevent its activation.

• Patent applications focusing on covalent inhibitors of the mutant GTPase KRAS^G12C from 2014 to 2019 are reported and discussed in this article. Since an initial filing in 2014, there has been enormous progress towards the development of covalent KRAS^G12C inhibitors, with nearly 40 applications from 9 unique applicants, and several other companies known to be active in the field.

• The work disclosed in these patent applications has led to three compounds entering phase I clinical trials. Emerging clinical data show that inhibition of KRAS^G12C may provide benefit in both lung and colorectal cancer patients.

This box summarizes key points contained in the article.

Declaration of interest

JG Kettle and DJ Cassar are employees and shareholders of AstraZeneca, and are also named inventors on AstraZeneca patent applications discussed in this article. The authors have no other 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 apart from those disclosed.

Reviewer disclosures

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

Additional information

Funding

This paper was not funded.