An updated patent review of small-molecule ROS1 kinase inhibitors (2015–2021)

ABSTRACT

Introduction

C-ros oncogene 1 (ROS1) is the sole member of the ROS1 receptor tyrosine kinase (ROS1-RTK) family, which is involved in the formation of non-small cell lung cancer (NSCLC), gastric adenocarcinoma, colorectal cancer, and other malignant tumors. At present, only crizotinib was approved for the treatment of advanced ROS1-positive NSCLC, and there have been reports of ROS1 mutations resulting in drug resistance. Consequently, it is necessary to develop new generations of inhibitors to overcome the existing problems.

Areas covered

This review summarizes the inhibitors with ROS1 inhibitory activity which are undergoing clinical trials and recent advances in patented ROS1 small molecular inhibitors from 2015 to 2021.

Expert opinion

ROS1 rearrangements have been found in approximately 1%–2% of patients with NSCLC. Since the approval of crizotinib as multi-targeted ALK/MET/ROS1 kinase inhibitor for ALK-mutated NSCLC therapy, the researchers are focusing on ROS1-mutated tumors, especially NSCLC. However, drug-resistant mutations have already been found in clinical application. Therefore, it is still urgent to develop new generation of ROS1 inhibitors.

KEYWORDS:

• ROS1 kinase
• cancer
• patent review
• small-molecule inhibitor

Article highlights

• ROS1 was well-documented as a culprit from patients with many kinds of tumors and some compounds have already been approved by FDA.

• This article reviewed the development of compounds with ROS1 inhibitory in patents from 2015 to 2021.

• Exploration of compounds with various chemical scaffolds and the available data of the representative compounds were provided.

• Although some compounds have been approved for the treatment of advanced ROS1-positive NSCLC, the occurrence of drug resistance mutations resulting that new generations of ROS1 inhibitors will become a trend.

This box summarizes key points contained in the article.

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

One reviewer is an employee of Pfizer. The remaining reviewers have no other relevant financial relationships or otherwise to disclose.

Additional information

Funding

This study was funded by National Natural Science Foundation of China (82160659), Natural Science Foundation of Jiangxi, China (20212BBG73033), Science and Technology Project Founded by the Education Department of Jiangxi Province, China (GJJ180628, GJJ190583), the Undergraduate research project of China (202111318011).