An updated patent review of anaplastic lymphoma kinase inhibitors (2018–2022)

ABSTRACT

Introduction

Anaplastic lymphoma kinase (ALK), a receptor tyrosine kinase in the insulin receptor superfamily, has emerged as a promising drug target for multiple cancers. Up to now, a total of seven ALK inhibitors have been approved for clinical cancer treatment. However, the issue of resistance to ALK inhibitors was subsequently reported, which led to the exploration of novel generations of ALK inhibitors recently.

Areas covered

This paper provides a comprehensive review of the patent literature from 2018 to 2022 about structures, pharmacological data of small molecular ALK inhibitors, and their utilization as anticancer agents. In addition, several potential ALK inhibitors on the market or under clinical investigations are described in detail.

Expert opinion

To date, there are no ALK inhibitors that have been approved are completely free of resistance issues, which is a plight needing urgent solution. Development of new ALK inhibitors through structure modification, multi-targeted inhibitors, type-I½ and type-II binding modes, as well as PROTAC and drug conjugates are proceeding. Over the last 5 years, lorlatinib, entrectinib, and ensartinib have been approved, and an increasing number of studies on ALK inhibitors, especially on macrocyclic compounds, have demonstrated their promising therapeutic potency.

KEYWORDS:

• ALK inhibitors
• anaplastic lymphoma kinase
• cancer therapy
• drug resistance
• patent review

Article highlights

• As a receptor tyrosine kinase of insulin receptor (IR) superfamily, ALK has been verified to play vital roles in various cancers, especially anaplastic large cell lymphoma (ALCL), non-small cell lung cancer (NSCLC), and neuroblastomas.

• In the last 5 years, three small-molecule inhibitors of ALK (lorlatinib, entrectinib, and ensartinib) have been approved by the U.S. Food and Drug Administration (FDA) against ALK-positive NSCLCs, and 15 agents are being evaluated in clinical trials for various therapeutic indications. However, despite great efforts that have been made in the past 5 years, drug resistance still remains a crucial issue.

• In recent years, there has been a considerable exploration of structural modifications to the approved ALK inhibitors as well as research toward a wide range of ALK targeted agents with novel scaffolds.

• Based on a structure guided approach, an amido-linked 12-membered macrocycle drug, lorlatinib, was successfully developed after dedicated efforts on improving the potency, selectivity, blood–brain barrier (BBB) permeability, and lipophilic efficiency. Given the outstanding performance of lorlatinib, macrocyclic compounds have become the focus in the exploration of novel ALK inhibitors in the last 5 years, as is specifically manifested by a large number of patents reported on macrocyclic compounds and multiple macrocyclic candidates in clinical trials.

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.

Author contribution

D Ma: Literature collection, Writing-original draft. M Guo: Data curation, Visualization. Xin Zhai: Writing-review & editing, Funding acquisition, Project administration.

Reviewer disclosures

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

Additional information

Funding

This paper was funded by the National Natural Science Foundation of China (No. 81673308) and Development Project of Ministry of Education Innovation Team (No. IRT1073).