Small molecule and peptide-based CXCR4 modulators as therapeutic agents. A patent review for the period from 2010 to 2018

ABSTRACT

Introduction: The chemokine receptor CXCR4 has been under intense study due to the central role it plays in immune system regulation and the pathology of many human diseases. The FDA approval of the first CXCR4 antagonist drug Plerixafor (i.e. AMD3100, Mozobil®) ushered in an increase in patent activity covering CXCR4 based therapeutic agents over the past decade.

Areas covered: This article describes patent documents published during the period of 2010 through 2018 for both small molecules and peptide-based CXCR4 modulators as therapeutic agents. There is an expansion of intellectual property (IP) around existing and new small molecules of clinical interest, including new chemotypes featuring aromatic and aliphatic heterocycles. There is also significant IP covering peptide-based therapeutics, although about half as many in number as those covering small molecules.

Expert opinion: In the last decade there has been significant interest in modulators of the CXCR4 receptor, as gauged by the number of patent filings and clinical investigations targeting this receptor for human disease intervention. Seven of the many CXCR4 modulators described herein, that are currently in human clinical trials, are likely to spur the creation of other FDA approved therapeutics in the near future, most likely as immune and oncology drugs.

KEYWORDS:

• CXCR4
• GCPRs
• CXCL12
• antagonists
• chemokine

Article highlights

• This article describes intellectual property (IP) published during the period of 2010 through 2018 for both small molecule and peptide-based CXCR4 modulators as therapeutic agents.

• An explanation of the CXCL12-CXCR4 ligand-receptor axis biology and the central role it plays in immune system regulation and the pathology of many human diseases is provided along with a historical perspective on the development of CXCR4 modulators.

• The small molecule IP covers 2nd and 3rd generation analogs based on AMD3100 and 11070, novel mono and bicyclic heterocycles, ureas and guanidines.

• The peptide IP covers both linear and cyclic sequences based on human and animal proteins such as CXCL12, loop region sequences of the CXCR4 receptor, the gp120 v3 loop in HIV, Polyphemusins from horseshoe crabs and neural regenerative peptides from humans.

• Also significant is the IP reviewed for 7 new therapeutic agents in human clinical trials, mainly as immune and oncolytic drugs.

This box summarizes key points contained in the article.

Declaration of interest

DC Liotta, LJ Wilson, E Jecs, EJ Miller and YA Tahirovic are co-inventors on Emory owned intellectual property that includes CXCR4 antagonists. 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.