Small-molecule CSF1R kinase inhibitors; review of patents 2015-present

ABSTRACT

Introduction

Colony stimulating factor 1 receptor (CSF-1R, also known as c-FMS kinase) is in the class III receptor tyrosine kinase family, along with c-Kit, Flt3 and PDGFRα. CSF-1/CSF-1R signaling promotes the differentiation and survival of myeloid progenitors into populations of monocytes, macrophages, dendritic cells and osteoclasts, as well as microglial cells and also recruits host macrophages to develop into tumor-associated macrophages (TAMs), which promote tumor progression and metastasis.

Areas covered

In the last 5 years, and recently stimulated by the approval of pexidartinib (Turalio™, Daiichi Sankyo) in 2019 for the treatment of tenosynovial giant cell tumors, there has been a large increase in activity (both journal articles and patent applications) around small molecule inhibitors of CSF1R. Features of this work have been the surprising diversity of chemical classes shown to be potent and selective inhibitors, and the breadth of disease states (cancer, arthritis, and ‘cytokine storm’ syndromes) covered by CSF1R inhibitors. All these aspects are covered in the following sections.

Expert opinion

The field has developed rapidly from 2014 to the present, with many different chemotypes proving to be potent inhibitors. The range of potential utilities of CSF1R inhibitors has also expanded to include dementia, ulcerative colitis/Crohn’s disease, rheumatoid arthritis inflammation, and fibrosis.

KEYWORDS:

• Colony-stimulating factor-1 receptor
• CSF1R
• cancer
• Alzheimers
• inflammation

Article highlights

• The CSF/CSF1R pathway is a critical regulator of the macrophage distribution in the body; most notably by combatting the ‘tumour-associated macrophage’ population that assists tumour growth in many cancers.

• A major recent step forward in the field has been the approval of pexidartinib (Turalio; Plexxikon Inc) for the treatment of giant synovial-cell tumours (a rare, indolent cancer driven specifically by CSF1R over-expression).

• Nevertheless, given the delicate macrophage-controlling role of CSF1R inhibitors, the clinical development of CSF1R inhibitors in with wider fields of cancer and inflammation (e.g. arthritis) has been difficult.

• A future promise of selective CSF1R inhibitors is in other autoimmune diseases, including Alzheimer’s dementia, Crohn’s disease, colitis and arthritis.

This box summarizes key points contained in the article.

Declaration of interest

The authors are co-inventors on patent WO 2018/083635 A1 [48], assigned to the University of Auckland. They 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. This includes employment, consultancies, honoraria, stock ownership, expert testimony.

Reviewer disclosures

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

Additional information

Funding

This study did not receive any dedicated funding.