Abstract A199: Development of a series of novel, potent and selective inhibitors of cFMS as a potential treatment for CSF1 expressing cancers via the modulation of the tumor microenvironment and the repolarization of macrophages
Authors: Mahale Sachin G. , Belfield Andrew , Wright Jamie , Campbell Mary-Ann , Bingham Matilda , Armer Richard 
Published: May 2016

Redx Oncology has developed novel small molecule inhibitors of Colony Stimulating Factor 1 Receptor (CSF1R or cFMS) which have proven to be efficacious in an in vivo bone erosion model.

cFMS is a key receptor involved in the survival, modulation and maintenance of cells of the monocyte- macrophage lineage (which include osteoclasts in the bone). In bone, osteoclasts express cFMS whilst osteoblasts express CSF1. The CSF1/cFMS axis is involved, along with RANKL, in the dynamics of bone metabolism. Metastatic tumor cells that express cFMS can be recruited into the bone as part of this dynamic metabolism. Moreover, recent literature has shown that cFMS inhibitors are able to ‘re-educate’ pro-tumurogenic M2 macrophages, which are present in the tumor microenvironment in a CSF positive tumor, into the anti-tumurogenic M1 phenotype.

We present here results of the lead optimization of our novel cFMS inhibitor series.

REDX05182 is a lead compound from the series and is a highly selective cFMS inhibitor which shows potent inhibition of cFMS. It also inhibits the related kinases cKIT, PDGFRA and PDGFRB. Interestingly, however, it exhibits good selectivity over related kinases Flt3 and KDR (VEGFR2). It displays low nanomolar binding affinity for cFMS in a biochemical assay (6nM (5 hours)) and displays slow binding kinetics.

In cellular assays, REDX05182 shows nanomolar inhibition of CSF1 driven cell proliferation of the M-NFS-60 cell line (126nM), CSF1 stimulated phosphorylation of CSF1R in THP-1 cells (182nM) and CSF-1 stimulated differentiation of rat primary macrophages into osteoclasts (102nM).

REDX05182 demonstrates good exposure and bioavailability in vivo and has shown efficacy in a rat model of cancer induced bone resorption using MRMT-1 cancer cells. At 30mg/kg BID a statistically significant improvement in the allodynia score is observed. Also at this dose the osteoclast count in the bone is returned to that of normal bone and the osteolysis is reduced.

Interestingly, REDX05182 has also demonstrated the re-polarization of macrophages from the pro-tumurogenic M2 phenotype to the anti-tumurogenic M1 phenotype in human pBMC's.

In summary, REDX05182 is a potent cFMS inhibitor which has shown activity in vivo and in vitro. Work is continuing on the project to further optimize this lead compound to deliver a clinical candidate.

Citation Format: Sachin G. Mahale, Andrew Belfield, Jamie Wright, Mary-Ann Campbell, Matilda Bingham, Richard Armer. Development of a series of novel, potent and selective inhibitors of cFMS as a potential treatment for CSF1 expressing cancers via the modulation of the tumor microenvironment and the repolarization of macrophages. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr A199.