Tuesday, November 3, 2015

Drugs in Clinical Pipeline: AC708

AC708 is a small molecule CSF1R inhibitor designed with rationale to impact the TAM-related progression of human tumors. Tumor-associated macrophages (TAMs) are thought to be regulators of solid tumor development based on their capacity to enhance metastatic, invasive, and angiogenic programming of neoplastic tissue. Colony stimulating factor-1 (CSF-1) is a key cytokine involved in recruitment and activation of tissue macrophages, exerting these effects through binding to a high-affinity receptor tyrosine kinase, the CSF-1 receptor.

AC708 possesses significant specificity for CSF1R when tested in a kinase selectivity assay, and to the closely related PDGFR family receptors PDGFRα and β, FLT3, and KIT. In cell based assays, AC708 potently inhibited CSF1R phosphorylation mediated by CSF-1 (IC50 = 26 nM) and by IL-34 (IC50 = 33 nM). It also inhibited the viability of growth-factor dependent cells cultured in CSF-1 (IC50 = 38 nM) or IL-34 (IC50 = 40 nM), and inhibited the CSF-1-mediated differentiation and survival of primary human osteoclast with an IC50 of 15 nM.

In cytokine release experiments where enriched human monocytes were stimulated with either CSF-1 or IL-34, AC708 inhibited MCP-1 release with nearly identical IC50 regardless of which cytokine was used (CSF-1 (IC50 = 93 nM), IL-34 (IC50 = 88 nM)), and with a lower IC50 than that obtained with the benchmark compound GW-2580 (CSF-1 (IC50 = 148 nM), IL-34 (IC50 = 140 nM)). 

Ambit's compound AC708 is in preclinical studies and could be used in oncology and inflammatory diseasesAmbit Bioscience Corporation was acquired by Daiichi Sankyo in November 2014.

The activity of AC708 is as follows:

IC50 (CSF1R phosphorylation, cell based assay) = 26 nM

Common Name: AC708
Synonyms:  AC708; AC 708; AC-708
IUPAC Name: 
CAS Number: 
Mechanism of Action: Kinase Inhibitor; CSF1R Inhibitor
Indication: Various Cancers; Anti-Tumor Agents
Development Stage: Pre-Clinical
Company: Ambit Biosciences: Daiichi Sankyo

Established solid tumors consist of both transformed neoplastic cells and non-transformed host cells such as stromal cells, lymphocytes, dendritic cells, macrophages, and myeloid derived suppressor cells (MDSC). In order to escape immune responses, tumor cells manipulate the surrounding tumor microenvironment by producing cytokines that suppress cytolytic T-cells and recruit immune suppressive cells. CSF-1 is a cytokine frequently produced by several cancers, including melanoma. The secreted CSF-1 binds to the tyrosine kinase receptor CSF-1R on the myeloid cells, which results in increased proliferation and differentiation of myeloid cells into type M2 macrophages and MDSC, and their recruitment into tumors. The M2-polarized macrophages and MDSC use several mechanisms to induce an immune suppressive tumor environment, such as the release of arginase I or inducible nitric oxide synthase (iNOS), leading to T-cell inhibition. Therefore, an immune suppressive tumor milieu mediated by CSF-1 may limit the anti-tumor activity of tumor immunotherapy and lead to low response rates.

Preclinical Characterisation

In vivo, AC708 was assessed for its ability to inhibit the intraperitoneal growth of M-NFS-60 cells in mice. AC708 inhibited M-NFS-60 growth in a dose-dependent manner, with a greater than 80% reduction in cell number at 100 mg/kg, similar to that achieved with the benchmark compound Ki-20227. Furthermore, to assess the ability of AC708 to modulate TAMs, researchers utilized the 4T-1 breast cancer line implanted orthotopically. Although primary tumor growth was relatively unchanged by AC708 treatment in this model, administration of drug for two weeks resulted in a dose-dependent reduction of tumor resident macrophages, with a 70% reduction at the 100 mg/kg dose relative to vehicle control.

1. Armstrong, R. C.; et. al. Abstract 903: AC708 is a potent and selective inhibitor of CSF1R and reduces tumor associated macrophage infiltration in a breast tumor model. Cancer Res 2013, 73, 903.