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 diseases. Ambit 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.

References:
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.

Drugs in Clinical Pipeline: BLZ945

BLZ945 [4-((2-(((1R,2R)-2-hydroxycyclohexyl)amino)benzo[d]thiazol-6-yl)oxy)-N-methylpicolinamide] is an orally active, brain-penetrant, potent and selective colony stimulating factor-1 receptor (CSF-1R) inhibitor. BLZ945 is an ATP competitive inhibitor with IC₅₀ for CSF-1R is 1 nM, which is more than 3200-fold higher than its affinity for other kinases it was tested with [1]. Research data demonstrate that BLZ945 is a potent new therapy that blocks tumor progression in a very aggressive glioma model in mice. The compound dramatically enhanced survival in a preclinical mouse model of gliomagenesis, and sharply reduced tumor growth rates and also reduced tumor size over a short and longer test period. In the long term test, BLZ945 appears to eliminate visible tumors in significant numbers of mice, and sharply reduces the tumor grade in most of the treated mice.

The activity of BLZ945 is as follows:

IC₅₀ (CSF-1R enzyme assay) = 0.001 uM

IC₅₀ (c-KIT enzyme assay) = 3.2 uM

IC₅₀ (PDGFR-β enzyme assay) = 4.8 uM

IC₅₀ (FLT3 enzyme assay) = 9.1 uM

Common Name: BLZ945

Synonyms: BLZ945; BLZ-945; BLZ 945

IUPAC Name: 4-((2-(((1R,2R)-2-hydroxycyclohexyl)amino)benzo[d]thiazol-6-yl)oxy)-N-methylpicolinamide

CAS Number: 953769-46-5

Mechanism of Action: Kinase Inhibitor; CSF-1R Inhibitor

Indication: Various Cancers; Solid Tumors; Treatment for Glioblastoma multiforme

Development Stage: Phase I

Company: Sloan-Kettering Institute For Cancer Research/Novartis

Colony stimulating factor-1 (CSF-1), also termed macrophage colony stimulating factor (M-CSF), signals through its receptor CSF-1 R (also known as c-FMS) to regulate the differentiation, proliferation, recruitment and survival of macrophages.

Glioblastoma multiforme (GBM) is the most common adult primary brain tumor and is notorious for its lethality and lack of responsiveness to current treatment approaches. Gliomas develop in a complex tissue microenvironment comprised of many different types of cells in the brain parenchyma in addition to the cancer cells themselves. Tumor-associated macrophages (TAMs) are one of the prominent stromal cell types present, and often account for a substantial portion of the cells in the tumor tissues. Their origin is not certain: these TAMs may originate either from microglia, the resident macrophage population in the brain, or they may be recruited from the periphery. Unfortunately, there have been no substantial improvements in treatment options in recent years, and minimal improvements in the survival prospects for patients with GBM. Thus there remains an urgent need for improved treatments for cancers of the brain such as gliomas [2].

TAMs can modulate tumor initiation and progression in a tissue-specific manner: they appear to suppress cancer development in some cases, but they enhance tumor progression in the majority of studies to date. Indeed, in approximately 80% of the cancers in which there is increased macrophage infiltration, the elevated TAM levels are associated with more aggressive disease and poor patient prognosis. Several studies have shown that human gliomas also exhibit a significant increase in TAM numbers, which correlates with advanced tumor grade, and TAMs are typically the predominant immune cell type in gliomas. However, the function of TAMs in gliomagenesis remains poorly understood, and it is currently not known whether targeting of these cells represents a viable therapeutic strategy [2].

The blockade of CSF-1R signaling has been shown to greatly decrease the number of macrophages in a tissue-specific manner. Using BLZ945, researchers have shown that CSF-1R inhibition attenuates the turnover rate of TAMs while increasing the number of CD8+ T cells that infiltrate cervical and breast carcinomas. It was found that BLZ945 decreased the growth of malignant cells in the mouse mammary tumor virus-driven polyomavirus middle T antigen (MMTV-PyMT) model of mammary carcinogenesis. Furthermore, BLZ945 prevented tumor progression in the keratin 14-expressing human papillomavirus type 16 (K14-HPV-16) transgenic model of cervical carcinogenesis. The results demonstrated that TAMs undergo a constant turnover in a CSF1R-dependent manner, and suggest that continuous inhibition of the CSF-1R pathway may be essential to maintain efficacious macrophage depletion as an anticancer therapy [3].

References:

1. Pyonteck, S. M.; et. al. CSF-1R inhibition alters macrophage polarization and blocks glioma progression. Nat Med 2013, 19(10), 1264-1272.
2. Daniel, D.; et. al. Csf-1r inhibitors for treatment of brain tumors. WO2012151523A1
3. Strachan, D. C.; et. al. CSF1R inhibition delays cervical and mammary tumor growth in murine models by attenuating the turnover of tumor-associated macrophages and enhancing infiltration by CD8+ T cells. Oncoimmunology 2013, 2(12), e26968.

Drugs in Clinical Pipeline: PLX3397

PLX3397 [5-((5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)methyl)-N-((6-(trifluoromethyl)pyridin-3-yl)methyl)pyridin-2-amine] is a novel, oral small molecule that potently and selectively inhibits Colony-Stimulating-Factor-1 Receptor (CSF1R), KIT, and oncogenic FLT3 kinases.

CSF1R and KIT regulate key components of both the tumor and its microenvironment (macrophages, osteoclasts, mast cells). PLX3397 is being evaluated in several other clinical indications, including breast cancer, pigmented villonodular synovitis (PVNS), glioblastoma, melanoma and Acute Myelogenous Leukemia (AML).

Plexxikon, a member of the Daiichi Sankyo Group since April 2011, is developing PLX3397. In collaboration with partners such as QuantumLeap Healthcare Collaborative, Plexxikon’s is carrying trails for PLX3397. QuantumLeap Healthcare Collaborative will partner in for study in the I-SPY 2 TRIAL (Investigation of Serial Studies to Predict Your Therapeutic Response with Imaging And Molecular Analysis 2). I-SPY 2 is a standing phase 2 randomized, controlled, multicenter trial for women with newly diagnosed, locally advanced breast cancer (minimum of Stage 2) that is designed to test whether adding investigational drugs to standard chemotherapy is better than standard chemotherapy alone in the neoadjuvant setting (prior to surgery).

PLX3397 received Orphan Drug designation by the FDA in February 2014 for the treatment of PVNS and giant cell tumor of tendon sheath. Plexxikon and Daiichi Sankyo plan to initiate a Phase 3 clinical trial in PVNS patients.

Common Name: PLX3397

Synonyms:  PLX-3397; PLX3397; PLX 3397; Pexidartinib; PLX108-01

IUPAC Name: 5-((5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)methyl)-N-((6-(trifluoromethyl)pyridin-3-yl)methyl) pyridin-2-amine

CAS Number: 1029044-16-3

Mechanism of Action: Kinase Inhibitor; KIT Inhibitor; Multi-kinase Inhibitor; CSF1R Inhibitor

Indication: Various Cancers; Glioblastomas

Development Stage: Phase I

Company: Plexxikon

What is PVNS?

Pigmented Villonodular Synovitis  (PVNS) is a rare proliferative neoplastic tumor that affects the synovium and tendon sheaths in young and middle-aged adults of both sexes. Patients are commonly diagnosed in their 20s to 50s and can experience severe debility as a result of local growth of tumor within or around a joint. Diffuse PVNS is an aggressive form of the disease, and can affect the entire lubricating membrane of either small or large joints, most commonly the knee. Surgical resection and/or local radiation are the standards of care, and there are no drugs currently approved to treat the condition. The diffuse form has an average annual incidence of 1.8 cases per million, and recurrence following surgery is common. PVNS tumors are known to express high levels of CSF1, which causes proliferation of tumor-associated macrophages, osteoclasts and other CSF1R-dependent cells. By selectively inhibiting CSF1R, PLX3397 should reverse the accumulation of macrophages and reduce PVNS tumor size. PLX3397 previously has been shown to inhibit CSF1R-dependent CD14+/CD16+ pro-inflammatory monocyte cell numbers in cancer patients.

PLX3397 v/s Imatinib

Researchers treated Kit(V558del/+) mice that develop Gastrointestinal stromal tumor (GIST) or mice with subcutaneous human GIST xenografts with imatinib or PLX3397 and analyzed tumor weight, cellular composition, histology, molecular signaling, and fibrosis. In vitro assays on human GIST cell lines were also performed. It was found that PLX3397 was more effective than imatinib in reducing tumor weight and cellularity in both Kit(V558del)(/+) murine GIST and human GIST xenografts. The superiority of PLX3397 did not depend on depletion of tumor-associated macrophages, because adding Colony-Stimulating-Factor-1 Receptor (CSF1R) inhibition did not improve the effects of imatinib. Instead, PLX3397 was a more potent KIT inhibitor than imatinib in vitro. PLX3397 therapy also induced substantial intratumoral fibrosis, which impaired the subsequent delivery of small molecules. PLX3397 therapy has greater efficacy than imatinib in preclinical GIST models and warrants study in patients with GIST. The resultant intratumoral fibrosis may represent one of the barriers to achieving complete tumor eradication [1].

References:
1. Kim, T. S.; et. al. Increased KIT inhibition enhances therapeutic efficacy in gastrointestinal stromal tumor. Clin Cancer Res 2014, 20(9), 2350-2362.