Friday, August 14, 2015

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].


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.