Abstract 3629: BLZ945, a selective c-fms (CSF-1R) kinase inhibitor for the suppression of tumor-induced osteolytic lesions in bone

Abstract

Aberrant activation of osteoclasts due to bone metastasis causes osteolysis, skeletal-related events and severe pain in cancer patients. Macrophage-Colony-stimulating Factor (M-CSF) signaling through its receptor c-fms / Colony-Stimulating Factor-1 Receptor (CSF-1R) in the monocytic lineage is essential for osteoclastogenesis, providing an opportunity to inhibit this pathway and suppress tumor-induced osteolysis. BLZ945 is an orally active, potent and selective CSF-1R inhibitor. BLZ945 inhibits CSF-1R activity with an IC50 of 1nM and is more than 1000-fold selective against its closest receptor tyrosine kinase homologs c-KIT and Platelet-derived Growth Factor Receptor beta (PDGFRb) as well as more than 200 additional kinases, confirming the selectivity of the compound. BLZ945 potently inhibited proliferation of the M-CSF-dependent murine leukemia cell line MNFS60 (EC50 67 nM) consistent with the inhibition of the CSF-1R kinase activity. Tyrosine phosphorylation in HEK293 cells overexpressing human CSF-1R was inhibited with an EC50 of 58 nM. Functional activity of BLZ945 was shown by inhibition of osteoclastogenesis using human osteoclast precursors. The MNFS60 allograft model was used to evaluate the pharmacodynamics of BLZ945 by monitoring dose and time dependent changes in tyrosine phoshorylation of CSF-1R to select doses and regimens for in vivo efficacy studies. A single dose of BLZ945 at 200 mg/kg maximally suppressed CSF-1R phosphorylation of >50% for more than 16 hours in this model and was selected for further evaluation in mouse models of breast (MDA-MB-231Luc) and prostate (PC-3MLuc) tumor-induced osteolysis (TIO). In these models human tumor cells are injected directly into the tibia of nude mice and bone destruction is measured by x-ray analysis and serum levels of tartrate-resistant acid phosphatase 5b (TRAP5b), a marker of osteoclast activity. Daily dosing of BLZ945 at 200 mg/kg resulted in a significant reduction in the progression of osteolysis, with > 50% reduction in osteolytic lesion severity in both TIO models, as compared to vehicle-treated animals. Reductions in serum TRAP5b were also observed at the end of the studies. BLZ945 showed enhanced activity in combination with zoledronate in the PC-3MLuc model, with the combination reducing osteolytic severity scores by 90%. In addition anti-osteolytic activity was observed in a nude rat model of osteolysis induced by intratibial injection of MDA-MB-231 cells. In naïve cynomolgus monkeys, treatment with BLZ945 resulted in dose-dependent reductions of serum TRAP5b and cross-linked collagen (CTX) in both serum and urine, consistent with the expected effect of inhibiting bone resorption. These data support the testing of CSF-1R inhibitors in advanced cancer patients with bone metastases and skeletal related events. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3629.

Microglial modulation through colony‐stimulating factor‐1 receptor inhibition attenuates demyelination

“…Strikingly, the MG-deprived brain is completely repopulated with new MG derived from Nestin+ cells 1 week after inhibitor withdrawal (Elmore et al, 2014). In contrast, the inhibition of CSF-1R signaling through a small molecule inhibitor such as 4-[2((1R,2R)-2-hydroxycyclohexylamino)-benzothiazol-6-yloxyl]-pyridine-2-carboxylic acid methylamide (BLZ945) has shown potential use in the treatment of an array of diseases associated with normal and deregulated function of precursor macrophages and osteoclasts from the monocytic lineage (Crespo et al, 2011;Klinkert et al, 1997;Martino et al, 1997;Pyonteck et al, 2013;Sutton et al, 2010;Uemura et al, 2008;Wang et al, 2011;Wiesmann et al, 2010). It is worth highlighting that our group has conducted pioneering work on the effects of BLZ945 on the de/remyelination processes in CPZ-treated mice (Wies Mancini, Pasquini, Correale, & Pasquini, 2017a;Wies Mancini, Pasquini, Correale, & Pasquini, 2017b).…”

Candidate Tracers for Imaging Colony-Stimulating Factor 1 Receptor in Neuroinflammation with Positron Emission Tomography: Issues and Progress

“…4-[2-((1 R ,2 R )-2-Hydroxy­cyclo­hexyl­amino)­benzo­thiazol-6-yloxy]­pyridine-2-carboxylic acid methyl­amide ( BLZ945 ) is a Type I CSF1R inhibitor Table ).…”

“…22 Consequently, one type of inhibitor may not be directly well displaced by another, and demonstration of specific binding in vitro or in vivo may therefore become challenging, depending on the choice of blocking/displacing agent and the understanding of its preferred binding mode. 77 BLZ945 appears to be one of the most selective (>3200-fold over >200 closely related kinases) and potent CSF1R inhibitors so far reported (Table 2). BLZ945 is capable of reducing tumor-associated macrophage and microglia concentrations in glioblastoma, a high-grade brain cancer with an abysmal prognosis.…”

Potential Stereoselective Binding of Trans-(±)-Kusunokinin and Cis-(±)-Kusunokinin Isomers to CSF1R

“…Pexidartinib, a pyrrolopyridine-based compound, is the first FDA-approved CSF1R tyrosine kinase inhibitor [27,28]. Moreover, several pyrrolopyridine-based selective CSF1R inhibitors are developed and currently used in clinical trials [14,29,30], i.e., sotuletinib [31], ARRY-382 [32] and JNJ-40346527 [33][34][35]. Nowadays, multi-targeted therapy has also become of interest in drug development to overcome the limitation of single-target drugs [36].…”