For research use only. Not for therapeutic Use.
Sotuletinib (BLZ945) is a potent, selective and brain-penetrant CSF-1R (c-Fms) inhibitor with an IC50 of 1 nM, showing more than 1,000-fold selectivity against its closest receptor tyrosine kinase homologs[1].
Treatment of bone marrow-derived macrophages (BMDMs) with Sotuletinib inhibits CSF-1-dependent proliferation (EC50=67 nM), and decreases CSF-1R phosphorylation, similar to CSF-1R antibody blockade. Sotuletinib also reduces viability of CRL-2467 microglia, Ink4a/Arf?/? BMDMs (PDG genetic background), and NOD/SCID BMDMs. Importantly, Sotuletinib treatment in culture does not affect proliferation of any PDG-derived tumor cell lines (all Csf-1r-negative), or U-87 MG human glioma cells, and PDG cell tumor sphere formation is unaffected. Thus, Sotuletinib has no direct effects on glioma cells, and perturbs macrophage survival through CSF-1R inhibition[1].
Mice are treated with Sotuletinib or vehicle, and evaluated for symptom-free survival. Median survival in the vehicle-treated cohort is 5.7 weeks. In striking contrast, Sotuletinib significantly improves long-term survival. This endpoint is chosen because Ink4a/Arf?/? mice develop spontaneous tumors, including lymphomas and sarcomas, beginning at ~30 weeks. Sotuletinib is well-tolerated over long-term treatment, with no visible side-effects, consistent with histopathological studies. Histological grading revealed high-grade, invasive gliomas in all vehicle-treated mice. By contrast, Sotuletinib-treated animals have significantly less-malignant tumors, and no detectable lesions in 55.6% of asymptomatic mice at the endpoint[1]. Mice receiving Sotuletinib shows reduced CSF1R staining in both cervical tumors and the associated stroma, with a significant decrease in CSF1R+ stromal macrophages relative to vehicle-treated mice (P<0.05)[2].
| Catalog Number | I005655 |
| CAS Number | 953769-46-5 |
| Synonyms | 4-[[2-[[(1R,2R)-2-hydroxycyclohexyl]amino]-1,3-benzothiazol-6-yl]oxy]-N-methylpyridine-2-carboxamide |
| Molecular Formula | C20H22N4O3S |
| Purity | ≥95% |
| InChI | InChI=1S/C20H22N4O3S/c1-21-19(26)16-10-13(8-9-22-16)27-12-6-7-15-18(11-12)28-20(24-15)23-14-4-2-3-5-17(14)25/h6-11,14,17,25H,2-5H2,1H3,(H,21,26)(H,23,24)/t14-,17-/m1/s1 |
| InChIKey | ADZBMFGQQWPHMJ-RHSMWYFYSA-N |
| SMILES | CNC(=O)C1=NC=CC(=C1)OC2=CC3=C(C=C2)N=C(S3)NC4CCCCC4O |
| Reference | [1]. Pyonteck SM, et al. CSF-1R inhibition alters macrophage polarization and blocks glioma progression. Nat Med. 2013 Oct;19(10):1264-72. [2]. Strachan DC, 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 Dec 1;2(12):e26968. |
