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L-5814 Linsitinib, Free Base, >99%
Synonyms : [OSI-906] [OSI 906AA]
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M.W. 421.49
[867160-71-2]
Storage: Store at or below -20 ºC. Solubility: Soluble in DMSO at 50 mg/mL; soluble in ethanol at 3 mg/mL with warming; very poorly soluble in water; maximum solubility in plain water is estimated to be about 2-5 µM; buffers, serum, or other additives may increase or decrease the aqueous solubility. Disposal: A.
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LNS-104 LNS-103 LNS-102 LNS-101
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Linsitinib, also known as OSI-906, is a novel, potent small-molecule dual insulin-like growth factor-1 receptor (IGF-1R)/insulin receptor (IR) kinase inhibitor.
As of August 18, 2016, we note that another vendor, Chemietek, is offering a batch of linsitinib that is neither the pure free base nor the pure HCl salt; it has only 0.4 equivalent of HCl.
Linsitinib inhibited IGF-1R and IR kinases with IC50 values of 35 nM and 75 nM, respectively. Linsitinib potently and selectively blocked autophosphorylation of both human IGF-1R and IR, inhibited the proliferation of a variety of tumor cell lines in vitro, and displayed robust in vivo anti-tumor efficacy in an IGF-1R-driven xenograft model when administered orally. Mulvihill, M.J., et al. "Discovery of OSI-906: a selective and orally efficacious dual inhibitor of the IGF-1 receptor and insulin receptor." Future Med. Chem. 1: 1153-1171 (2009).
Linsitinib showed superior efficacy compared with MAB391, a selective anti-IGF-1R antibody, in human tumor xenograft models in which both IGF-1R and IR were phosphorylated. Buck, E., et al. "Compensatory insulin receptor (IR) activation on inhibition of insulin-like growth factor-1 receptor (IGF-1R): rationale for cotargeting IGF-1R and IR in cancer." Mol. Cancer Ther. 9: 2652-2664 (2010).
Following a single dose of linsitinib, 18FDG-PET was shown to serve as a rapid, noninvasive pharmacodynamic biomarker of IGF-1R/IR inhibition. McKinley, E.T., et al. "18FDG-PET predicts pharmacodynamic response to OSI-906, a dual IGF-1R/IR inhibitor, in preclinical mouse models of lung cancer." Clin. Cancer Res. 17: 3332-3340 (2011).
IGF-1 was shown to be overexpressed in low-grade serous ovarian carcinoma (SOC) when compared with serous borderline ovarian tumors (SBOTs) and high-grade SOCs. Low-grade SOC cell lines were more sensitive to IGF-1 stimulation and IGF-1R inhibition than were high-grade lines. Therefore, the IGF-1 pathway is a potential therapeutic target in low-grade SOC. King, E.R., et al. "The insulin-like growth factor 1 pathway is a potential therapeutic target for low-grade serous ovarian carcinoma." Gynecol. Oncol. 123: 13-18 (2011).
Linsitinib blocked IGF-1 signaling in LCC6 xenograft tumors in vivo. When given once a week, combined administration simultaneously of OSI-906 and doxorubicin significantly improved the anti-tumor effect of doxorubicin. Zeng X., et al. "Enhancement of doxorubicin cytotoxicity of human cancer cells by tyrosine kinase inhibition of insulin receptor and type I IGF receptor." Breast Cancer Res. Treat. 133: 117-126 (2012).
Therapeutic targeting of both IR and IGF-1R by linsitinib was shown to be more effective than targeting IGF-1R alone by MAB391 in abrogating resistance to endocrine therapy in breast cancer. Fox, E.M., et al. "A kinome-wide screen identifies the insulin/IGF-1 receptor pathway as a mechanism of escape from hormone dependence in breast cancer." Cancer Res. 71: 6773-6784 (2011).
Epithelial-mesenchymal transition (EMT) was demonstrated to predict hepatocellular carcinoma cell sensitivity to linsitinib, as the epithelial phenotype was strongly associated with expression of IGF-2 and IR, and activation of IGF-1R and IR. Induction of EMT by TGFβ reduced sensitivity to linsitinib. Zhao, H., et al. "Epithelial-mesenchymal transition predicts sensitivity to the dual IGF-1R/IR inhibitor OSI-906 in hepatocellular carcinoma cell lines." Mol. Cancer Ther. 11: 503-513 (2012)
Sold for laboratory or manufacturing purposes only; not for human, veterinary, food, or household use.
This product is offered for R&D use in accordance with (i) 35 USC 271(e)+A13(1) in the U.S.; (ii) Section 69.1 of Japanese Patent Law in Japan; (iii) Section 11, No. 2 of the German Patent Act of 1981 in Germany; (iv) Section 60, Paragraph 5b of the U.K. Patents Act of 1977 in the U.K.; (v) Sections 55.2(1) and 55.2(6) and other common law exemptions of Canadian patent law; (vi) Section 68B of the Patents Act of 1953 in New Zealand together with the amendment of same by the Statutes Amendment Bill of 2002; (vii) such related legislation and/or case law as may be or become applicable in the aforementioned countries; and (viii) such similar laws and rules as may apply in various other countries.
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