OSI-906
[CAS# 867160-71-2]

Identification

• Classification: Biochemical >> Inhibitor >> Protein tyrosine kinase
• Name: OSI-906
• Synonyms: Linsitinib; cis-3-[8-Amino-1-(2-phenyl-7-quinolinyl)imidazo[1,5-a]pyrazin-3-yl]-1-methylcyclobutanol
• Molecular Formula: C₂₆H₂₃N₅O
• Molecular Weight: 421.49
• CAS Registry Number: 867160-71-2
• SMILES: CC1(CC(C1)C2=NC(=C3N2C=CN=C3N)C4=CC5=C(C=C4)C=CC(=N5)C6=CC=CC=C6)O

Properties

• Density: 1.4±0.1 g/cm³ Calc.^*
• Index of refraction: 1.748 (Calc.)^*

^* Calculated using Advanced Chemistry Development (ACD/Labs) Software.

Safety Data

• Hazard Symbols: GHS07 Warning
• Hazard Statements: H302
• Precautionary Statements: P280-P305+P351+P338

Discovory and Applicatios

OSI-906, also known as linsitinib, is a small-molecule inhibitor specifically developed to target the insulin-like growth factor 1 receptor (IGF-1R) and the insulin receptor (IR). These receptor tyrosine kinases are frequently implicated in cancer cell proliferation, survival, and resistance to therapies. OSI-906 was designed to interfere with both receptors simultaneously, thereby disrupting downstream signaling pathways such as the PI3K/AKT and MAPK pathways, which play crucial roles in oncogenesis.

The discovery of OSI-906 was part of a broader effort to develop dual-targeted therapies aimed at metabolic and proliferative signaling in tumor cells. Unlike some earlier selective IGF-1R inhibitors, OSI-906 binds to both IGF-1R and IR with high affinity, providing a broader inhibition profile that is especially relevant in cancers where IR signaling compensates for IGF-1R blockade. Structurally, OSI-906 is an orally bioavailable small molecule, facilitating its use in both preclinical and clinical settings.

Preclinical studies demonstrated that OSI-906 effectively reduced phosphorylation of IGF-1R and IR in cancer cell lines, leading to decreased cellular proliferation and increased apoptosis. Tumor xenograft models, including those of colon, breast, and non-small cell lung cancers, showed tumor regression or growth inhibition upon treatment with OSI-906. These findings encouraged the initiation of clinical trials to evaluate its therapeutic potential in humans.

In early-phase clinical trials, OSI-906 was tested as a monotherapy in patients with advanced solid tumors. The compound showed a manageable safety profile with commonly observed adverse events such as fatigue, nausea, hyperglycemia, and occasional gastrointestinal disturbances. Dose-limiting toxicities were primarily metabolic, as expected due to the involvement of the insulin receptor in glucose regulation. Nevertheless, a maximum tolerated dose was established, and pharmacokinetic analysis revealed an acceptable half-life conducive to twice-daily oral administration.

Subsequent phase II trials investigated OSI-906 in specific cancer indications, including adrenocortical carcinoma, colorectal cancer, and non-small cell lung cancer. In adrenocortical carcinoma, some clinical responses were noted, particularly in patients whose tumors demonstrated IGF-2 overexpression, a characteristic hallmark of this malignancy. In colorectal and lung cancers, the efficacy results were less promising, with limited objective responses and disease stabilization observed only in a small subset of patients.

Beyond solid tumors, OSI-906 was also evaluated in hematologic malignancies, such as multiple myeloma. The rationale was based on evidence that IGF-1R contributes to myeloma cell survival and drug resistance. In these settings, OSI-906 was explored both as a monotherapy and in combination with established agents. However, further development in hematologic cancers was not extensively pursued following limited clinical success.

The dual inhibition approach of OSI-906 posed both opportunities and challenges. While targeting both IGF-1R and IR improved the potential for robust antitumor activity, it also increased the risk of metabolic side effects, particularly hyperglycemia. This necessitated careful patient monitoring and sometimes the use of adjunct therapies to manage glucose levels. Nevertheless, the compound demonstrated that dual inhibition could be a viable therapeutic strategy, and it provided valuable insights into the pharmacology of IGF-1R/IR signaling inhibition.

OSI-906 has not received regulatory approval for routine clinical use, and its development has been largely discontinued. However, it remains an important molecule in the study of IGF-1R/IR inhibition and continues to be referenced in research focused on targeted cancer therapies. The compound has contributed to a deeper understanding of the compensatory mechanisms within receptor tyrosine kinase signaling networks and highlighted the importance of biomarker-based patient selection in targeted therapy development.

References

2007. A novel, potent, and selective insulin-like growth factor-I receptor kinase inhibitor blocks insulin-like growth factor-I receptor signaling in vitro and inhibits insulin-like growth factor-I receptor�dependent tumor growth in vivo. Molecular Cancer Therapeutics, 6(8).
DOI: 10.1158/1535-7163.mct-07-0070

2009. Discovery of OSI-906: A Selective and Orally Efficacious Dual Inhibitor of the IGF-1 Receptor and Insulin Receptor. Future Medicinal Chemistry, 1(6).
DOI: 10.4155/fmc.09.89

2010. Exciting New Targets in Lung Cancer Therapy: ALK, IGF-1R, HDAC, and Hh. Current Treatment Options in Oncology, 11(1-2).
DOI: 10.1007/s11864-010-0120-6