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Based on over three decades of pre-clinical data, insulin-like growth factor-1 receptor (IGF-1R) signaling has gained recognition as a promoter of tumorogenesis, driving cell survival and proliferation in multiple human cancers. As a result, IGF-1R has been pursued as a target for cancer treatment. Early pioneering efforts targeting IGF-1R focused on highly selective monoclonal antibodies, with multiple agents advancing to clinical trials. However, despite some initial promising results, recent clinical disclosures have been less encouraging. Moreover, recent studies have revealed that IGF-1R participates in a dynamic and complex signaling network, interacting with additional targets and pathways thereof through various crosstalk and compensatory signaling mechanisms. Such mechanisms of bypass signaling help to shed some light on the decreased effectiveness of selective IGF- 1R targeted therapies (e.g. monoclonal antibodies) and suggest that targeting multiple nodes within this signaling network might be necessary to produce a more effective therapeutic response. Additionally, such findings have led to the development of small molecule IGF-1R inhibitors which also co-inhibit additional targets such as insulin receptor and epidermal growth factor receptor. Such findings have helped to guide the design rationale of numerous drug combinations that are currently being evaluated in clinical trials. [ABSTRACT FROM AUTHOR]

A general and efficient synthesis of 5-aryl imidazo[1,5- a]pyrazines by palladium-catalyzed coupling of the corresponding 8-substituted derivatives with aryl halides is described. The scope of this new reaction for the imidazo[1,5- a]pyrazine ring system was explored using three readily available 8-substituted precursors, X = NH 2, NMe 2, and OMe, as well as 8-aryl derivatives, X = Ar′. On the basis of these results as well as studies using a deuterated derivative, a Heck-like mechanism is proposed for this transformation. [ABSTRACT FROM AUTHOR]

Imidazo[1,5-a]pyrazines 1undergo regioselective C3-metalation and C5/C3-dimetalation to afford a range of functionalized derivatives 2a−2g(Table 1), and 4a−4d(Table 2). Under similar conditions, the C3-methyl derivatives 2aand 5undergo surprising regioselective C5-deprotonation to afford, after electrophile quench, products 4b and 6a−6p(Table 3), results that are rationalized by quantum mechanical calculations. Benzamide 7b, obtained from such metalation chemistry followed by Suzuki cross coupling, undergoes directed remote metalation-cyclization to afford 8, representing the hitherto unknown triazadibenzo[cd,f]azulen-7(6H)-one tricyclic ring system. [ABSTRACT FROM AUTHOR]