Macrocyclization as a Source of Desired Polypharmacology. Discovery of Triple PI3K/mTOR/PIM Inhibitors

The PI3K/AKT/mTOR and PIM kinase pathways contribute to the development of several hallmarks of cancer. Cotargeting of these pathways has exhibited promising synergistic therapeutic effects in liquid and solid tumor types. To identify molecules with combined activities, we cross-screened our collection of PI3K/(+/- mTOR) macrocycles (MCXs) and identified the MCX thieno[3,2-d]pyrimidine derivative 2 as a moderate dual PI3K/PIM-1 inhibitor. We report the medicinal chemistry exploration and biological characterization of a series of thieno[3,2-d]pyrimidine MCXs, which led to the discovery of IBL-302 (31), a potent, selective, and orally bioavailable triple PI3K/mTOR/PIM inhibitor. IBL-302, currently in late preclinical development (AUM302), has recently demonstrated efficacy in neuroblastoma and breast cancer xenografts. Additionally, during the course of our experiments, we observed that macrocyclization was essential to obtain the desired multitarget profile. As a matter of example, the open precursors 35-37 were inactive against PIM whereas MCX 28 displayed low nanomolar activity.

Automated summary

The PI3K/AKT/mTOR and PIM kinase pathways play critical roles in cancer development, and cotargeting these pathways has shown promising therapeutic effects. Through cross-screening of compounds, a dual PI3K/PIM-1 inhibitor was identified, leading to the discovery of a potent triple PI3K/mTOR/PIM inhibitor, IBL-302. This compound has demonstrated efficacy in neuroblastoma and breast cancer xenografts and macrocyclization was found to be essential for multitarget activity.