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

Area of Science:

• Medicinal Chemistry
• Oncology
• Pharmacology

Background:

• The PI3K/AKT/mTOR and PIM kinase pathways are crucial in cancer development.
• Co-targeting these pathways offers synergistic therapeutic potential in various cancers.
• Identifying dual or triple inhibitors is a key strategy in cancer drug discovery.

Purpose of the Study:

• To discover novel molecules that simultaneously inhibit PI3K/mTOR and PIM kinase pathways.
• To explore the structure-activity relationship of thieno[3,2-d]pyrimidine macrocycles (MCXs) for multitarget inhibition.
• To characterize the biological activity and preclinical efficacy of lead compounds.

Main Methods:

• Cross-screening of PI3K/(±mTOR) macrocycle collection to identify dual inhibitors.
• Medicinal chemistry optimization and synthesis of thieno[3,2-d]pyrimidine derivatives.
• Biological characterization including kinase inhibition assays, selectivity profiling, and in vivo efficacy studies in xenograft models.

Main Results:

• Identified thieno[3,2-d]pyrimidine derivative 2 as a moderate dual PI3K/PIM-1 inhibitor.
• Discovered IBL-302 (31), a potent, selective, orally bioavailable triple PI3K/mTOR/PIM inhibitor.
• Demonstrated IBL-302 efficacy in neuroblastoma and breast cancer xenografts; macrocyclization was essential for PIM inhibition.

Conclusions:

• IBL-302 is a promising triple kinase inhibitor advancing to late preclinical development (AUM302).
• Macrocyclization is critical for achieving the desired multitarget inhibition profile, particularly for PIM kinase.
• This study highlights the therapeutic potential of cotargeting PI3K/mTOR and PIM pathways with novel macrocyclic inhibitors.