- Macrocyclization as a Source of Desired Polypharmacology. Discovery of Triple PI3K/mTOR/PIM Inhibitors
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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.
- Aguirre, Enara,Ajenjo, Nuria,Albarran, M. I.,Alvarez, Rosa M.,Blanco-Aparicio, Carmen,Cebria, Antonio,Cebrian, David,Cunningham, Darren,Dave, Harish P. G.,Di Geronimo, Bruno,Garcia, Ana Belen,Gomez-Casero, Elena,Gonzalez Cantalapiedra, Esther,Martin, Jose I.,Martinez-Gonzalez, Sonia,Oneill, Michael,Pastor, Joaquin,Riesco-Fagundo, Concepcion,Rodriguez Hergueta, Antonio,Varela, Carmen
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p. 1794 - 1801
(2021/11/18)
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- NEW COMPOUNDS
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There is provided compounds of formula I, wherein R1, R2a, R2b, R2c, X, Y, Z, R3 and ring A/B have meanings given in the description, and pharmaceutically-acceptable esters, amides, solvates or salts thereof, which compounds are useful in the treatment of diseases in which inhibition of a protein or lipid kinase (e.g. PI3-K, particularly class I PI3K, PIM family kinase and/or mTOR) is desired and/or required, and particularly in the treatment of cancer. The invention also relates to combinations containing such compounds.
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Page/Page column 127; 87
(2012/12/13)
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