2. Academic Validation
  3. Macrocyclization as a Source of Desired Polypharmacology. Discovery of Triple PI3K/mTOR/PIM Inhibitors

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

  • ACS Med Chem Lett. 2021 Nov 2;12(11):1794-1801. doi: 10.1021/acsmedchemlett.1c00412.
Sonia Martínez-González 1,  Rosa M Alvarez 1,  José I Martín 1,  Ana Belén García 1,  Concepción Riesco-Fagundo 1,  Carmen Varela 1,  Antonio Rodríguez Hergueta 1,  Esther González Cantalapiedra 1,  M I Albarrán 1,  Elena Gómez-Casero 1,  Antonio Cebriá 1,  Enara Aguirre 1,  Nuria Ajenjo 1,  David Cebrián 1,  Bruno Di Geronimo 1,  Darren Cunningham 2,  Michael O'Neill 2,  Harish P G Dave 3,  Carmen Blanco-Aparicio 1,  Joaquín Pastor 1
Affiliations

Affiliations

  • 1 Experimental Therapeutics Programme, Spanish National Cancer Research Centre (CNIO), C/Melchor Fernández Almagro 3, E-28029 Madrid, Spain.
  • 2 Inflection Biosciences Ltd., Suite 15, Anglesea 419 House, Carysfort Avenue Blackrock, Dublin A94 VC59, Ireland.
  • 3 AUM Biosciences, 24-428 16A, 10 Anson Road, International Plaza, Singapore 429 079903.
PMID: 34795869 DOI: 10.1021/acsmedchemlett.1c00412
Abstract

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.

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