Omipalisib inspired macrocycles as dual PI3K/mTOR inhibitors

Álvarez, Rosa; García, Ana; Riesco‐Fagundo, Concepción; Martín, José Ignacio; Varela, Carmen; Hergueta, Antonio R.; Cantalapiedra, Esther González; Oyarzábal, Julen; Geronimo, Bruno Di; Lorenzo, Milagros; Albarran, Maria I.; Cebriá, Antonio; Cebrián, David; Martínez-González, Sonia; Blanco‐Aparicio, Carmen; Pastor, Joaquı́n

doi:10.1016/j.ejmech.2020.113109

Cited by 10 publications

(8 citation statements)

References 24 publications

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“…MCXs, a series of small molecule macrocyclic compounds, are novel PI3K/mTOR dual inhibitors designed and synthesized based on omipalisib ( 3 ) ( Álvarez et al, 2021 ), that show powerful antitumour effects. The macrocyclisation strategy used to regulate the dual inhibition of PI3K/mTOR has strong biochemistry, cell activity and kinase selectivity and has outstanding drug-like properties.…”

Section: Small Molecule Macrocyclic Compound: Mcx83 (25)mentioning

confidence: 99%

Recent Advances in Dual PI3K/mTOR Inhibitors for Tumour Treatment

Liang

et al. 2022

Front. Pharmacol.

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The PI3K-Akt-mTOR pathway is a viable target for cancer treatment and can be used to treat various malignant tumours, including follicular lymphoma and breast cancer. Both enzymes, PI3K and mTOR, are critical in this pathway. Hence, in recent years, an array of inhibitors targeting these two targets have been studied, showing dual PI3K/mTOR inhibition compared with single targeting small molecule inhibitors. Inhibitors not only inhibit cell proliferation but also promote cell apoptosis. These inhibitors show high potency and little drug resistance even at low doses, suggesting that PI3K/mTOR inhibitors are promising cancer drugs. Herein, we summarised the recent research of PI3K/mTOR dual inhibitors—for example, structure-activity relationship, pharmacokinetics, and clinical practice, and briefly commented on them.Clinical Trial Registration:https://clinicaltrials.gov.

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Section: Small Molecule Macrocyclic Compound: Mcx83 (25)mentioning

confidence: 99%

Recent Advances in Dual PI3K/mTOR Inhibitors for Tumour Treatment

Liang

et al. 2022

Front. Pharmacol.

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“…Next, we selected several A-rings which rendered potent PI3K-(±mTOR) inhibition with other scaffolds, such as phenyl, 4-pyridyl, 3-pyridyl, and pyrazolyl, with the latter two providing MCXs with good pharmacokinetics. 23 Furthermore, we included other phenyl isosteres based on thiophene ring and other 5-membered ring heterocycles such as furane and thiazole. Finally, the methoxypyridinylbenzenesulfonamide fragment and the amide linkage were maintained along the exploration due also to their known contribution to PI3K-(±mTOR) inhibition and synthetic feasibility reasons.…”

Section: Acs Medicinal Chemistry Lettersmentioning

confidence: 99%

“…Finally, the methoxypyridinylbenzenesulfonamide fragment and the amide linkage were maintained along the exploration due also to their known contribution to PI3K-(±mTOR) inhibition and synthetic feasibility reasons. 23 We replaced then the phenyl moiety of 2 with heteroaryls (16−23). This modification led to noticeable changes in the combined activity, including an outstanding improvement in PIM-1 inhibition for certain compounds.…”

Section: Acs Medicinal Chemistry Lettersmentioning

confidence: 99%

“…Conversely, MCXs with other scaffolds retained a selective PI3K(±mTOR) profile, without PIM-1 activity as omipalisib. 23 Here, we report the medicinal chemistry exploration around MCX 2 which led to the discovery of IBL-302 (31), a potent, selective, and orally bioavailable triple PI3K/mTOR/PIM inhibitor (Table 1). The synthetic route used to prepare the described compounds is outlined in Scheme 1.…”

mentioning

confidence: 99%

“…The cross-screening of these molecules against PIM-1 identified MCX thieno[3,2- d ]pyrimidine derivative 2 (unpublished previously, Table ) as a prototype of dual PI3K/PIM inhibitor (IC 50s : PI3K 16.8 nM; PIM-1 279 nM; mTOR > 10 μM). Conversely, MCXs with other scaffolds retained a selective PI3K(±mTOR) profile, without PIM-1 activity as omipalisib . Here, we report the medicinal chemistry exploration around MCX 2 which led to the discovery of IBL-302 ( 31 ), a potent, selective, and orally bioavailable triple PI3K/mTOR/PIM inhibitor (Table ).…”

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confidence: 99%

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

Martínez-González

Álvarez

Martín

et al. 2021

ACS Med. Chem. Lett.

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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.

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Role of intracellular signaling pathways and their inhibitors in the treatment of inflammation

Nailwal

Doshi

2021

Inflammopharmacol

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Omipalisib inspired macrocycles as dual PI3K/mTOR inhibitors

Cited by 10 publications

References 24 publications

Recent Advances in Dual PI3K/mTOR Inhibitors for Tumour Treatment

Recent Advances in Dual PI3K/mTOR Inhibitors for Tumour Treatment

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

Role of intracellular signaling pathways and their inhibitors in the treatment of inflammation

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