Preparation and optimization of new 4-(morpholin-4-yl)-(6-oxo-1,6-dihydropyrimidin-2-yl)amide derivatives as PI3Kβ inhibitors

Certal, Victor; Halley, Frank; Virone-Oddos, Angela; Thompson, Fabienne; Filoche-Rommé, Bruno; El-Ahmad, Youssef; Carry, Jean‐Christophe; Delorme, Cécile; Karlsson, Andreas; Abecassis, Pierre Yves; Vincent, Loı̈c; Bonnevaux, Hélène; Nicolas, Jean Paul; Morales, Renaud; Michot, Nadine; Vade, Isabelle; Louboutin, Audrey; Perron, Sébastien; Doerflinger, Gilles; Tric, Bernadette; Monget, Sylvie; Lengauer, Christoph; Schio, Laurent

doi:10.1016/j.bmcl.2012.08.072

Cited by 23 publications

(25 citation statements)

References 12 publications

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“…Indeed, a survey of PI3Kβ selective inhibitors shows that the specificity pocket binding motifs are generally, but not exclusively, smaller than those found in PI3Kδ inhibitors. In a series of pyrimidone PI3Kβ inhibitors ( 45 ) with a phenyl specificity pocket motif, substitutions around the phenyl ring significantly affected the selectivity for PI3Kβ against the other isoforms [123]. Meta substitutions in particular seemed to improve both PI3Kβ potency and selectivity.…”

Section: Structural Determinants Of Isoform Selectivitymentioning

confidence: 99%

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Structural Determinants of Isoform Selectivity in PI3K Inhibitors

Miller

Thompson²,

Gabelli

2019

Biomolecules

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Phosphatidylinositol 3-kinases (PI3Ks) are important therapeutic targets for the treatment of cancer, thrombosis, and inflammatory and immune diseases. The four highly homologous Class I isoforms, PI3K, PI3K, PI3K and PI3K have unique, non-redundant physiological roles and as such, isoform selectivity has been a key consideration driving inhibitor design and development. In this review, we discuss the structural biology of PI3Ks and how our growing knowledge of structure has influenced the medicinal chemistry of PI3K inhibitors. We present an analysis of the available structure-selectivity-activity relationship data to highlight key insights into how the various regions of the PI3K binding site influence isoform selectivity. The picture that emerges is one that is far from simple and emphasizes the complex nature of protein-inhibitor binding, involving protein flexibility, energetics, water networks and interactions with non-conserved residues.

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Section: Structural Determinants Of Isoform Selectivitymentioning

confidence: 99%

“…In many of the PI3Kβ selective inhibitors, the carbonyl sits in the affinity pocket, interacting with βTyr839 or βLys833 [71,98,123,125,126,134,135,136]. These do not extend as deeply into the affinity pocket as many of the PI3Kδ inhibitors [85].…”

Section: Structural Determinants Of Isoform Selectivitymentioning

confidence: 99%

Structural Determinants of Isoform Selectivity in PI3K Inhibitors

Miller

Thompson²,

Gabelli

2019

Biomolecules

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“…The Sanofi oncology drug discovery group published a series of manuscripts from 2012 to 2014 detailing a successful optimization campaign [31,47,48].…”

Section: Sar260301 Pi3kβmentioning

confidence: 99%

Isoform Selective PI3K Inhibitors for Treating Cancer

Staben¹

2017

Topics in Medicinal Chemistry

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The PI3K/AKT pathway is one of the most frequently altered in cancer and several promising small-molecule inhibitors of this pathway have entered advanced stages of clinical research. This chapter intends to highlight substantial medicinal chemistry lead identification and optimization efforts that led to the discovery of key isoform-and PIK family-selective PI3K inhibitors. Coverage is given for those disclosed PI3K isoform-selective inhibitors that have entered clinical trials in oncology, regardless of their current status. Where possible based on existing information, a focus is placed on discussion of potential structural rationale for isoform selectivity.

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“…28 The derivatives were prepared via condensation of aromatic diamines or aminophenols with the morpholino pyrimidine carboxylate salt ( 81 )(Figure 20). The morpholino pyrimidine ( 80 ) was prepared via reaction of excess ethyl 3-amino-3-ethoxyacrylate with morpholine.…”

Section: Pyrimidines and Quinazolinesmentioning

confidence: 99%

Recent syntheses of PI3K/Akt/mTOR signaling pathway inhibitors

Welker

Kulik

2013

Bioorganic & Medicinal Chemistry

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This review focuses on the syntheses of PI3K/Akt/mTOR inhibitors that have been reported outside of the patent literature in the last 5 years but is largely centered on synthetic work reported in 2011 and 2012. While focused on syntheses of inhibitors, some information on in vitro and in vivo testing of compounds is also included. Many of these reported compounds are reversible, competitive adenosine triphosphate (ATP) binding inhibitors, so given the structural similarities of many of these compounds to the adenine core, this review presents recent work on inhibitors based on where the synthetic chemistry was started, i.e. inhibitor syntheses which started with purines/pyrimidines are followed by inhibitor syntheses which began with pyridines, pyrazines, azoles, and triazines then moves to inhibitors which bear no structural resemblance to adenine: liphagal, wortmannin and quercetin analogs. The review then finishes with a short section on recent syntheses of phosphotidyl inositol (PI) analogs since competitive PI binding inhibitors represent an alternative to the competitive ATP binding inhibitors which have received the most attention.

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Preparation and optimization of new 4-(morpholin-4-yl)-(6-oxo-1,6-dihydropyrimidin-2-yl)amide derivatives as PI3Kβ inhibitors

Cited by 23 publications

References 12 publications

Structural Determinants of Isoform Selectivity in PI3K Inhibitors

Structural Determinants of Isoform Selectivity in PI3K Inhibitors

Isoform Selective PI3K Inhibitors for Treating Cancer

Recent syntheses of PI3K/Akt/mTOR signaling pathway inhibitors

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