An insight into PI3k/Akt pathway and associated protein–protein interactions in metabolic syndrome: A recent update

Verma, Kanika; Jaiswal, Ritika; Paliwal, Sarvesh; Dwivedi, Jaya; Sharma, Swapnil

doi:10.1002/jcb.30433

Cited by 5 publications

(2 citation statements)

References 169 publications

(280 reference statements)

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“…Importantly, it results in the dissociation of the PH domain from the kinase domain. 6 The PH domain is likely to fully detach from the kinase domain, thereby enhancing the flexibility and accessibility of the kinase domain. This, in turn, enables the activation of the kinase domain through phosphorylation, allowing it to subsequently phosphorylate its downstream targets.…”

Section: Introductionmentioning

confidence: 99%

“…In the absence of PIP3, the PH domain interacts with the kinase domain in a closed conformation, preventing the interaction with phospholipids. , When PIP3 binds to the PH domain of Akt, this interaction induces a change in the spatial arrangement of Akt’s structural domains. Importantly, it results in the dissociation of the PH domain from the kinase domain . The PH domain is likely to fully detach from the kinase domain, thereby enhancing the flexibility and accessibility of the kinase domain.…”

Section: Introductionmentioning

confidence: 99%

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Akt Inhibitor Advancements: From Capivasertib Approval to Covalent-Allosteric Promises

Pervanidis,

D’Angelo,

Weisner

et al. 2024

J. Med. Chem.

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Akt kinase is vital in cell growth, survival, metabolism, and migration. Dysregulation of Akt signaling is implicated in cancer and metabolic disorders. In the context of cancer, overactive Akt promotes cell survival and proliferation. This has spurred extensive research into developing Akt inhibitors as potential therapeutic agents to disrupt aberrant Akt signaling. Akt inhibitors are classified into three main types: ATP-competitive, allosteric, and covalent-allosteric inhibitors (CAAIs). ATPcompetitive inhibitors compete with ATP for binding to Akt, allosteric inhibitors interact with the Pleckstrin homology (PH) domain, and covalent-allosteric inhibitors form covalent bonds, making them more potent and selective. Notably, capivasertib (AZD5363), a potent ATP-competitive Akt inhibitor, received FDA approval in November 2023 for use in combination with the estrogen receptor degrader fulvestrant to treat breast cancer. Challenges remain, including improving selectivity, identifying biomarkers to tailor treatments, and enhancing therapeutic efficacy while minimizing adverse effects. Particularly covalent-allosteric inhibitors hold promise for future more effective and personalized treatments. ■ SIGNIFICANCE This Perspective highlights the pivotal role of Akt kinase in cancer and metabolic diseases. It focuses on the landmark FDA approval of capivasertib, a first-generation Akt inhibitor, for the treatment of breast cancer. It heralds the emergence of nextgeneration Akt inhibitors, allosteric and covalent-allosteric, that promise improved selectivity and potency, ushering in a new era of therapeutic strategies and personalized, more effective interventions.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Akt Inhibitor Advancements: From Capivasertib Approval to Covalent-Allosteric Promises

Pervanidis,

D’Angelo,

Weisner

et al. 2024

J. Med. Chem.

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Green Methodologies for Tetrazole Synthesis from Different Starting Materials: A Recent Update

Jaiswal,

Dwivedi,

Kishore

et al. 2024

COC

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Tetrazole is a most versatile pharmacophore of which more than twenty FDA-approved drugs have been marketed globally for the management of various diseases. In spite of many remarkable and consistent efforts having been made by the chemists towards the development of greener and sustainable strategies for the synthesis of tetrazole derivatives, this approach still needs more attention. The present review focuses on the green synthetic approach for the preparation of tetrazole derivatives from different starting materials such as nitrile, isonitrile, carbonyl, amine, amide, oxime and terminal alkyne functions. The mechanism of tetrazole synthesis from different substrates is discussed. In addition to this, a four component Ugi-azide reaction to the tetrazole synthesis is also described. Of note, the present articles exploited several water-mediated and solventfree methodologies for tetrazole synthesis. The important key features of tetrazole synthesis were pinpointing in each synthetic scheme which provides excellent guide to those searching for selective procedure to achieve the desired transformation. This review seeks to present a timely account (2011-2023) on the splendid array of ecofriendly procedures of synthesis known today for the preparation of tetrazole derivatives from different starting materials. The rational of this review is to enlighten recent advancements in the synthesis of tetrazole derivatives from different substrates.

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Preclinical and phase I studies of an antisense oligonucleotide drug targeting IGF-1R in liver cancer

Li,

Xu,

et al. 2024

Future Oncology

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Aim: To evaluate a novel antisense oligonucleotide drug targeting human IGF-1R in preclinical and phase I studies of liver cancer. Materials & methods: The tolerability and safety of an investigational new drug were evaluated in a dose-escalation trial involving 17 patients with advanced liver cancer after preclinical assessment of pharmacokinetics and pharmacodynamics. Results: The drug exposure levels in the phase I trial were determined by the in vivo efficacy with pharmacokinetics evaluation in rats and rhesus monkeys. This clinical study showed that the maximum tolerated dose was 3.96 mg/kg, and the dose-limiting toxicity dose was 4.4 mg/kg. Conclusion: The drug was safe and tolerable in patients with advanced liver cancer. Clinical Trial Registration: ChiCTR2100044235 ( www.chictr.org.cn )

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An insight into PI3k/Akt pathway and associated protein–protein interactions in metabolic syndrome: A recent update

Cited by 5 publications

References 169 publications

Akt Inhibitor Advancements: From Capivasertib Approval to Covalent-Allosteric Promises

Akt Inhibitor Advancements: From Capivasertib Approval to Covalent-Allosteric Promises

Green Methodologies for Tetrazole Synthesis from Different Starting Materials: A Recent Update

Preclinical and phase I studies of an antisense oligonucleotide drug targeting IGF-1R in liver cancer

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