Structure-based optimization leads to the discovery of NSC765844, a highly potent, less toxic and orally efficacious dual PI3K/mTOR inhibitor

Han, Jaeseok; Chen, Ying; Yang, Chao; Liu, Ting; Wang, Mingping; Xu, Helan; Zhang, Ling; Zheng, Canhui; Song, Yuelin; Zhu, Jü

doi:10.1016/j.ejmech.2016.06.030

Cited by 17 publications

(3 citation statements)

References 37 publications

(55 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…It significantly promotes tumour progression and the development of drug resistance to chemotherapeutics ( Lindblad et al, 2016 ). As mentioned above, among the known PI3K/mTOR inhibitors, some reportedly have an arylsulfonamide scaffold, including omipalisib, SN202, NSC765844 and CMG002, indicating that arylsulfonamide is a potential privileged structure of dual PI3K/mTOR inhibitor ( Han et al, 2016 ). Also, the PI3K inhibitor pictilisib contains this structure, which could serve as a starting point in the process of synthesising more compounds.…”

Section: Discussionmentioning

confidence: 99%

“…NSC765844 ( Figure 3 ), a compound synthesized on the arylsulfonamide scaffold as a structurally optimized core structure, is an oral, highly potent and effective dual PI3K/mTOR inhibitor with low toxicity [IC 50 values of 1.3, 1.8, 1.5, 3.8 and 3.8 nM for PI3Kα, β, γ, δ, and mTOR, respectively ( Han et al, 2016 )]. Han et al (2016) found that the arylsulfonamide scaffold is a common privileged structure in PI3K/mTOR inhibitors. For example, omipalisib, voxtalisib, and apitolisib all contain this structure.…”

Section: Compounds With Quinoline Corementioning

confidence: 99%

See 1 more Smart Citation

Recent Advances in Dual PI3K/mTOR Inhibitors for Tumour Treatment

Liang

et al. 2022

Front. Pharmacol.

View full text Add to dashboard Cite

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.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Compounds With Quinoline Corementioning

confidence: 99%

Recent Advances in Dual PI3K/mTOR Inhibitors for Tumour Treatment

Liang

et al. 2022

Front. Pharmacol.

View full text Add to dashboard Cite

show abstract

“…Starting materials 1a , 1e , 1n , 1q , 3b , 3h , 3i , 1b , 1c , 1i , 1l , 3f , 1f , 1g , 1h , and 1m were prepared according to the reported procedures.…”

Section: Methodsmentioning

confidence: 99%

Copper-Catalyzed Reaction of C₆₀ with Tertiary Amines for the Preparation of Spiro-Linked Methanofullerenes and Fullerenoalkanals

Liu

Miao

et al. 2019

J. Org. Chem.

View full text Add to dashboard Cite

CuI-catalyzed reaction of C60 with tertiary amines by using air as the sole oxidant has been developed. Spiro-linked methanofullerenes bearing cyclic amides and fullerenoalkanals can be obtained selectively using the cyclic and acyclic amines as starting materials, respectively. The reactions show a wide functional group tolerance. In addition, four ([6,6]-phenyl-C61-butyric acid methyl ester) analogues can be easily prepared through the developed method.

show abstract

Recent Advances in Dual BRD4‐Kinase Inhibitors Based on Polypharmacology

Chen

Liu

2022

ChemMedChem

View full text Add to dashboard Cite

The epigenetic reader BRD4 is involved in chromatin remodelling and transcriptional regulation, making it a promising therapeutic target. However, over the past decades, many BRD4 inhibitors that entered clinical trials were, in the main, unsatisfactory, due to some therapeutic limitations such as offtarget effects and drug resistance. Combining a BRD4 inhibitor with another drug was expected to be an ideal option to overcome these hurdles and to improve therapeutic outcomes. However, such combination therapy could trigger toxicity caused by drug-drug interactions, complex pharmacokinetics, and additive effects. Recently, the application of dual-target drugs targeting BRD4 and other kinases has become an attractive approach to remedy the defects of a single BRD4 inhibitor. This review focuses on recent advances in the discovery of dual BRD4-kinase inhibitors, with an emphasis on their co-crystal structures and structure-activity relationships (SARs), as well as future perspectives in this field.

show abstract

Structure-based optimization leads to the discovery of NSC765844, a highly potent, less toxic and orally efficacious dual PI3K/mTOR inhibitor

Cited by 17 publications

References 37 publications

Recent Advances in Dual PI3K/mTOR Inhibitors for Tumour Treatment

Recent Advances in Dual PI3K/mTOR Inhibitors for Tumour Treatment

Copper-Catalyzed Reaction of C₆₀ with Tertiary Amines for the Preparation of Spiro-Linked Methanofullerenes and Fullerenoalkanals

Recent Advances in Dual BRD4‐Kinase Inhibitors Based on Polypharmacology

Contact Info

Product

Resources

About

Structure-based optimization leads to the discovery of NSC765844, a highly potent, less toxic and orally efficacious dual PI3K/mTOR inhibitor

Cited by 17 publications

References 37 publications

Recent Advances in Dual PI3K/mTOR Inhibitors for Tumour Treatment

Recent Advances in Dual PI3K/mTOR Inhibitors for Tumour Treatment

Copper-Catalyzed Reaction of C60 with Tertiary Amines for the Preparation of Spiro-Linked Methanofullerenes and Fullerenoalkanals

Recent Advances in Dual BRD4‐Kinase Inhibitors Based on Polypharmacology

Contact Info

Product

Resources

About

Copper-Catalyzed Reaction of C₆₀ with Tertiary Amines for the Preparation of Spiro-Linked Methanofullerenes and Fullerenoalkanals