Design, synthesis and docking studies of novel thienopyrimidine derivatives bearing chromone moiety as mTOR/PI3Kα inhibitors

Zhu, Wufu; Chen, Chen; Sun, Chengyu; Xu, Shan; Wu, Chunjiang; Lei, Fei; Hui, Xia; Tu, Qidong; Zheng, Pengwu

doi:10.1016/j.ejmech.2015.01.061

Cited by 50 publications

(14 citation statements)

References 16 publications

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“…Four of the thienopyrimidine analogues (5a-5d) exhibited good inhibitory activity against FLT3 (IC 50 range from 0.055 to 0.208 lM) with similar or improved activities compared to AC220, a selective FLT3 inhibitor (IC 50 = 0.120 lM). In addition to the kinase Paper Discovery of a novel series of thienopyrimidine as highly potent and selective PI3K inhibitors (Han et al 2015) mTOR/PI3Ka Paper Design, synthesis and docking studies of novel thienopyrimidine derivatives bearing chromone moiety as mTORa/ PI3Ka inhibitors (Zhu et al 2015) EGFR Paper Truncated structures used in search for new lead compounds and in a retrospective analysis of thienopyrimidine-abased EGFR inhibitors (Bugge et al 2015) Aurora A Paper Identification of new novel scaffold for Aurora A inhibition by pharmacophore modeling and virtual screening (Chavan et al 2014) Aurora B Paper A thienopyrimidine derivative induces growth inhibition and apoptosis in human cancer cell lines via inhibiting aurora B kinase activity (Li et al 2013) ErbB2…”

Section: Resultsmentioning

confidence: 99%

Identification of a thienopyrimidine derivatives target by a kinome and chemical biology approach

2015

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Target identification through chemical biology has been considered one of the most efficient approaches for drug discovery. Thienopyrimidine derivatives were designed to discover potent IκB kinase β (IKKβ) inhibitors based on a known IKKβ inhibitor library. Most of the thienopyrimidine derivatives inhibited nitric oxide and tumor necrosis factor alpha, which are downstream of the NF-κB signaling pathway, but not IKKβ. To identify the appropriate targets of thienopyrimidine analogues, chemical biology approaches, including text mining and a subsequent kinase panel assay from the kinome profiling were used. Based on the results, Fms-like tyrosine kinase 3 was found to be the target for thienopyrimidine derivatives, and was confirmed to be a potent inhibitor for acute myeloid leukemia.

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Section: Resultsmentioning

confidence: 99%

Identification of a thienopyrimidine derivatives target by a kinome and chemical biology approach

2015

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“…In Scheme , commercially available 4 reacted with morpholine in methanol to produce key intermediate 5 according to a similar method reported previously (Srimongkolpithak, Sundriyal, Li, Vedadi, & Fuchter, ). Then, 5 was treated with (3‐hydroxy‐5‐nitrophenyl)boronic acid under Suzuki conditions to provide 6 (Zhu et al., ). Reduction of 6 with iron powder and aqueous acidified ethanol gave the corresponding aniline 7 .…”

Section: Methodsmentioning

confidence: 99%

Design, synthesis, and biological evaluation of thieno[3,2‐d]pyrimidine derivatives as potential simplified phosphatidylinositol 3‐kinase alpha inhibitors

et al. 2019

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A series of thieno[3,2‐d]pyrimidine derivatives as phosphatidylinositol 3‐kinase (PI3K) inhibitors was designed using the combination strategy. The synthesis and biological evaluation of the derivatives demonstrated their potent inhibition of PI3K, culminating in the discovery of 7 and 21. Determination of a co‐crystal structure of 7 complexed with PI3Kα provided the structural basis for the high enzymatic activity. Furthermore, cellular investigation of compounds 7 and 21 revealed that they efficiently suppressed cancer cell lines proliferation through inhibition of intracellular PI3K/AKT/mammalian target of rapamycin pathway. The results provided potent simplified inhibitors of PI3K with a promising overall profile and a chemical series for further optimization to progress into vivo experiments.

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“…Although many PI3K inhibitors have already been developed, their drug-like properties are seriously limited due to poor selectivity and side effects. [291][292][293] Moreover, the high mutation rate of the PIK3CA gene, which encodes PI3Kα in solid tumors, makes the development of PI3Kα inhibitors more difficult. 294,295 Therefore, the development of novel protein degradation agents targeting the PI3K protein has become an excellent strategy.…”

Section: Pi3kmentioning

confidence: 99%

PROTACs: great opportunities for academia and industry

Sun

Gao

Yang

et al. 2019

Sig Transduct Target Ther

453

414

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Although many kinds of therapies are applied in the clinic, drug-resistance is a major and unavoidable problem. Another disturbing statistic is the limited number of drug targets, which are presently only 20-25% of all protein targets that are currently being studied. Moreover, the focus of current explorations of targets are their enzymatic functions, which ignores the functions from their scaffold moiety. As a promising and appealing technology, PROteolysis TArgeting Chimeras (PROTACs) have attracted great attention both from academia and industry for finding available approaches to solve the above problems. PROTACs regulate protein function by degrading target proteins instead of inhibiting them, providing more sensitivity to drug-resistant targets and a greater chance to affect the nonenzymatic functions. PROTACs have been proven to show better selectivity compared to classic inhibitors. PROTACs can be described as a chemical knockdown approach with rapidity and reversibility, which presents new and different biology compared to other gene editing tools by avoiding misinterpretations that arise from potential genetic compensation and/or spontaneous mutations. PRTOACs have been widely explored throughout the world and have outperformed not only in cancer diseases, but also in immune disorders, viral infections and neurodegenerative diseases. Although PROTACs present a very promising and powerful approach for crossing the hurdles of present drug discovery and tool development in biology, more efforts are needed to gain to get deeper insight into the efficacy and safety of PROTACs in the clinic. More target binders and more E3 ligases applicable for developing PROTACs are waiting for exploration.

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Design, synthesis and docking studies of novel thienopyrimidine derivatives bearing chromone moiety as mTOR/PI3Kα inhibitors

Cited by 50 publications

References 16 publications

Identification of a thienopyrimidine derivatives target by a kinome and chemical biology approach

Identification of a thienopyrimidine derivatives target by a kinome and chemical biology approach

Design, synthesis, and biological evaluation of thieno[3,2‐d]pyrimidine derivatives as potential simplified phosphatidylinositol 3‐kinase alpha inhibitors

PROTACs: great opportunities for academia and industry

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