Discovery of novel quinazoline derivatives as potent PI3Kδ inhibitors with high selectivity

Teng, Yu‐Ning; Li, Xinyu; Ren, Shengnan; Yu, Changhong; Xi, Kun; Shen, Hongtao; Ma, Wenzhuo; Luo, Guoshun; Xiang, Hua

doi:10.1016/j.ejmech.2020.112865

Cited by 15 publications

(5 citation statements)

References 22 publications

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“…For more understanding the druggable properties, the molsoft/druglikeness prediction tool was employed to predict the physicochemical properties and drug-like properties of S5 compared with idelalisib (Supporting Information: Table S1) (Teng et al, 2020). S5 exhibited acceptable drug-like properties (HBA < 10, HBD < 5, tPSA < 90 Å) and relatively better solubility (MlogP = 1.05, MlogS = −2.34 mol/L) than idelalisib (MlogP = 2.74, MlogS = −3.25 mol/L).…”

Section: Physicochemical and Drug-likeness Properties Studiesmentioning

confidence: 99%

Discovery of novel pyrido[3,2‐d]pyrimidine derivatives as selective and potent PI3Kδ inhibitors

Bai,

Sun,

Lei

et al. 2023

Drug Development Research

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The δ isoform of class I PI3K (PI3Kδ) has been shown as a promising target for the treatment of hematologic malignancies and immune diseases. Herein, a series of pyrido[3,2‐d]pyrimidine derivatives were designed, synthesized and evaluated for the preliminary bioactivity. Compared with idelalisib, compound S5 exhibited excellent enzyme activity against PI3Kδ (IC50 = 2.82 nM) and strong antiproliferation activity against SU‐DHL‐6 cells (IC50 = 0.035 μM). Besides, S5 inhibited the phosphorylation of Akt, which is downstream of PI3Kδ, in concentration‐dependent manner. In view of the significant improvement in potency of PI3Kδ and selectivity over other PI3K isoforms, Compound S5 deserved further investigation as a promising PI3Kδ inhibitor.

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Section: Physicochemical and Drug-likeness Properties Studiesmentioning

confidence: 99%

Discovery of novel pyrido[3,2‐d]pyrimidine derivatives as selective and potent PI3Kδ inhibitors

Bai,

Sun,

Lei

et al. 2023

Drug Development Research

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“…Compound 18 (a PIK3/mTOR dual inhibitor) had its imidazoquinoline scaffold broken down into a quinazoline skeleton, which was then optimized to produce a candidate ( 36 ) for treating B cell malignancies …”

Section: Targeting the Pi3k/akt/mtor Signaling Pathway With Atp-compe...mentioning

confidence: 99%

“…127 Compound 18 (a PIK3/mTOR dual inhibitor) had its imidazoquinoline scaffold broken down into a quinazoline skeleton, which was then optimized to produce a candidate (36) for treating B cell malignancies. 128 36 exhibited a potent effect MSD-496486311 ( 38) is a selective PI3Kδ inhibitor (IC 50 values of 180, 1600, 1.2, and 4400 nM against PI3Kα, β, δ, and γ, respectively) bearing a heterocycloalkyl purine group, which forms an H-bond with Val828 (Figure 6A). 130 Compound 38 130 Compound 39 (IC 50 values of 4400, 44,000, 3.8, and 4200 nM against PI3Kα, β, δ, and γ, respectively) is a selective PI3Kδ inhibitor by linking an oxindole moiety to the hinge-binding core of 1.…”

Section: Targeting the Pi3k/akt/mtor Signaling Pathway With Atp-compe...mentioning

confidence: 99%

Targeting the PI3K/AKT/mTOR Signaling Pathway in the Treatment of Human Diseases: Current Status, Trends, and Solutions

Huang

Chen

et al. 2022

J. Med. Chem.

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The phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) pathway is one of the most important intracellular pathways involved in cell proliferation, growth, differentiation, and survival. Therefore, this route is a prospective biological target for treating various human diseases, such as tumors, neurodegenerative diseases, pulmonary fibrosis, and diabetes. An increasing number of clinical studies emphasize the necessity of developing novel molecules targeting the PI3K/AKT/mTOR pathway. This review focuses on recent advances in ATP-competitive inhibitors, allosteric inhibitors, covalent inhibitors, and proteolysis-targeting chimeras against the PI3K/AKT/mTOR pathway, and highlights possible solutions for overcoming the toxicities and acquired drug resistance of currently available drugs. We also provide recommendations for the future design and development of promising drugs targeting this pathway.

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“…There area number of PI3K inhibitors have been approved by FDA for the treatment of B-cell malignancies. Among the synthesized compound 15c found to be a prominent candidate, Compound 15c exhibited excellent enzyme activity against PI3Kδ (IC 50 = 27.5 nM) compared with BEZ235 as well as the significant anti-proliferation activities 36 .…”

Section: Niemantowski Reactionmentioning

confidence: 99%

Untitled

2022

IJPSR

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The aim of this review is to provide an extensive overview of the diverse pharmacological activities of quinazoline moiety. Quinazolines are well-known and important nitrogen-containing heterocyclic compounds made chemical formula C 8 H 6 N 2 . For the last few years, the heterocyclic fused nucleus quinazoline has drawn immense attention due to its diversified application in medicinal chemistry research. In the growing world of intense research, Quinazoline was considered as a privileged scaffold; the modification made with different substituents around the centroid paved the researchers away to deal with at ease. Being a fused ring, the heterocycle itself is capable of great pharmacological quality. Quinazoline is one of the heterocycles with diversifying scaffolds for various important biological activities for which considerable research has been done in order to examine its biomedical applications. In a number of biologically active compounds and drug molecules, the quinazoline nucleus is used as a basic framework. This paper is a sincere attempt to highlight the tremendous potential of this ring system because of its wide spectrum of pharmacological actions. This study can also speed up the design and synthesis process in order to create more therapeutically viable clinical candidates. INTRODUCTION:Quinazoline heterocycle consists of two fused six-member aromatic rings, benzene & pyrimidine. Quinazoline derivatives, which belong to the N-containing heterocyclic compounds, have caused universal concerns due to their wide and distinct biopharmaceutical activities. The research on the biological activity of quinazoline compounds started when the compound 2-methyl-1,3-aryl-4-quinazoline derivative was synthesized 1 .

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Discovery of novel quinazoline derivatives as potent PI3Kδ inhibitors with high selectivity

Cited by 15 publications

References 22 publications

Discovery of novel pyrido[3,2‐d]pyrimidine derivatives as selective and potent PI3Kδ inhibitors

Discovery of novel pyrido[3,2‐d]pyrimidine derivatives as selective and potent PI3Kδ inhibitors

Targeting the PI3K/AKT/mTOR Signaling Pathway in the Treatment of Human Diseases: Current Status, Trends, and Solutions

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