Discovery of 2H-benzo[b][1,4]oxazin-3(4H)-one derivatives as potent and selective CDK9 inhibitors that enable transient target engagement for the treatment of hematologic malignancies

Wang, Xinren; Liu, Xiaoyue; Huang, Jiankang; Liu, Chenhe; Li, Hongmei; Hong, Qianqian; Yan, Lei; Xia, Jiawei; Yu, Ziheng; Dong, Ruinan; Xu, Junyu; Tu, Zhenlin; Duan, Chunqi; Li, Shuwen; Lü, Tao; Tang, Weifang; Chen, Yadong

doi:10.1016/j.ejmech.2022.114461

Cited by 8 publications

(3 citation statements)

References 20 publications

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“…The C8 and C9 positions of quinazolino are located in the entranceway of the ATP-binding pocket and extend into the solvent-accessible area. Other research in the literature has reported that chemical structural modifications in solvent-accessible areas improve cellular activity [21,40], which is similar to our previous finding that the introduction of different groups on the benzene ring at this region leads to significant changes in antitumour cell activity. Thus, the pyrazolo-[1,5-c]quinazolinone compounds have the potential to exhibit antitumour effects by targeting CDK2, and could be used as a starting skeleton for the development of CDK inhibitors via a structure-based drug design, for which further research is already underway.…”

Section: In Silico Studies Of Biological Target and Molecular Modellingsupporting

confidence: 90%

Design, Synthesis, Antitumour Evaluation, and In Silico Studies of Pyrazolo-[1,5-c]quinazolinone Derivatives Targeting Potential Cyclin-Dependent Kinases

Zheng,

Yang,

et al. 2023

Molecules

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An efficient, straightforward, and metal-free methodology to rapidly access functionalised pyrazolo-[1,5-c]quinazolinones via a [3 + 2] dipolar cycloaddition and regioselective ring expansion process was developed. The synthesised compounds were characterised by methods such as NMR, HRMS, and HPLC. The in vitro antiproliferative activity against A549 cells (non-small cell lung cancer) was significant for compounds 4i, 4m, and 4n with IC50 values of 17.0, 14.2, and 18.1 μM, respectively. In particular, compounds 4t and 4n showed inhibitory activity against CDK9/2. Predicted biological target and molecular modelling studies suggest that the compound 4t may target CDKs for antitumour effects. The synthesised derivatives were considered to have moderate drug-likeness and sufficient safety in silico. In summary, a series of pyrazolo-[1,5-c]quinazolinone derivatives with antitumour activity is reported for the first time. We provide not only a simple and efficient synthetic method but also helpful lead compounds for the further development of novel cyclin-dependent kinase (CDK) inhibitors.

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Section: In Silico Studies Of Biological Target and Molecular Modellingsupporting

confidence: 90%

Design, Synthesis, Antitumour Evaluation, and In Silico Studies of Pyrazolo-[1,5-c]quinazolinone Derivatives Targeting Potential Cyclin-Dependent Kinases

Zheng,

Yang,

et al. 2023

Molecules

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“…There’s still one fly in the ointment that 45 displays low selectivity, inhibiting CDK2/7/8/12, GSK3β, TRKB, JAK3, and HGK. Of course, its outstanding cytotoxic effects on tumor cells may brought by the broad spectrum of inhibition . Compound 47 , along with 49 , shares structural similarities with 45 (Figure C).…”

Section: Cdk9 Inhibitorsmentioning

confidence: 99%

“…Of course, its outstanding cytotoxic effects on tumor cells may brought by the broad spectrum of inhibition. 93 Compound 47, along with 49, shares structural similarities with 45 (Figure 8C). 47 retains the same core structure, lipophilic group, and coumarin moiety as 45, with the addition of a morpholino on the coumarin, resulting in a slightly increased potency.…”

Section: Pyrimidine Derivativesmentioning

confidence: 99%

Recent Discovery and Development of Inhibitors that Target CDK9 and Their Therapeutic Indications

Zhang,

Shan,

Tang

et al. 2024

J. Med. Chem.

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CDK9 is a cyclin-dependent kinase that plays pivotal roles in multiple cellular functions including gene transcription, cell cycle regulation, DNA damage repair, and cellular differentiation. Targeting CDK9 is considered an attractive strategy for antitumor therapy, especially for leukemia and lymphoma. Several potent small molecule inhibitors, exemplified by TG02 (4), have progressed to clinical trials. However, many of them face challenges such as low clinical efficacy and multiple adverse reactions and may necessitate the exploration of novel strategies to lead to success in the clinic. In this perspective, we present a comprehensive overview of the structural characteristics, biological functions, and preclinical status of CDK9 inhibitors. Our focus extends to various types of inhibitors, including pan-inhibitors, selective inhibitors, dual-target inhibitors, degraders, PPI inhibitors, and natural products. The discussion encompasses chemical structures, structure–activity relationships (SARs), biological activities, selectivity, and therapeutic potential, providing detailed insight into the diverse landscape of CDK9 inhibitors.

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Exploring the cytotoxic effect and CDK-9 inhibition potential of novel sulfaguanidine-based azopyrazolidine-3,5-diones and 3,5-diaminoazopyrazoles

Husseiny

Abulkhair

El-Dydamony

et al. 2023

Bioorganic Chemistry

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Discovery of 2H-benzo[b][1,4]oxazin-3(4H)-one derivatives as potent and selective CDK9 inhibitors that enable transient target engagement for the treatment of hematologic malignancies

Cited by 8 publications

References 20 publications

Design, Synthesis, Antitumour Evaluation, and In Silico Studies of Pyrazolo-[1,5-c]quinazolinone Derivatives Targeting Potential Cyclin-Dependent Kinases

Design, Synthesis, Antitumour Evaluation, and In Silico Studies of Pyrazolo-[1,5-c]quinazolinone Derivatives Targeting Potential Cyclin-Dependent Kinases

Recent Discovery and Development of Inhibitors that Target CDK9 and Their Therapeutic Indications

Exploring the cytotoxic effect and CDK-9 inhibition potential of novel sulfaguanidine-based azopyrazolidine-3,5-diones and 3,5-diaminoazopyrazoles

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