Discovery of coumarin derivatives as potent and selective cyclin-dependent kinase 9 (CDK9) inhibitors with high antitumour activity

Xu, Junyu; Li, Hongmei; Wang, Xinren; Huang, Jiankang; Li, Shuwen; Liu, Chenhe; Dong, Ruinan; Zhu, Gaoyuan; Duan, Chunqi; Jiang, Fei; Zhang, Yanmin; Zhu, Yi; Zhang, Tianyi; Chen, Yadong; Tang, Weifang; Lü, Tao

doi:10.1016/j.ejmech.2020.112424

Cited by 37 publications

(29 citation statements)

References 49 publications

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“…In our previous study, compound 5 (Figure ) was demonstrated good potency and selectivity in vitro activity against CDK9 (IC 50 = 2.0 nM). However, its cellular antiproliferative activity against HM is not remarkable (Molm-13, IC 50 = 0.26 μM; MV4-11, IC 50 = 0.09 μM).…”

Section: Resultsmentioning

confidence: 81%

“…The synthesis of compounds 14a – 14j is outlined in Scheme , which was adapted from a previously described method in the literature . Briefly, Paeonol 6 reacted with diethyl carbonate to generate 4-hydroxy-7-methoxycoumarin 7 , followed by Claisen rearrangement, nucleophilic substitution, demethylation, and esterification to get the key intermediate 11 .…”

Section: Resultsmentioning

confidence: 99%

“…Previously, we have reported compound 5 as a potent and highly selective CDK9 inhibitor . However, this compound has limited cellular potency (Molm-13, IC 50 = 0.26 μM; MV4–11, IC 50 = 0.09 μM) and poor aqueous solubility.…”

Section: Introductionmentioning

confidence: 99%

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Discovery of N-(4-(3-isopropyl-2-methyl-2H-indazol-5-yl)pyrimidin-2-yl)-4-(4-methylpiperazin-1-yl)quinazolin-7-amine as a Novel, Potent, and Oral Cyclin-Dependent Kinase Inhibitor against Haematological Malignancies

et al. 2021

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Hematologic malignancies (HM) start in blood forming tissue or in the cells of the immune system. Cyclin-dependent kinases (CDKs) regulate cell cycle progression, and some of them control cellular transcription. CDK inhibition can trigger apoptosis and could be particularly useful in hematological malignancies. Herein, we describe our efforts toward the discovery of a novel series of quinazoline derivatives as CDK inhibitors. Intensive structural modifications lead to the identification of compound 37d as the most active inhibitors of CDKs 1, 2, 4, 8 and 9 with balancing potency and selectivity against CDKs. Further biological studies revealed that compound 37d can arrest the cell cycle and induce apoptosis via activating PARP and caspase 3. More importantly, compound 37d showed good antitumor efficacy in multiple HM mice xenograft models with no obvious toxicity. These results indicated that CDK 1, 2, 4, 8, and 9 inhibitors could be potentially used to treat certain hematologic malignancies.

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Section: Resultsmentioning

confidence: 81%

Section: Resultsmentioning

confidence: 99%

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Discovery of N-(4-(3-isopropyl-2-methyl-2H-indazol-5-yl)pyrimidin-2-yl)-4-(4-methylpiperazin-1-yl)quinazolin-7-amine as a Novel, Potent, and Oral Cyclin-Dependent Kinase Inhibitor against Haematological Malignancies

et al. 2021

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“…These scaffolds have diverse biological properties including anticancer, 10 antioxidant, 11 antidepressant, 12 antimicrobial, 13 anti-nociceptive, 14 anti-asthmatic, 15 anti-inflammatory, 16 anti-pyretic, 17 antileishmanial, 18 anti-coagulant, 19 anti-tubercular, 20 antiviral, 21 antibacterial, 22 antifungal, 23 antimalarial, 24 antidiabetic, 25 anti-hepatitis C virus, 26 anti-HIV, 27 anti-proliferative, 28 antiplatelet, 29 and antiplasmodial 30 activities. They are also well-known inhibitors of urease, 31 acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), 32 cyclooxygenase (COX), 33 lipoxygenase (LOX), 34 monoamine oxidases A and B (MAO-A and MAO-B), 35 tubulin polymerization, 36 carbonic anhydrase, 37 α-glucosidase, 38 inositol-requiring enzyme 1 (IRE-1) RNase, 39 mitochondria-targeting antitumor STAT3, 40 selective cyclin-dependent kinase 9 (CDK9), 41 selective aldehyde dehydrogenase 1A1, 42 coagulation factor XIIa (FXIIa), 43 casein kinase 2 (CK2), 44 steroid sulfatase (STS), 45 chitin synthase (CHS), 46 etc. These heterocyclic scaffolds have antagonistic behavior against chemokine-like factor 1 (CKLF1), 47 G-protein-coupled receptor 35 (GPR35), 48 orphan G-protein-coupled receptor 55 (GPR55), 49 A 3 adenosine receptor, 50 and many others.…”

Section: Introductionmentioning

confidence: 99%

Diverse and efficient catalytic applications of new cockscomb flower-like Fe₃O₄@SiO₂@KCC-1@MPTMS@Cu^IImesoporous nanocomposite in the environmentally benign reduction and reductive acetylation of nitroarenes and one-pot synthesis of some coumarin compounds

2022

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“…It display in vivo F I G U R E 11 Aminopyridines 63-69 [Color figure can be viewed at wileyonlinelibrary.com]efficacy in MOLT-4 (leukemia) and MIAPaCa-2 (pancreatic cancer) xenograft models with >50% TGI at 50 mg/kg, PO (QD × 21) 220. Lu et al221 have recently reported a hybrid structure comprising an aminopyrimidine with coumarin nucleus, 75, that exhibits potent and selective CDK9/T1 inhibition with an IC 50 value of 2 nM. It exhibits potent in vitro and in vivo cytotoxicity in MV-4-11 AML.…”

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Analyzing the scaffold diversity of cyclin‐dependent kinase inhibitors and revisiting the clinical and preclinical pipeline

Bhurta

Bharate

2021

Medicinal Research Reviews

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Kinases have gained an important place in the list of vital therapeutic targets because of their overwhelming clinical success in the last two decades. Among various clinically validated kinases, the cyclin‐dependent kinases (CDK) are one of the extensively studied drug targets for clinical development. Food and Drug Administration has approved three CDK inhibitors for therapeutic use, and at least 27 inhibitors are under active clinical development. In the last decade, research and development in this area took a rapid pace, and thus the analysis of scaffold diversity is essential for future drug design. Available reviews lack the systematic study and discussion on the scaffold diversity of CDK inhibitors. Herein we have reviewed and critically analyzed the chemical diversity present in the preclinical and clinical pipeline of CDK inhibitors. Our analysis has shown that although several scaffolds represent CDK inhibitors, only the amino‐pyrimidine is a well‐represented scaffold. The three‐nitrogen framework of amino‐pyrimidine is a fundamental hinge‐binding unit. Further, we have discussed the selectivity aspects among CDKs, the clinical trial dose‐limiting toxicities, and highlighted the most advanced clinical candidates. We also discuss the changing paradigm towards selective inhibitors and an overview of ATP‐binding pockets of all druggable CDKs. We carefully analyzed the clinical pipeline to unravel the candidates that are currently under active clinical development. In addition to the plenty of dual CDK4/6 inhibitors, there are many selective CDK7, CDK9, and CDK8/19 inhibitors in the clinical pipeline.

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Discovery of coumarin derivatives as potent and selective cyclin-dependent kinase 9 (CDK9) inhibitors with high antitumour activity

Cited by 37 publications

References 49 publications

Discovery of N-(4-(3-isopropyl-2-methyl-2H-indazol-5-yl)pyrimidin-2-yl)-4-(4-methylpiperazin-1-yl)quinazolin-7-amine as a Novel, Potent, and Oral Cyclin-Dependent Kinase Inhibitor against Haematological Malignancies

Discovery of N-(4-(3-isopropyl-2-methyl-2H-indazol-5-yl)pyrimidin-2-yl)-4-(4-methylpiperazin-1-yl)quinazolin-7-amine as a Novel, Potent, and Oral Cyclin-Dependent Kinase Inhibitor against Haematological Malignancies

Diverse and efficient catalytic applications of new cockscomb flower-like Fe₃O₄@SiO₂@KCC-1@MPTMS@Cu^IImesoporous nanocomposite in the environmentally benign reduction and reductive acetylation of nitroarenes and one-pot synthesis of some coumarin compounds

Analyzing the scaffold diversity of cyclin‐dependent kinase inhibitors and revisiting the clinical and preclinical pipeline

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Discovery of coumarin derivatives as potent and selective cyclin-dependent kinase 9 (CDK9) inhibitors with high antitumour activity

Cited by 37 publications

References 49 publications

Discovery of N-(4-(3-isopropyl-2-methyl-2H-indazol-5-yl)pyrimidin-2-yl)-4-(4-methylpiperazin-1-yl)quinazolin-7-amine as a Novel, Potent, and Oral Cyclin-Dependent Kinase Inhibitor against Haematological Malignancies

Discovery of N-(4-(3-isopropyl-2-methyl-2H-indazol-5-yl)pyrimidin-2-yl)-4-(4-methylpiperazin-1-yl)quinazolin-7-amine as a Novel, Potent, and Oral Cyclin-Dependent Kinase Inhibitor against Haematological Malignancies

Diverse and efficient catalytic applications of new cockscomb flower-like Fe3O4@SiO2@KCC-1@MPTMS@CuIImesoporous nanocomposite in the environmentally benign reduction and reductive acetylation of nitroarenes and one-pot synthesis of some coumarin compounds

Analyzing the scaffold diversity of cyclin‐dependent kinase inhibitors and revisiting the clinical and preclinical pipeline

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Diverse and efficient catalytic applications of new cockscomb flower-like Fe₃O₄@SiO₂@KCC-1@MPTMS@Cu^IImesoporous nanocomposite in the environmentally benign reduction and reductive acetylation of nitroarenes and one-pot synthesis of some coumarin compounds