Discovery and Characterization of 2-Anilino-4- (Thiazol-5-yl)Pyrimidine Transcriptional CDK Inhibitors as Anticancer Agents

Wang, Shudong; Griffiths, G.; Midgley, Carol A.; Barnett, Anna; Cooper, Michael R.; Grabarek, Joanna B.; Ingram, Laura; Jackson, Wayne; Kontopidis, George; McClue, Steven J.; McInnes, Campbell; McLachlan, Janice; Meades, Christopher; Mezna, Mokdad; Stuart, Iain; Thomas, Mark; Zheleva, Daniella; Lane, David P.; Jackson, Robert; Glover, David M.; Blake, David G.; Fischer, Peter M.

doi:10.1016/j.chembiol.2010.07.016

Cited by 93 publications

(91 citation statements)

References 57 publications

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“…Our interest in the development of kinase inhibitors has resulted in a number of clinical and pre-clinical drug candidates [21][22][23][24][25][26]. We have now discovered another novel class of 2,4,5-trisubstituted pyrimidine CDK inhibitors.…”

Section: Introductionmentioning

confidence: 97%

In vitro antitumor mechanism of a novel cyclin-dependent kinase inhibitor CDKI-83

et al. 2011

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Cancer is regarded as a proliferative disorder. Inhibition of cyclin-dependent kinases (CDKs), which are the key regulators of the cell-cycle and RNA transcription, represents an attractive strategy for cancer therapy. In this study, we report the cellular mechanistic investigation of CDKI-83, a K (i)-nanomolar CDK9 inhibitor. The compound shows effective anti-proliferative activity in human tumour cell lines with GI(50) <1 μM, and is capable of inducing apoptosis in A2780 human ovarian cancer cells as determined by the activated caspase-3, Annexin V/PI double staining and accumulated cells at the sub-G1 phase of cell-cycle. While A2780 cells were arrested in G(2)/M phase with CDKI-83 treatment, phosphorylation at Thr(320) of PP1α was significantly reduced, indicating CDK1 inhibition. Importantly, this compound reduced phosphorylation at Ser-2 of RNA polymerase II (RNAPII) by inhibiting cellular CDK9 activity, and down-regulated Mcl-1 and Bcl-2. These results suggest that combined inhibition of CDK9 and CDK1 may result in the effective induction of apoptosis and CDKI-83 has the potential to be developed as an anti-cancer agent.

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Section: Introductionmentioning

confidence: 97%

In vitro antitumor mechanism of a novel cyclin-dependent kinase inhibitor CDKI-83

et al. 2011

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“…There have been many efforts to develop CDK9 inhibitors and as a result several compounds have been shown to possess promising antitumor activities via inhibition of CDK9 in many human cancer models in vitro as well as in vivo (Table 3). The earliest compounds were multikinase inhibitors, while the recent developments focus on selectively targeting CDK9 (Wang et al 2010, Shao et al 2013, Scholz et al 2015.…”

Section: Development Of Pharmacological Inhibitors Of Cdk9 For Pcamentioning

confidence: 99%

Targeting CDK9: a promising therapeutic opportunity in prostate cancer

Rahaman

Kumarasiri

Mekonnen

et al. 2016

Endocrine-Related Cancer

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Cyclin-dependent kinase 9 (CDK9) is a key transcriptional regulator and a lucrative target for cancer treatment. Targeting CDK9 can effectively confine the hyperactivity of androgen receptor and the constitutive expression of anti-apoptotic proteins; both being main causes of prostate cancer (PCa) development and progression. In castrate-resistant PCa, traditional therapies that only target androgen receptor (AR) have become obsolete due to reprograming in AR activity to make the cells independent of androgen. CDK9 inhibitors may provide a new and better therapeutic opportunity over traditional treatment options by targeting both androgen receptor activity and antiapoptotic proteins, improving the chances of positive outcomes, especially in patients with the advanced disease. This review focuses on biological functions of CDK9, its involvement with AR and the potential for therapeutic opportunities in PCa treatment.

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“…[13] Derivatives of N-phenyl-imidazo [4,5-b] pyridin-2-amines, 4-indazolyl-N-phenylpyrimidin-2-amines and Nphenyl-4-pyrazolo [3,4-b] pyridin-pyrimidin-2-amines [ Table-2] were used as potent anti-proliferative and CDK9 inhibitory activities in the present study. [14] Table 3 identifies the evaluated ADME physico chemical properties of all ligands under study.…”

Section: Dataset Selectionmentioning

confidence: 99%

Virtual Screening of CDK9 Inhibitors as Potential Anti Cancer Drugs

Kumar¹,

Giri²,

Nadendla³

2017

IJCA

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Cell cycle inhibition is important hallmark of anti cancer research. CDKs are divided into two types based on their Cell cycle controlling and transcriptional control. CDK 9, a transcriptional regulator serves as potential drug target. Only few drugs are under clinical trials phase 1/2/3 of CDK 9 inhibitory potential. 3BLR (pdb id) is used as docking target. Virtual screening is carried out based on the pharmacophore information generated from literature. Docking is carried out using Molegro virtual docker with all the compounds and top ranking compounds are shortlisted. The best compound (ZINC91643349) was identified and further analyzed by Invitro assays.

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Discovery and Characterization of 2-Anilino-4- (Thiazol-5-yl)Pyrimidine Transcriptional CDK Inhibitors as Anticancer Agents

Abstract: The Open University's repository of research publications and other research outputs Discovery and characterization of 2-Anilino-4-(Thiazol-5-yl)Pyrimidine transcriptional CDK inhibitors as anticancer agents

Cited by 93 publications

References 57 publications

In vitro antitumor mechanism of a novel cyclin-dependent kinase inhibitor CDKI-83

In vitro antitumor mechanism of a novel cyclin-dependent kinase inhibitor CDKI-83

Targeting CDK9: a promising therapeutic opportunity in prostate cancer

Virtual Screening of CDK9 Inhibitors as Potential Anti Cancer Drugs

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