- Structure-based design of highly selective 2,4,5-trisubstituted pyrimidine CDK9 inhibitors as anti-cancer agents
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Cyclin-dependent kinases (CDKs) are a family of Ser/Thr kinases involved in cell cycle and transcriptional regulation. CDK9 regulates transcriptional elongation and this unique property has made it a potential target for several diseases. Due to the conserved ATP binding site, designing selective CDK9 inhibitors has been challenging. Here we report our continued efforts in the optimization of 2,4,5-tri-substituted pyrimidine compounds as potent and selective CDK9 inhibitors. The most selective compound 30m was >100-fold selective for CDK9 over CDK1 and CDK2. These compounds showed broad anti-proliferative activities in various solid tumour cell lines and patient-derived chronic lymphocytic leukaemia (CLL) cells. Decreased phosphorylation of the carboxyl terminal domain (CTD) of RNAPII at Ser-2 and down-regulation of anti-apoptotic protein Mcl-1 were confirmed in both the ovarian cancer model A2780 and patient-derived CLL cells.
- Shao, Hao,Foley, David W.,Huang, Shiliang,Abbas, Abdullahi Y.,Lam, Frankie,Gershkovich, Pavel,Bradshaw, Tracey D.,Pepper, Chris,Fischer, Peter M.,Wang, Shudong
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- Preparation method and application of N-(pyrimidine-2-yl) coumarin-7-amine derivative as protein kinase inhibitor
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The invention discloses a cyclin-dependent kinase inhibitor. The cyclin-dependent kinase inhibitor comprises an N-(pyrimidine-2-yl) coumarin-7-amine derivative shown as a general formula (I). In-vitropharmacodynamic tests prove that the compound has a high-selectivity inhibition effect on CDK9 kinase, and can be applied to reducing or inhibiting the activity of CDK9 kinase in cells. The inventionalso discloses a preparation method of the inhibitor and application of the inhibitor in drugs for CDK family kinase mediated diseases, especially hyperproliferative diseases, virus-induced infectious diseases and cardiovascular diseases.
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Paragraph 0297; 0300-0302
(2020/12/14)
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- Dual Inhibition of Mnk2 and FLT3 for potential treatment of acute myeloid leukaemia
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The discovery of novel anti-AML therapeutic agents is urgently needed, but the complex heterogeneity of the disease has so far hampered the development of a curative treatment. FLT3 inhibitors have shown therapeutic potential in clinical trials; but a monotherapy regimen has been associated with resistance mediated by the activation of parallel signalling circuitry, including MAPK and mTOR. Therefore, inhibiting a nexus of the two signalling pathways along with inhibition of FLT3 might be advantageous. Herein, we propose that a dual inhibition of FLT3 and Mnk would provide a better clinical option for AML patients compared to targeting FLT3 alone. Thus, a series of N-phenyl-4-(thiazol-5-yl)pyrimidin-2-amines and 4-(indol-3-yl)-N-phenylpyrimidin-2-amines were prepared. Potent Mnk2 inhibitors, FLT3 inhibitors, and dual inhibitors of Mnk2 and FLT3 were identified and their anti-proliferative activities assessed against MV4-11 AML cell lines. Dual inhibition of FLT3 and Mnk2 caused the increased apoptotic cell death of MV4-11 cells compared to inhibition of FLT3 or Mnk2 alone.
- Diab, Sarah,Abdelaziz, Ahmad M.,Li, Peng,Teo, Theodosia,Basnet, Sunita K.C.,Noll, Ben,Rahaman, Muhammed H.,Lu, Jingfeng,Hou, Jinqiang,Yu, Mingfeng,Le, Bich T.,Albrecht, Hugo,Milne, Robert W.,Wang, Shudong
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supporting information
p. 762 - 772
(2017/09/02)
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- Thiazole-based aminopyrimidines and N-phenylpyrazolines as potent antimicrobial agents: Synthesis and biological evaluation
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A series of eight thiazole-based N-phenylpyrazolines and two aminopyrimidines having several chalcone derivatives as precursors have been synthesized and evaluated for their antimicrobial activity. All compounds showed antimicrobial activity. The best activity was achieved for compounds 3a and 3b, while compounds 4d and 4g showed the lowest antimicrobial potential.
- Liaras, Konstantinos,Geronikaki, Athina,Glamo?lija, Jasmina,?iri?, Ana,Sokovi?, Marina
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p. 915 - 922
(2014/07/08)
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- Synthesis, structure-activity relationship and biological evaluation of 2,4,5-trisubstituted pyrimidine CDK inhibitors as potential anti-tumour agents
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A series of 2,4,5-trisubstituted pyrimidines have been synthesised and characterised, which exhibited potent CDK inhibition and anti-proliferative activities. The structure-activity relationship is analysed and a rational for CDK9 selectivity is discussed
- Shao, Hao,Shi, Shenhua,Foley, David W.,Lam, Frankie,Abbas, Abdullah Y.,Liu, Xiangrui,Huang, Shiliang,Jiang, Xiangrui,Baharin, Nadiah,Fischer, Peter M.,Wang, Shudong
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p. 447 - 455
(2013/11/19)
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- Thiazole-based chalcones as potent antimicrobial agents. Synthesis and biological evaluation
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As part of ongoing studies in developing new antimicrobials, we report the synthesis of a new class of structurally novel derivatives, that incorporate two known bioactive structures a thiazole and chalcone, to yield a class of compounds with interesting
- Liaras,Geronikaki,Glamo?lija,?iri?,Sokovi?
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experimental part
p. 3135 - 3140
(2011/06/26)
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- Novel (E)-1-(4-methyl-2-(alkylamino)thiazol-5-yl)-3-arylprop-2-en-1-ones as potent antimicrobial agents
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New (E)-1-(4-methyl-2-(alkylamino)thiazol-5-yl)-3-arylprop-2-en-1-ones, unsubstituted or carrying fluoro, bromo, methoxy, nitro, methyl and chloro groups on the benzene ring, were synthesized and assayed in vitro for their antimicrobial activity against Gram positive and Gram negative bacteria and fungi. The compounds were very potent towards all tested microorganisms and in most cases their activity was better than that of reference drugs.
- Liaras,Geronikaki,Glamo?lija,?iri?,Sokovi?
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experimental part
p. 7349 - 7356
(2012/01/03)
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- Discovery of N-Phenyl-4-(thiazol-5-yl)pyrimidin-2-amine aurora kinase inhibitors
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Through cell-based screening of our kinase-directed compound collection, we discovered that a subset of N-phenyl-4-(thiazol-5-yl)pyrimidin-2-amines were potent cytotoxic agents against cancer cell lines, suppressed mitotic histone H3 phosphorylation, and caused aberrant mitotic phenotypes. It was subsequently established that these compounds were in fact potent inhibitors of aurora A and B kinases. It was shown that potency and selectivity of aurora kinase inhibition correlated with the presence of a substituent at the aniline para-position in these compounds. The anticancer effects of lead compound 4-methyl-5-(2-(4- morpholinophenylamino)pyrimidin-4-yl)thiazol-2-amine (18; Ki values of 8.0 and 9.2 nM for aurora A and B, respectively) were shown to emanate from cell death following mitotic failure and increased polyploidy as a consequence of cellular inhibition of aurora A and B kinases. Preliminary in vivo assessment showed that compound 18 was orally bioavailable and possessed anticancer activity. Compound 18 (CYC116) is currently undergoing phase I clinical evaluation in cancer patients.
- Wang, Shudong,Midgley, Carol A.,Sca?rou, Frederic,Grabarek, Joanna B.,Griffiths, Gary,Jackson, Wayne,Kontopidis, George,McClue, Steven J.,McInnes, Campbell,Meades, Christopher,Mezna, Mokdad,Plater, Andy,Stuart, Iain,Thomas, Mark P.,Wood, Gavin,Clarke, Rosemary G.,Blake, David G.,Zheleva, Daniella I.,Lane, David P.,Jackson, Robert C.,Glover, David M.,Fischer, Peter M.
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scheme or table
p. 4367 - 4378
(2010/09/04)
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- 2-Anilino-4-(thiazol-5-yl)pyrimidine CDK Inhibitors: Synthesis, SAR Analysis, X-ray Crystallography, and Biological Activity
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Following the identification through virtual screening of 4-(2,4-dimethyl-thiazol-5-yl)pyrimidin-2-ylamines as moderately potent inhibitors of cyclin-dependent kinase-2 (CDK2), a CDK inhibitor analogue program was initiated. The first aims were to optimize potency and to evaluate the cellular mode of action of lead candidate molecules. Here the synthetic chemistry, the structure-guided design approach, and the structure-activity relationships (SARs) that led to the discovery of 2-anilino-4-(thiazol-5-yl)pyrimidine ATP-antagonistic CDK2 inhibitors, many with very low nM Kis against CDK2, are reported. Furthermore, X-ray crystal structures of four representative analogues from our chemical series in complex with CDK2 are presented, and these structures are used to rationalize the observed biochemical SARs. Finally results are reported that show, using the most potent CDK2 inhibitor compound from the current series, that the observed antiproliferative and proapoptotic effects are consistent with cellular CDK2 and CDK9 inhibition.
- Wang, Shudong,Meades, Christopher,Wood, Gavin,Osnowski, Andrew,Anderson, Sian,Yuill, Rhoda,Thomas, Mark,Mezna, Mokdad,Jackson, Wayne,Midgley, Carol,Griffiths, Gary,Fleming, Ian,Green, Simon,McNae, Iain,Wu, Su-Ying,McInnes, Campbell,Zheleva, Daniella,Walkinshaw, Malcolm D.,Fischer, Peter M.
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p. 1662 - 1675
(2007/10/03)
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- Anti-cancer compounds
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The present invention relates to 2-substituted 4-heteroaryl-pyrimidines, their preparation, pharmaceutical compositions containing them and their use as inhibitors of cyclin-dependent kinases (CDKs) and hence their use in the treatment of proliferative disorders such as cancer, leukaemia, psoriasis and the like.
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- Thiazole derivatives and pharmaceutical composition comprising the same
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The invention relates to novel pharmaceutical compounds for treatment for ulcer of the formula: STR1 wherein R1 is lower alkyl, carboxy, hydroxymethyl, halomethyl, lower alkylthiomethyl or hydroxyiminomethyl, R2 is hydrogen, hydroxy, lower alkyl, pyridyl, amino, lower alkylamino, pyridylamino or guanidino optionally substituted with dimethylaminomethylene, R3 is dihydroisoquinolyl which may be substituted with halogen, lower alkyl, lower alkoxy, carboxy, hydroxy, pyridyl, amino, lower alkylamino, pyridylamino or guanidino, Q is --CO--, and n is an integer of 0 or 1, and pharmaceutically acceptable salts thereof.
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