Discovery of N-Phenyl-4-(1H-pyrrol-3-yl)pyrimidin-2-amine Derivatives as Potent Mnk2 Inhibitors: Design, Synthesis, SAR Analysis, and Evaluation of in vitro Anti-leukaemic Activity

Author(s): Ahmed M. Abdelaziz, Sarah Diab, Saiful Islam, Sunita K.C. Basnet, Benjamin Noll, Peng Li, Laychiluh B. Mekonnen, Jingfeng Lu, Hugo Albrecht, Robert W. Milne, Cobus Gerber, Mingfeng Yu*, Shudong Wang*

Journal Name: Medicinal Chemistry

Volume 15 , Issue 6 , 2019

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Graphical Abstract:


Background: Aberrant expression of eukaryotic translation initiation factor 4E (eIF4E) is common in many types of cancer including acute myeloid leukaemia (AML). Phosphorylation of eIF4E by MAPK-interacting kinases (Mnks) is essential for the eIF4E-mediated oncogenic activity. As such, the pharmacological inhibition of Mnks can be an effective strategy for the treatment of cancer.

Methods: A series of N-phenyl-4-(1H-pyrrol-3-yl)pyrimidin-2-amine derivatives was designed and synthesised. The Mnk inhibitory activity of these derivatives as well as their anti-proliferative activity against MV4-11 AML cells was determined.

Results: These compounds were identified as potent Mnk2 inhibitors. Most of them demonstrated potent anti-proliferative activity against MV4-11 AML cells. The cellular mechanistic studies of the representative inhibitors revealed that they reduced the level of phosphorylated eIF4E and induced apoptosis by down-regulating the anti-apoptotic protein myeloid cell leukaemia 1 (Mcl-1) and by cleaving poly(ADP-ribose)polymerase (PARP). The lead compound 7k possessed desirable pharmacokinetic properties and oral bioavailability.

Conclusion: This work proposes that exploration of the structural diversity in the context of Nphenyl- 4-(1H-pyrrol-3-yl)pyrimidin-2-amine would offer potent and selective Mnk inhibitors.

Keywords: Mnk, eIF4E, inhibitor, structure-activity relationship, N-Phenyl-4-(1H-pyrrol-3-yl)pyrimidin-2-amine, antileukaemia.

Waskiewicz, A.J.; Flynn, A.; Proud, C.G.; Cooper, J.A. Mitogen-activated protein kinases activate the serine/threonine kinases Mnk1 and Mnk2. EMBO J., 1997, 16, 1909-1920.
Cargnello, M.; Roux, P.P. Activation and function of the MAPKs and their substrates, the MAPK-activated protein kinases. Microbiol. Mol. Biol. Rev., 2011, 75, 50-83.
O’Loghlen, A.; González, V.M.; Salinas, M.; Elena Martín, M. Suppression of human Mnk1 by small interfering RNA increases the eukaryotic initiation factor 4F activity in HEK293T cells. FEBS Lett., 2004, 578, 31-35.
Maimon, A.; Mogilevsky, M.; Shilo, A.; Golan-Gerstl, R.; Obiedat, A.; Ben-Hur, V.; Lebenthal-Loinger, I.; Stein, I.; Reich, R.; Beenstock, J.; Zehorai, E. Andersen, Claus L.; Thorsen, K.; Ørntoft, Torben F.; Davis, Roger J.; Davidson, B.; Mu, D.; Karni, R. Mnk2 alternative splicing modulates the p38-MAPK pathway and ompacts Ras-induced transformation. Cell Rep., 2014, 7, 501-513.
Fukunaga, R.; Hunter, T. MNK1, a new MAP kinase‐activated protein kinase, isolated by a novel expression screening method for identifying protein kinase substrates. EMBO J., 1997, 16, 1921-1933.
Korneeva, N.L.; Song, A.; Gram, H.; Edens, M.A.; Rhoads, R.E. Inhibition of MAP kinase-interacting kinase (MNK) preferentially affects translation of mRNAs containing both a 5′-terminal cap and hairpin. J. Biol. Chem., 2015, 291, 3455-3467.
Buxade, M.; Parra-Palau, J.L.; Proud, C.G. The Mnks: MAP kinase-interacting kinases (MAP kinase signal-integrating kinases). Front. Biosci., 2008, 13, 5359-5373.
Joshi, S.; Platanias, L.C. Mnk kinase pathway: Cellular functions and biological outcomes. World J. Biol. Chem., 2014, 5, 321-333.
Hou, J.; Lam, F.; Proud, C.G.; Wang, S. Targeting Mnks for cancer therapy. Oncotarget, 2012, 3, 118-131.
Diab, S.; Kumarasiri, M.; Yu, M.; Teo, T.; Proud, C.G.; Milne, R.; Wang, S. MAP kinase-interacting kinases - Emerging targets against cancer. Chem. Biol., 2014, 21, 441-452.
Lim, S.; Saw, T.Y.; Zhang, M.; Janes, M.R.; Nacro, K.; Hill, J.; Lim, A.Q.; Chang, C.T.; Fruman, D.A.; Rizzieri, D.A.; Tan, S.Y.; Fan, H.; Chuah, C.T.; Ong, S.T. Targeting of the MNK-eIF4E axis in blast crisis chronic myeloid leukemia inhibits leukemia stem cell function. Proc. Natl. Acad. Sci. USA, 2013, 110, E2298-E2307.
Bianchini, A.; Loiarro, M.; Bielli, P.; Busa, R.; Paronetto, M.P.; Loreni, F.; Geremia, R.; Sette, C. Phosphorylation of eIF4E by MNKs supports protein synthesis, cell cycle progression and proliferation in prostate cancer cells. Carcinogenesis, 2008, 29, 2279-2288.
Zheng, J.; Li, J.; Xu, L.; Xie, G.; Wen, Q.; Luo, J.; Li, D.; Huang, D.; Fan, S. Phosphorylated Mnk1 and eIF4E are associated with lymph node metastasis and poor prognosis of nasopharyngeal carcinoma. PLoS One, 2014, 9, 89220-89228.
Flynn, A.; Proud, C.G. Serine 209, not serine 53, is the major site of phosphorylation in initiation factor eIF-4E in serum-treated Chinese hamster ovary cells. J. Biol. Chem., 1995, 270, 21684-21688.
Joshi, B.; Cai, A.L.; Keiper, B.D.; Minich, W.B.; Mendez, R.; Beach, C.M.; Stepinski, J.; Stolarski, R.; Darzynkiewicz, E.; Rhoads, R.E. Phosphorylation of eukaryotic protein synthesis initiation factor 4E at Ser-209. J. Biol. Chem., 1995, 270, 14597-14603.
Duncan, R.; Milburn, S.C.; Hershey, J.W. Regulated phosphorylation and low abundance of HeLa cell initiation factor eIF-4F suggest a role in translational control. Heat shock effects on eIF-4F. J. Biol. Chem., 1987, 262, 380-388.
Gingras, A.C.; Raught, B.; Sonenberg, N. eIF4 initiation factors: Effectors of mRNA recruitment to ribosomes and regulators of translation. Annu. Rev. Biochem., 1999, 68, 913-963.
Rhoads, R.E. Cap recognition and the entry of mRNA into the protein synthesis initiation cycle. Trends Biochem. Sci., 1988, 13, 52-56.
Bhat, M.; Robichaud, N.; Hulea, L.; Sonenberg, N.; Pelletier, J.; Topisirovic, I. Targeting the translation machinery in cancer. Nat. Rev. Drug Discov., 2015, 14, 261-278.
Adesso, L.; Calabretta, S.; Barbagallo, F.; Capurso, G.; Pilozzi, E.; Geremia, R.; Delle Fave, G.; Sette, C. Gemcitabine triggers a pro-survival response in pancreatic cancer cells through activation of the MNK2/eIF4E pathway. Oncogene, 2013, 32, 2848-2857.
Fan, S.; Ramalingam, S.S.; Kauh, J.; Xu, Z.; Khuri, F.R.; Sun, S-Y. Phosphorylated eukaryotic translation initiation factor 4 (eIF4E) is elevated in human cancer tissues. Cancer Biol. Ther., 2009, 8, 1463-1469.
Liang, S.; Guo, R.; Zhang, Z.; Liu, D.; Xu, H.; Xu, Z.; Wang, X.; Yang, L. Upregulation of the eIF4E signaling pathway contributes to the progression of gastric cancer, and targeting eIF4E by perifosine inhibits cell growth. Oncol. Rep., 2013, 29, 2422-2430.
Proud, C.G. Mnks, eIF4E phosphorylation and cancer. Biochim. Biophys. Acta, 2014, 1849, 766-773.
Han, M.; Wang, W.; Wang, L.; Jiang, Y. Expression of eukaryotic initiation factor 4 E in hypopharyngeal carcinoma. J. Int. Med. Res., 2014, 42, 976-983.
Bramham, C.R.; Jensen, K.B.; Proud, C.G. Tuning specific translation in cancer metastasis and synaptic memory: Control at the MNK–eIF4E axis. Trends Biochem. Sci., 2016, 41, 847-858.
Ueda, T.; Watanabe-Fukunaga, R.; Fukuyama, H.; Nagata, S.; Fukunaga, R. Mnk2 and Mnk1 are essential for constitutive and inducible phosphorylation of eukaryotic initiation factor 4E but not for cell growth or development. Mol. Cell. Biol., 2004, 24, 6539-6549.
Ueda, T.; Sasaki, M.; Elia, A.J. Chio, II; Hamada, K.; Fukunaga, R.; Mak, T.W. Combined deficiency for MAP kinase-interacting kinase 1 and 2 (Mnk1 and Mnk2) delays tumor development. Proc. Natl. Acad. Sci. USA, 2010, 107, 13984-13990.
Furic, L.; Rong, L.; Larsson, O.; Koumakpayi, I.H.; Yoshida, K.; Brueschke, A.; Petroulakis, E.; Robichaud, N.; Pollak, M.; Gaboury, L.A.; Pandolfi, P.P.; Saad, F.; Sonenberg, N. eIF4E phosphorylation promotes tumorigenesis and is associated with prostate cancer progression. Proc. Natl. Acad. Sci. USA, 2010, 107, 14134-14139.
Wendel, H.G.; Silva, R.L.; Malina, A.; Mills, J.R.; Zhu, H.; Ueda, T.; Watanabe-Fukunaga, R.; Fukunaga, R.; Teruya-Feldstein, J.; Pelletier, J.; Lowe, S.W. Dissecting eIF4E action in tumorigenesis. Genes Dev., 2007, 21, 3232-3237.
Santag, S.; Siegel, F.; Wengner, A.M.; Lange, C.; Bömer, U.; Eis, K.; Pühler, F.; Lienau, P.; Bergemann, L.; Michels, M.; von Nussbaum, F.; Mumberg, D.; Petersen, K. BAY 1143269, a novel MNK1 inhibitor, targets oncogenic protein expression and shows potent anti-tumor activity. Cancer Lett., 2017, 390, 21-29.
Webster, K.R.; Goel, V.K.; Hung, I.N.; Parker, G.S.; Staunton, J.; Neal, M.; Molter, J.; Chiang, G.G.; Jessen, K.A.; Wegerski, C.J.; Sperry, S.; Huang, V.; Chen, J.; Thompson, P.A.; Appleman, J.R.; Webber, S.E.; Sprengeler, P.A.; Reich, S.H. eFT508, a potent and selective mitogen-activated protein kinase interacting kinase (MNK) 1 and 2 inhibitor, is efficacious in preclinical models of diffuse large B-cell lymphoma (DLBCL). Blood, 2015, 126, 1554-1554.
Reich, S.H.; Sprengeler, P.A.; Chiang, G.G.; Appleman, J.R.; Chen, J.; Clarine, J.; Eam, B.; Ernst, J.T.; Han, Q.; Goel, V.K.; Han, E.Z.R.; Huang, V.; Hung, I.N.J.; Jemison, A.; Jessen, K.A.; Molter, J.; Murphy, D.; Neal, M.; Parker, G.S.; Shaghafi, M.; Sperry, S.; Staunton, J.; Stumpf, C.R.; Thompson, P.A.; Tran, C.; Webber, S.E.; Wegerski, C.J.; Zheng, H.; Webster, K.R. Structure-based design of pyridone-aminal eFT508 targeting dysregulated translation by selective mitogen-activated protein kinase interacting kinases 1 and 2 (MNK1/2) inhibition. J. Med. Chem., 2018, 61, 3516-3540.
Lineham, E.; Spencer, J.; Morley, S.J. Dual abrogation of MNK and mTOR: A novel therapeutic approach for the treatment of aggressive cancers. Future Med. Chem., 2017, 9, 1539-1555.
Li, P.; Diab, S.; Yu, M.; Adams, J.; Islam, S.; Basnet, S.K.; Albrecht, H.; Milne, R.; Wang, S. Inhibition of Mnk enhances apoptotic activity of cytarabine in acute myeloid leukemia cells. Oncotarget, 2016, 7, 56811-56825.
Diab, S.; Abdelaziz, A.M.; Li, P.; Teo, T.; Basnet, S.K.; Noll, B.; Rahaman, M.H.; Lu, J.; Hou, J.; Yu, M.; Le, B.T.; Albrecht, H.; Milne, R.W.; Wang, S. Dual Inhibition of Mnk2 and FLT3 for potential treatment of acute myeloid leukaemia. Eur. J. Med. Chem., 2017, 139, 762-772.
Diab, S.; Teo, T.; Kumarasiri, M.; Li, P.; Yu, M.; Lam, F.; Basnet, S.K.; Sykes, M.J.; Albrecht, H.; Milne, R.; Wang, S. Discovery of 5-(2-(phenylamino) pyrimidin-4-yl) thiazol-2(3H)-one derivatives as potent Mnk2 inhibitors: Synthesis, SAR analysis and biological evaluation. ChemMedChem, 2014, 9, 962-972.
Kumarasiri, M.; Teo, T.; Wang, S. Dynamical insights of Mnk2 kinase activation by phosphorylation to facilitate inhibitor discovery. Future Med. Chem., 2015, 7, 91-102.
Teo, T.; Yang, Y.; Yu, M.; Basnet, S.K.; Gillam, T.; Hou, J.; Schmid, R.M.; Kumarasiri, M.; Diab, S.; Albrecht, H.; Sykes, M.J.; Wang, S. An integrated approach for discovery of highly potent and selective Mnk inhibitors: Screening, synthesis and SAR analysis. Eur. J. Med. Chem., 2015, 103, 539-550.
Yu, M.; Li, P.; Basnet, S.K.; Kumarasiri, M.; Diab, S.; Teo, T.; Albrecht, H.; Wang, S. Discovery of 4-(dihydropyridinon-3-yl) amino-5-methylthieno[2,3-d] pyrimidine derivatives as potent Mnk inhibitors: Synthesis, structure-activity relationship analysis and biological evaluation. Eur. J. Med. Chem., 2015, 95, 116-126.
Basnet, S.K.; Diab, S.; Schmid, R.; Yu, M.; Yang, Y.; Gillam, T.A.; Teo, T.; Li, P.; Peat, T.; Albrecht, H.; Wang, S. Identification of a highly conserved allosteric binding site on Mnk1 and Mnk2. Mol. Pharmacol., 2015, 88, 935-948.
Diab, S.; Li, P.; Basnet, S.K.; Lu, J.; Yu, M.; Albrecht, H.; Milne, R.W.; Wang, S. Unveiling new chemical scaffolds as Mnk inhibitors. Future Med. Chem., 2016, 8, 271-285.
Teo, T.; Lam, F.; Yu, M.; Yang, Y.; Basnet, S.K.; Albrecht, H.; Sykes, M.J.; Wang, S. Pharmacologic inhibition of MNKs in acute myeloid leukemia. Mol. Pharmacol., 2015, 88, 380-389.
Altman, J.K.; Szilard, A.; Konicek, B.W.; Iversen, P.W.; Kroczynska, B.; Glaser, H.; Sassano, A.; Vakana, E.; Graff, J.R.; Platanias, L.C. Inhibition of Mnk kinase activity by cercosporamide and suppressive effects on acute myeloid leukemia precursors. Blood, 2013, 121, 3675-3681.
Agnieszka, D.; Maciej, M.; Mariusz, M.; Charles-Henry, F.; Krzysztof, B.; Tomasz, R. Mitogen-activated protein kinase (MAPK) interacting kinases 1 and 2 (MNK1 and MNK2) as targets for cancer therapy: Recent progress in the development of MNK inhibitors. Curr. Med. Chem., 2017, 24, 1-28.
Falchook, G.S.; Infante, J.R.; Meric-Bernstam, F.; Miller, L.L.; Morison, K.; Vallner, D.; Sperry, S.; Goel, V.; Chiang, G.G.; Webster, K.; Barton, J.; Patel, M.R. A phase 1 dose escalation study of eFT508, an inhibitor of mitogen-activated protein kinase-interacting serine/threonine kinase-1 (MNK-1) and MNK-2 in patients with advanced solid tumors. J. Clin. Oncol., 2017, 35, 2579-2579.
Matsui, Y.; Yasumatsu, I.; Yoshida, K.I.; Iimura, S.; Ikeno, Y.; Nawano, T.; Fukano, H.; Ubukata, O.; Hanzawa, H.; Tanzawa, F.; Isoyama, T. A novel inhibitor stabilizes the inactive conformation of MAPK-interacting kinase 1. Acta Crystallogr. F Struct. Biol. Commun., 2018, 74, 156-160.
Hole, A.J.; Baumli, S.; Shao, H.; Shi, S.; Huang, S.; Pepper, C.; Fischer, P.M.; Wang, S.; Endicott, J.A.; Noble, M.E. Comparative structural and functional studies of 4-(Thiazol-5-yl)-2-(phenylamino) pyrimidine-5-carbonitrile CDK9 inhibitors suggest the basis for isotype selectivity. J. Med. Chem., 2013, 56, 660-670.
Wang, S.; Midgley, C.A.; Scaërou, F.; Grabarek, J.B.; Griffiths, G.; Jackson, W.; Kontopidis, G.; McClue, S.J.; McInnes, C.; Meades, C.; Mezna, M.; Plater, A.; Stuart, I.; Thomas, M.P.; Wood, G.; Clarke, R.G.; Blake, D.G.; Zheleva, D.I.; Lane, D.P.; Jackson, R.C.; Glover, D.M.; Fischer, P.M. Discovery of N-phenyl-4-(thiazol-5-yl) pyrimidin-2-amine Aurora kinase inhibitors. J. Med. Chem., 2010, 53, 4367-4378.
Lukasik, P.M.; Elabar, S.; Lam, F.; Shao, H.; Liu, X.; Abbas, A.Y.; Wang, S. Synthesis and biological evaluation of imidazo[4,5-b] pyridine and 4-heteroaryl-pyrimidine derivatives as anti-cancer agents. Eur. J. Med. Chem., 2012, 57, 311-322.
Wang, S.; Wood, G.; Meades, C.; Griffiths, G.; Midgley, C.; McNae, I.; McInnes, C.; Anderson, S.; Jackson, W.; Mezna, M.; Yuill, R.; Walkinshaw, M.; Fischer, P.M. Synthesis and biological activity of 2-anilino-4-(1H-pyrrol-3-yl) pyrimidine CDK inhibitors. Bioorg. Med. Chem. Lett., 2004, 14, 4237-4240.
Lam, F.; Abbas, A.Y.; Shao, H.; Teo, T.; Adams, J.; Li, P.; Bradshaw, T.D.; Fischer, P.M.; Walsby, E.; Pepper, C.; Chen, Y.; Ding, J.; Wang, S. Targeting RNA transcription and translation in ovarian cancer cells with pharmacological inhibitor CDKI-73. Oncotarget, 2014, 5, 7691-7704.
Knorr, L. Synthese von Pyrrolderivaten. Ber. Dtsch. Chem. Ges., 1884, 17, 1635-1642.
Groves, J.K. The Friedel-Crafts acylation of alkenes. Chem. Soc. Rev., 1972, 1, 73-97.
Kondal Reddy, K.; Subba Rao, N.V. Alkylation and aralkylation of N-heterocycles. Proc. Indiana Acad. Sci., 1969, 70, 81-88.
Lee, S.K.; Song, J.W.; Lim, D.C.; Cho, W.Y.; Park, C.M. 2011.
Bredereck, H.; Effenberger, F.; Botsch, H. Acid amide reactions. XLV. Reactivity of formamidines, dimethylformamide diethyl acetal (amide acetal), and bis (dimethylamino) methoxymethane (aminal ester). Chem. Ber., 1964, 97, 3397-3406.
Topisirovic, I.; Guzman, M.L.; McConnell, M.J.; Licht, J.D.; Culjkovic, B.; Neering, S.J.; Jordan, C.T.; Borden, K.L. Aberrant eukaryotic translation initiation factor 4E-dependent mRNA transport impedes hematopoietic differentiation and contributes to leukemogenesis. Mol. Cell. Biol., 2003, 23, 8992-9002.
Assouline, S.; Culjkovic, B.; Cocolakis, E.; Rousseau, C.; Beslu, N.; Amri, A.; Caplan, S.; Leber, B.; Roy, D.C.; Miller, W.H., Jr; Borden, K.L. Molecular targeting of the oncogene eIF4E in acute myeloid leukemia (AML): A proof-of-principle clinical trial with ribavirin. Blood, 2009, 114, 257-260.
Platanias, L.C. Map kinase signaling pathways and hematologic malignancies. Blood, 2003, 101, 4667-4679.
Reynolds, C.H. Ligand efficiency metrics: Why all the fuss? Future Med. Chem., 2015, 7, 1363-1365.
Kuntz, I.D.; Chen, K.; Sharp, K.A.; Kollman, P.A. The maximal affinity of ligands. Proc. Natl. Acad. Sci. USA, 1999, 96, 9997-10002.
Wang, S.; Meades, C.; Wood, G.; Osnowski, A.; Anderson, S.; Yuill, R.; Thomas, M.; Mezna, M.; Jackson, W.; Midgley, C.; Griffiths, G.; Fleming, I.; Green, S.; McNae, I.; Wu, S-Y.; McInnes, C.; Zheleva, D.; Walkinshaw, M.D.; Fischer, P.M. 2-Anilino-4-(thiazol-5-yl) pyrimidine CDK Inhibitors: Synthesis, SAR Analysis, X-ray crystallography, and biological activity. J. Med. Chem., 2004, 47, 1662-1675.
Wang, S.; Griffiths, G.; Midgley, C.A.; Barnett, A.L.; Cooper, M.; Grabarek, J.; Ingram, L.; Jackson, W.; Kontopidis, G.; McClue, S.J.; McInnes, C.; McLachlan, J.; Meades, C.; Mezna, M.; Stuart, I.; Thomas, M.P.; Zheleva, D.I.; Lane, D.P.; Jackson, R.C.; Glover, D.M.; Blake, D.G.; Fischer, P.M. Discovery and characterization of 2-anilino-4-(thiazol-5-yl) pyrimidine transcriptional CDK inhibitors as anticancer agents. Chem. Biol., 2010, 17, 1111-1121.
Shao, H.; Shi, S.; Huang, S.; Hole, A.J.; Abbas, A.Y.; Baumli, S.; Liu, X.; Lam, F.; Foley, D.W.; Fischer, P.M.; Noble, M.; Endicott, J.A.; Pepper, C.; Wang, S. Substituted 4-(thiazol-5-yl)-2-(phenylamino) pyrimidines are highly active CDK9 Inhibitors: Synthesis, X-ray crystal structures, structure-activity relationship, and anticancer activities. J. Med. Chem., 2013, 56, 640-659.
Hou, J.; Teo, T.; Sykes, M.J.; Wang, S. Insights into the importance of DFD-motif and insertion I1 in stabilizing the DFD-out conformation of Mnk2 kinase. ACS Med. Chem. Lett., 2013, 4, 736-741.
Dai, Y.; Dent, P.; Grant, S. Induction of apoptosis in human leukemia cells by the CDK1 inhibitor CGP74514A. Cell Cycle, 2002, 1, 143-152.
Radomska, H.S.; Alberich-Jordà, M.; Will, B.; Gonzalez, D.; Delwel, R.; Tenen, D.G. Targeting CDK1 promotes FLT3-activated acute myeloid leukemia differentiation through C/EBPα. J. Clin. Invest., 2012, 122, 2955-2966.
Hedblom, A.; Laursen, K.B.; Miftakhova, R.; Sarwar, M.; Anagnostaki, L.; Bredberg, A.; Mongan, N.P.; Gudas, L.J.; Persson, J.L. CDK1 interacts with RARγ and plays an important role in treatment response of acute myeloid leukemia. Cell Cycle, 2013, 12, 1251-1266.
Wang, S.; Griffiths, G.; Midgley, C.A.; Barnett, A.L.; Cooper, M.; Grabarek, J.; Ingram, L.; Jackson, W.; Kontopidis, G.; McClue, S.J.; McInnes, C.; McLachlan, J.; Meades, C.; Mezna, M.; Stuart, I.; Thomas, M.P.; Zheleva, D.I.; Lane, D.P.; Jackson, R.C.; Glover, D.M.; Blake, D.G.; Fischer, P.M. Discovery and characterization of 2-anilino-4-(thiazol-5-yl) pyrimidine transcriptional CDK inhibitors as anticancer agents. Chem. Biol., 2010, 17, 1111-1121.
Wang, S.; Meades, C.; Wood, G.; Osnowski, A.; Anderson, S.; Yuill, R.; Thomas, M.; Mezna, M.; Jackson, W.; Midgley, C.; Griffiths, G.; Fleming, I.; Green, S.; McNae, I.; Wu, S.Y.; McInnes, C.; Zheleva, D.; Walkinshaw, M.D.; Fischer, P.M. 2-Anilino-4-(thiazol-5-yl) pyrimidine CDK inhibitors: Synthesis, SAR analysis, X-ray crystallography, and biological activity. J. Med. Chem., 2004, 47, 1662-1675.

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Year: 2019
Published on: 25 August, 2019
Page: [602 - 623]
Pages: 22
DOI: 10.2174/1573406415666181219111511

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