Structure-based design and synthesis of 5-benzyl-2-phenylpyrimidin-4(3H)-one derivatives as novel MEK1 inhibitors

doi:10.5246/jcps.2018.10.070

Abstract

Abstract:

Previous studies have shown that Ras/Raf/MEK/ERK signaling pathway is up-regulated in almost all cancer cells. Blocking of this pathway by MEK inhibition is an efficient therapeutic approach of cancer. In the present study, we described the discovery of 5-benzyl-2-phenylpyrimidin-4(3H)-one as a novel skeleton of allosteric MEK inhibitor. All acquired target compounds exhibited modest potency to inhibit MEK1 in Raf-MEK cascading assay, and docking studies revealed that the binding mode of the most potent compound (SJ3) was very similar to that of the well known diarylamine-based inhibitor (PD0325901). The results provided valuable guidance for further optimizations on this novel scaffold to achieve druggable molecules.

Key words: 5-Benzyl-2-phenylpyrimidin-4(3H)-one, MEK1 inhibitor, Docking

CLC Number:

R916

Supporting:

Can Li, Hongyue Li, Jing Sun, Dandan Xi, Chao Wang, Lei Liang, Fengrong Xu, Yan Niu, Ping Xu. Structure-based design and synthesis of 5-benzyl-2-phenylpyrimidin-4(3H)-one derivatives as novel MEK1 inhibitors[J]. Journal of Chinese Pharmaceutical Sciences, 2018, 27(10): 686-695.

References

[1] Roger, D. The mitogen-activated protein kinase signal transduction pathway. J. Biol. Chem. 1993, 268, 14553–14556.

[2] Wallace, M.B.; Adams, M.E.; Kanouni, T.; Mol, C.D.; Dougan, D.R.; Feher, V.A.; O’Connell, S.M.; Shi, L.; Halkowycz, P.; Dong, Q. Structure-based design and synthesis of pyrrole derivatives as MEK inhibitors. Bioorg. Med. Chem. Lett. 2010, 20, 4156–4158.

[3] Duncan, K.E.; Chang, L.Y.; Patronas, M. MEK inhibitors: a new class of chemotherapeutic agents with ocular toxicity. Eye. 2015, 29, 1003–1012.

[4] Roskoski, R.Jr. ERK1/2 MAP kinases: Structure, function, and regulation. Pharmacol. Res. 2012, 66, 105–143.

[5] Haura, E.B.; Ricart, A.D.; Larson, T.G.; Stella, P.J.; Bazhenova, L.; Miller, V.A.; Cohen, R.B.; Eisenberg, P.D.; Selaru, P.; Wilner, K.D.; Gadgeel, S.M. A Phase II Study of PD-0325901, an Oral MEK Inhibitor, in Previously Treated Patients with Advanced Non-Small Cell Lung Cancer. Clin. Cancer Res. 2010, 16, 2450–2457.

[6] Uehling, D.E.; Harris, P.A. Recent progress on MAP kinase pathway inhibitors. Bioorg. Med. Chem. Lett. 2015, 25, 4047–4056.

[7] Rice, K.D.; Aay, N.; Anand, N.K.; Blazey, C.M.; Bowles, O.J.; Bussenius, J.; Costanzo, S.; Curtis, J.K.; Defina, S.C.; Dubenko, L.; Engst, S.; Joshi, A.A.; Kennedy, A.R.; Kim, A.I.; Koltun, E.S.; Lougheed, J.C.; Manalo, J.C.; Martini, J.F.; Nuss, J. M.; Peto, C.J.; Tsang, T.H.; Yu, P.; Johnston, S. Novel Carboxamide-Based Allosteric MEK Inhibitors: Discovery and Optimization Efforts toward XL518 (GDC-0973). ACS Med. Chem. Lett. 2012, 3, 416–421.

[8] Patel, Y.T.; Daryani, V.M.; Patel, P.; Zhou, D.; Fangusaro, J.; Carlile, D.J.; Martin, P.D.; Aarons, L.; Stewart, C.F. Population Pharmacokinetics of Selumetinib and Its Metabolite N-desmethyl-selumetinib in Adult Patients With Advanced Solid Tumors and Children With Low-Grade Gliomas. CPT Pharmacometrics Syst. Pharmacol. 2017, 6, 305–314.

[9] Wang, C.; Zhang, H.; Xu, F.; Niu, Y.; Wu, Y.; Wang, X.; Peng, Y.; Sun, J.; Liang, L.; Xu, P. Substituted 3-benzylcoumarins as allosteric MEK1 inhibitors: design, synthesis and biological evaluation as antiviral agents. Molecules. 2013, 18, 6057–6091.

[10] Sun, J.; Niu, Y.; Wang, C.; Zhang, H.; Xie, B.; Xu, F.; Jin, H.; Peng, Y.; Liang, L.; Xu, P., Discovery of 3-benzyl-1,3-benzoxazine-2,4-dione analogues as allosteric mitogen-activated kinase kinase (MEK) inhibitors and anti-enterovirus 71 (EV71) agents. Bioorg. Med. Chem. 2016, 24, 3472–3482.

[11] Sun, J.; Niu, Y.; Xu, F.; Liang, L.; Wang, C.; Xu, P. Design, synthesis and biological evaluation of 3H-pyrano[2,3-d]pyrimidine-4,7-dionederivatives as MEK inhibitors. China Sci. Paper. 2015, 10, 2823–2829.

[12] Dong, Q.; Dougan, D.R.; Gong, X.; Halkowycz, P.; Jin, B.; Kanouni, T.; O'Connell, S.M.; Scorah, N.; Shi, L.; Wallace, M.B.; Zhou, F. Discovery of TAK-733, a potent and selective MEK allosteric site inhibitor for the treatment of cancer. Bioorg. Med. Chem. Lett. 2011, 21, 1315–1319.

[13] El Kaim, L.; Grimaud, L.; Oble, J. New Ugi-Smiles-metathesis strategy toward the synthesis of pyrimidoazepines. J. Org. Chem. 2007, 72, 5835–5838.

[14] Zhang, X.; Raghavan, S.; Ihnat, M.; Hamel, E.; Zammiello, C.; Bastian, A.; Mooberry, S.L.; Gangjee, A. The design, synthesis and biological evaluation of conformationally restricted 4-substituted-2,6-dimethylfuro[2,3-d]pyrimidines as multi-targeted receptor tyrosine kinase and microtubule inhibitors as potential antitumor agents. Bioorg. Med. Chem. 2015, 23, 2408–2423.

[15] Goldys, A.M.; Nunez, M.G.; Dixon, D.J. Creation through Immobilization: A New Family of High Performance Heterogeneous Bifunctional Iminophosphorane (BIMP) Superbase Organocatalysts. Org. Lett. 2014, 16, 6294–6297.

[16] Hagmann, W.K.; Basha, F.Z.; Hashimoto, M.; Frye, R.B.; Kojo, S.; Hecht, S.M. Chemistry of 2-substituted pyrimidines. Studies directed toward the synthesis of the pyrimidine moiety of bleomycin. J. Org. Chem. 1981, 46, 1413–1423.

[17] Fischmann, T.O.; Smith, C.K.; Mayhood, T.W.; Myers, J.E.; Reichert, P.; Mannarino, A.; Carr, D.; Zhu, H.; Wong, J.; Yang, R.S.; Le, H.V.; Madison, V.S. Crystal Structures of MEK1 Binary and Ternary Complexes with Nucleotides and Inhibitors. Biochemistry. 2009, 48, 2661–2674.