Synthesis and biological evaluation of novel analogues of the pan class i phosphatidylinositol 3-kinase (PI3K) inhibitor 2-(Difluoromethyl)-1-[4,6-di(4- morpholinyl)-1,3,5-triazin-2-yl]-1 H -benzimidazole (ZSTK474)

Rewcastle, Gordon W.;Gamage, Swarna A.;Flanagan, Jack U.;Frédérick, Raphaël;Shepherd, Peter R.;et.al.
(2011) Journal of Medicinal Chemistry — Vol. 54, n° 20, p. 7105-7126 (2011)

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Authors
  • Rewcastle, Gordon W.
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  • Gamage, Swarna A.
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  • Flanagan, Jack U.
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  • Frédérick, Raphaëlorcid-logoUCLouvain
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  • Shepherd, Peter R.
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Abstract
A structure-activity relationship (SAR) study of the pan class I PI 3-kinase inhibitor 2-(difluoromethyl)-1-[4,6-di(4-morpholinyl)-1,3,5-triazin-2- yl]-1H-benzimidazole (ZSTK474) identified substitution at the 4 and 6 positions of the benzimidazole ring as having significant effects on the potency of substituted derivatives. The 6-amino-4-methoxy analogue displayed a greater than 1000-fold potency enhancement over the corresponding 6-aza-4-methoxy analogue against all three class Ia PI 3-kinase enzymes (p110α, p110β, and p110δ) and also displayed significant potency against two mutant forms of the p110α isoform (H1047R and E545K). This compound was also evaluated in vivo against a U87MG human glioblastoma tumor xenograft model in Rag1 -/- mice, and at a dose of 50 mg/kg given by ip injection at a qd ø- 10 dosing schedule it dramatically reduced cancer growth by 81% compared to untreated controls. © 2011 American Chemical Society.
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Rewcastle, G. W., Gamage, S. A., Flanagan, J. U., Frédérick, R., Denny, W. A., Baguley, B. C., Kestell, P., Singh, R., Kendall, J. D., Marshall, E. S., Lill, C. L., Lee, W.-J., Kolekar, S., Buchanan, C. M., Jamieson, S. M. F., & Shepherd, P. R. (2011). Synthesis and biological evaluation of novel analogues of the pan class i phosphatidylinositol 3-kinase (PI3K) inhibitor 2-(Difluoromethyl)-1-[4,6-di(4- morpholinyl)-1,3,5-triazin-2-yl]-1 H -benzimidazole (ZSTK474). Journal of Medicinal Chemistry, 54(20), 7105-7126. https://doi.org/10.1021/jm200688y (Original work published 2011)