Design, synthesis and SAR of new-di-substituted pyridopyrimidines as ATP-competitive dual PI3Kα/mTOR inhibitors

Aisha A.K. Al-Ashmawy; Fatma A. Ragab; Khaled M. Elokely; Manal M. Anwar; Oscar Perez-Leal; Mario C. Rico; John Gordon; Eugeney Bichenkov; George Mateo; Emad M.M. Kassem; Gehan H. Hegazy; Magid Abou-Gharbia; Wayne Childers

doi:10.1016/j.bmcl.2017.05.044

Design, synthesis and SAR of new-di-substituted pyridopyrimidines as ATP-competitive dual PI3Kα/mTOR inhibitors

Aisha A.K. Al-Ashmawy, Fatma A. Ragab, Khaled M. Elokely, Manal M. Anwar, Oscar Perez-Leal, Mario C. Rico, John Gordon, Eugeney Bichenkov, George Mateo, Emad M.M. Kassem, Gehan H. Hegazy, Magid Abou-Gharbia, Wayne Childers^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

16 Citations (Scopus)

Abstract

PI3Kα/mTOR ATP-competitive inhibitors are considered as one of the promising molecularly targeted cancer therapeutics. Based on lead compound A from the literature, two similar series of 2-substituted-4-morpholino-pyrido[3,2-d]pyrimidine and pyrido[2,3-d]pyrimidine analogs were designed and synthesized as PI3Kα/mTOR dual inhibitors. Interestingly, most of the series gave excellent inhibition for both enzymes with IC₅₀ values ranging from single to double digit nM. Unlike many PI3Kα/mTOR dual inhibitors, our compounds displayed selectivity for PI3Kα. Based on its potent enzyme inhibitory activity, selectivity for PI3Kα and good therapeutic index in 2D cell culture viability assays, compound 4h was chosen to be evaluated in 3D culture for its IC₅₀ against MCF7 breast cancer cells as well as for docking studies with both enzymes.

Original language	English
Pages (from-to)	3117-3122
Number of pages	6
Journal	Bioorganic and Medicinal Chemistry Letters
Volume	27
Issue number	14
DOIs	https://doi.org/10.1016/j.bmcl.2017.05.044
Publication status	Published - 2017
Externally published	Yes

Keywords

3-Kinase alpha
Dual inhibitor
Pyrido[2,3-d]pyrimidine phosphoinositide
Pyrido[3,2-d]pyrimidine
mTOR

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Al-Ashmawy, A. A. K., Ragab, F. A., Elokely, K. M., Anwar, M. M., Perez-Leal, O., Rico, M. C., Gordon, J., Bichenkov, E., Mateo, G., Kassem, E. M. M., Hegazy, G. H., Abou-Gharbia, M., & Childers, W. (2017). Design, synthesis and SAR of new-di-substituted pyridopyrimidines as ATP-competitive dual PI3Kα/mTOR inhibitors. Bioorganic and Medicinal Chemistry Letters, 27(14), 3117-3122. https://doi.org/10.1016/j.bmcl.2017.05.044

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title = "Design, synthesis and SAR of new-di-substituted pyridopyrimidines as ATP-competitive dual PI3Kα/mTOR inhibitors",

abstract = "PI3Kα/mTOR ATP-competitive inhibitors are considered as one of the promising molecularly targeted cancer therapeutics. Based on lead compound A from the literature, two similar series of 2-substituted-4-morpholino-pyrido[3,2-d]pyrimidine and pyrido[2,3-d]pyrimidine analogs were designed and synthesized as PI3Kα/mTOR dual inhibitors. Interestingly, most of the series gave excellent inhibition for both enzymes with IC50 values ranging from single to double digit nM. Unlike many PI3Kα/mTOR dual inhibitors, our compounds displayed selectivity for PI3Kα. Based on its potent enzyme inhibitory activity, selectivity for PI3Kα and good therapeutic index in 2D cell culture viability assays, compound 4h was chosen to be evaluated in 3D culture for its IC50 against MCF7 breast cancer cells as well as for docking studies with both enzymes.",

keywords = "3-Kinase alpha, Dual inhibitor, Pyrido[2,3-d]pyrimidine phosphoinositide, Pyrido[3,2-d]pyrimidine, mTOR",

author = "Al-Ashmawy, {Aisha A.K.} and Ragab, {Fatma A.} and Elokely, {Khaled M.} and Anwar, {Manal M.} and Oscar Perez-Leal and Rico, {Mario C.} and John Gordon and Eugeney Bichenkov and George Mateo and Kassem, {Emad M.M.} and Hegazy, {Gehan H.} and Magid Abou-Gharbia and Wayne Childers",

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year = "2017",

doi = "10.1016/j.bmcl.2017.05.044",

language = "English",

volume = "27",

pages = "3117--3122",

journal = "Bioorganic and Medicinal Chemistry Letters",

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Al-Ashmawy, AAK, Ragab, FA, Elokely, KM, Anwar, MM, Perez-Leal, O, Rico, MC, Gordon, J, Bichenkov, E, Mateo, G, Kassem, EMM, Hegazy, GH, Abou-Gharbia, M & Childers, W 2017, 'Design, synthesis and SAR of new-di-substituted pyridopyrimidines as ATP-competitive dual PI3Kα/mTOR inhibitors', Bioorganic and Medicinal Chemistry Letters, vol. 27, no. 14, pp. 3117-3122. https://doi.org/10.1016/j.bmcl.2017.05.044

TY - JOUR

T1 - Design, synthesis and SAR of new-di-substituted pyridopyrimidines as ATP-competitive dual PI3Kα/mTOR inhibitors

AU - Al-Ashmawy, Aisha A.K.

AU - Ragab, Fatma A.

AU - Elokely, Khaled M.

AU - Anwar, Manal M.

AU - Perez-Leal, Oscar

AU - Rico, Mario C.

AU - Gordon, John

AU - Bichenkov, Eugeney

AU - Mateo, George

AU - Kassem, Emad M.M.

AU - Hegazy, Gehan H.

AU - Abou-Gharbia, Magid

AU - Childers, Wayne

PY - 2017

Y1 - 2017

N2 - PI3Kα/mTOR ATP-competitive inhibitors are considered as one of the promising molecularly targeted cancer therapeutics. Based on lead compound A from the literature, two similar series of 2-substituted-4-morpholino-pyrido[3,2-d]pyrimidine and pyrido[2,3-d]pyrimidine analogs were designed and synthesized as PI3Kα/mTOR dual inhibitors. Interestingly, most of the series gave excellent inhibition for both enzymes with IC50 values ranging from single to double digit nM. Unlike many PI3Kα/mTOR dual inhibitors, our compounds displayed selectivity for PI3Kα. Based on its potent enzyme inhibitory activity, selectivity for PI3Kα and good therapeutic index in 2D cell culture viability assays, compound 4h was chosen to be evaluated in 3D culture for its IC50 against MCF7 breast cancer cells as well as for docking studies with both enzymes.

AB - PI3Kα/mTOR ATP-competitive inhibitors are considered as one of the promising molecularly targeted cancer therapeutics. Based on lead compound A from the literature, two similar series of 2-substituted-4-morpholino-pyrido[3,2-d]pyrimidine and pyrido[2,3-d]pyrimidine analogs were designed and synthesized as PI3Kα/mTOR dual inhibitors. Interestingly, most of the series gave excellent inhibition for both enzymes with IC50 values ranging from single to double digit nM. Unlike many PI3Kα/mTOR dual inhibitors, our compounds displayed selectivity for PI3Kα. Based on its potent enzyme inhibitory activity, selectivity for PI3Kα and good therapeutic index in 2D cell culture viability assays, compound 4h was chosen to be evaluated in 3D culture for its IC50 against MCF7 breast cancer cells as well as for docking studies with both enzymes.

KW - 3-Kinase alpha

KW - Dual inhibitor

KW - Pyrido[2,3-d]pyrimidine phosphoinositide

KW - Pyrido[3,2-d]pyrimidine

KW - mTOR

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U2 - 10.1016/j.bmcl.2017.05.044

DO - 10.1016/j.bmcl.2017.05.044

M3 - Article

C2 - 28571824

AN - SCOPUS:85019666796

SN - 0960-894X

VL - 27

SP - 3117

EP - 3122

JO - Bioorganic and Medicinal Chemistry Letters

JF - Bioorganic and Medicinal Chemistry Letters

IS - 14

ER -

Design, synthesis and SAR of new-di-substituted pyridopyrimidines as ATP-competitive dual PI3Kα/mTOR inhibitors

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Keywords

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