Synthesis and biological evaluation of pyrazolo[1,5- A ]pyrimidine compounds as potent and selective pim-1 inhibitors

Yong Xu, Benjamin G. Brenning, Steven G. Kultgen, Jason M. Foulks, Adrianne Clifford, Shuping Lai, Ashley Chan, Shannon Merx, Michael V. McCullar, Steven B. Kanner, Koc Kan Ho

Research output: Contribution to journalArticle

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Abstract

Pim-1 has emerged as an attractive target for developing therapeutic agents for treating disorders involving abnormal cell growth, especially cancers. Herein we present lead optimization, chemical synthesis and biological evaluation of pyrazolo[1,5-a]pyrimidine compounds as potent and selective inhibitors of Pim-1 starting from a hit from virtual screening. These pyrazolo[1,5-a]pyrimidine compounds strongly inhibited Pim-1 and Flt-3 kinases. Selected compounds suppressed both the phosphorylation of BAD protein in a cell-based assay and 2-dimensional colony formation in a clonogenic cell survival assay at submicromolar potency, suggesting that cellular activity was mediated through inhibition of Pim-1. Moreover, these Pim-1 inhibitors did not show significant hERG inhibition at 30 μM concentration. The lead compound proved to be highly selective against a panel of 119 oncogenic kinases, indicating it had an improved safety profile compared with the first generation Pim-1 inhibitor SGI-1776.

Original languageEnglish (US)
Pages (from-to)63-67
Number of pages5
JournalACS Medicinal Chemistry Letters
Volume6
Issue number1
DOIs
StatePublished - Jan 8 2015

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Assays
Phosphotransferases
Colony-Forming Units Assay
Lead compounds
Phosphorylation
Cell growth
Cell Survival
Screening
Cells
Safety
Growth
Neoplasms
Proteins
pyrimidine
pyrazolo(1,5-a)pyrimidine
Therapeutics
SGI 1776
Lead

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Drug Discovery
  • Organic Chemistry

Cite this

Xu, Yong ; Brenning, Benjamin G. ; Kultgen, Steven G. ; Foulks, Jason M. ; Clifford, Adrianne ; Lai, Shuping ; Chan, Ashley ; Merx, Shannon ; McCullar, Michael V. ; Kanner, Steven B. ; Ho, Koc Kan. / Synthesis and biological evaluation of pyrazolo[1,5- A ]pyrimidine compounds as potent and selective pim-1 inhibitors. In: ACS Medicinal Chemistry Letters. 2015 ; Vol. 6, No. 1. pp. 63-67.
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abstract = "Pim-1 has emerged as an attractive target for developing therapeutic agents for treating disorders involving abnormal cell growth, especially cancers. Herein we present lead optimization, chemical synthesis and biological evaluation of pyrazolo[1,5-a]pyrimidine compounds as potent and selective inhibitors of Pim-1 starting from a hit from virtual screening. These pyrazolo[1,5-a]pyrimidine compounds strongly inhibited Pim-1 and Flt-3 kinases. Selected compounds suppressed both the phosphorylation of BAD protein in a cell-based assay and 2-dimensional colony formation in a clonogenic cell survival assay at submicromolar potency, suggesting that cellular activity was mediated through inhibition of Pim-1. Moreover, these Pim-1 inhibitors did not show significant hERG inhibition at 30 μM concentration. The lead compound proved to be highly selective against a panel of 119 oncogenic kinases, indicating it had an improved safety profile compared with the first generation Pim-1 inhibitor SGI-1776.",
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Xu, Y, Brenning, BG, Kultgen, SG, Foulks, JM, Clifford, A, Lai, S, Chan, A, Merx, S, McCullar, MV, Kanner, SB & Ho, KK 2015, 'Synthesis and biological evaluation of pyrazolo[1,5- A ]pyrimidine compounds as potent and selective pim-1 inhibitors', ACS Medicinal Chemistry Letters, vol. 6, no. 1, pp. 63-67. https://doi.org/10.1021/ml500300c

Synthesis and biological evaluation of pyrazolo[1,5- A ]pyrimidine compounds as potent and selective pim-1 inhibitors. / Xu, Yong; Brenning, Benjamin G.; Kultgen, Steven G.; Foulks, Jason M.; Clifford, Adrianne; Lai, Shuping; Chan, Ashley; Merx, Shannon; McCullar, Michael V.; Kanner, Steven B.; Ho, Koc Kan.

In: ACS Medicinal Chemistry Letters, Vol. 6, No. 1, 08.01.2015, p. 63-67.

Research output: Contribution to journalArticle

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AU - Brenning, Benjamin G.

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AU - Foulks, Jason M.

AU - Clifford, Adrianne

AU - Lai, Shuping

AU - Chan, Ashley

AU - Merx, Shannon

AU - McCullar, Michael V.

AU - Kanner, Steven B.

AU - Ho, Koc Kan

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AB - Pim-1 has emerged as an attractive target for developing therapeutic agents for treating disorders involving abnormal cell growth, especially cancers. Herein we present lead optimization, chemical synthesis and biological evaluation of pyrazolo[1,5-a]pyrimidine compounds as potent and selective inhibitors of Pim-1 starting from a hit from virtual screening. These pyrazolo[1,5-a]pyrimidine compounds strongly inhibited Pim-1 and Flt-3 kinases. Selected compounds suppressed both the phosphorylation of BAD protein in a cell-based assay and 2-dimensional colony formation in a clonogenic cell survival assay at submicromolar potency, suggesting that cellular activity was mediated through inhibition of Pim-1. Moreover, these Pim-1 inhibitors did not show significant hERG inhibition at 30 μM concentration. The lead compound proved to be highly selective against a panel of 119 oncogenic kinases, indicating it had an improved safety profile compared with the first generation Pim-1 inhibitor SGI-1776.

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