Discovery of pyrazolo[1,5-a]pyrimidine-based Pim inhibitors: A template-based approach

Dwyer, Michael P.; Keertikar, Kartik M.; Paruch, Kamil; Álvarez, Carmen; Labroli, Marc; Poker, Cory; Fischmann, Thierry O.; Mayer-Ezell, Rosemary; Bond, Richard; Wang, Yan; Azevedo, Rita; Guzi, Timothy J.

doi:10.1016/j.bmcl.2013.08.110

Cited by 33 publications

(18 citation statements)

References 27 publications

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“…In this study, FDA-approved small-molecule compounds were screened for candidate drugs and PI003 was modified from the best one, P9, and more hydrogen bonds were formatted to increase the stability. Compared with other pan-PIM inhibitors, such as 7-(4H-1,2,4-Triazol-3-yl)benzo[c] [ 2 , 6 ] naphthyridines and pyrazolo[1,5-a]pyrimidine-based Pim inhibitors PI003, modified from a FDA-approved drug, had more druggability [ 16 , 17 ]. A series of experimental data have demonstrated that PI003-induced apoptosis was the death-receptor and mitochondrial pathways in HeLa cells.…”

Section: Discussionmentioning

confidence: 99%

Computational prediction and experimental validation of a novel synthesized pan-PIM inhibitor PI003 and its apoptosis-inducing mechanisms in cervical cancer

Liu

Gao

et al. 2015

Oncotarget

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PIM protein family, short-lived serine/threonine kinases (PIM1, PIM2 and PIM3), are weak oncogenes but contribute to tumorigenesis as cancer targets. Thus, design of a novel pan-PIM inhibitor is still a challenge for current cancer drug discovery. Herein, we used a Naïve Bayesian model to construct the PIM network and identified Bad and Hsp90 to interact with PIMs. Then, we screened a series of candidate small-molecule compounds targeting PIMs, and subsequently synthesized a novel small-molecule compound PI003 with remarkable anti-proliferative activities in cervical cancer cells. Moreover, we found that PI003 induced apoptosis via the death-receptor and mitochondrial pathways by targeting PIMs and affecting Bad and Hsp90. Combined with microRNA microarray analyses, we demonstrated that some microRNAs such as miR-1296 and miR-1299 could affect PIM1-STAT3 pathway in PI003-induced apoptosis. Finally, we reported that PI003 had remarkable anti-tumor activity and apoptosis-inducing effect in in vivo mouse model. In conclusion, these results demonstrate that PI003, as a novel synthesized pan-PIM inhibitor, induces the death-receptor and mitochondrial apoptosis involved in microRNA regulation, and also possessed remarkable anti-tumor activity and apoptosis-inducing effect in vivo. Thus, these findings would shed light on discovering more potential new small-molecule pan-PIM inhibitors in future cervical cancer therapy.

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Section: Discussionmentioning

confidence: 99%

Computational prediction and experimental validation of a novel synthesized pan-PIM inhibitor PI003 and its apoptosis-inducing mechanisms in cervical cancer

Liu

Gao

et al. 2015

Oncotarget

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“…Thethree routes depicted in Scheme 1provided astarting library of 20 compounds,a nd they were profiled against ap anel of 206 human protein kinases at 1 mm concentration (Eurofins). In addition, IC 50 values of the compounds 7i-k and 7m-o,a nalogues of known pyrazolo[1,5-a]pyrimidinebased inhibitors of CDK2 [12] and PIM [13] kinases,w ere also determined. TheC DK2 and PIM furo[3,2-b]pyridine inhibitors 7i-k and 7m-o were significantly less potent than the corresponding pyrazolo[1,5-a]pyrimidines (see Table S1 A and S1 Bi nt he Suppporting Information).…”

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confidence: 99%

Furo[3,2‐b]pyridine: A Privileged Scaffold for Highly Selective Kinase Inhibitors and Effective Modulators of the Hedgehog Pathway

et al. 2018

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Reported is the identification of the furo [3,2b]pyridine core as an ovel scaffold for potent and highly selective inhibitors of cdc-like kinases (CLKs) and efficient modulators of the Hedgehog signaling pathway.I nitially, ad iverse target compound set was prepared by synthetic sequences based on chemoselective metal-mediated couplings, including assembly of the furo[3,2-b]pyridine scaffold by copper-mediated oxidative cyclization. Optimization of the subseries containing 3,5-disubstituted furo[3,2-b]pyridines afforded potent, cell-active,a nd highly selective inhibitors of CLKs.P rofiling of the kinase-inactive subset of 3,5,7-trisubstituted furo[3,2-b]pyridines revealed sub-micromolar modulators of the Hedgehog pathway.

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“…This study may explain the mechanism of candidate novel compounds. To the best of our knowledge, although some Pim-1 and pan-Pim inhibitors have been reported, no Pim-2-specific inhibitors have been described [32][33][34][35][36] . Compared with other compounds, HJ-PI01 has better druggability because it is based on chlor- promazine, which is an FDA-approved drug.…”

Section: Discussionmentioning

confidence: 99%

Characterization of HJ-PI01 as a novel Pim-2 inhibitor that induces apoptosis and autophagic cell death in triple-negative human breast cancer

et al. 2016

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Discovery of pyrazolo[1,5-a]pyrimidine-based Pim inhibitors: A template-based approach

Cited by 33 publications

References 27 publications

Computational prediction and experimental validation of a novel synthesized pan-PIM inhibitor PI003 and its apoptosis-inducing mechanisms in cervical cancer

Computational prediction and experimental validation of a novel synthesized pan-PIM inhibitor PI003 and its apoptosis-inducing mechanisms in cervical cancer

Furo[3,2‐b]pyridine: A Privileged Scaffold for Highly Selective Kinase Inhibitors and Effective Modulators of the Hedgehog Pathway

Characterization of HJ-PI01 as a novel Pim-2 inhibitor that induces apoptosis and autophagic cell death in triple-negative human breast cancer

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