Discovery of 4-amino-5,6-biaryl-furo[2,3-d]pyrimidines as inhibitors of Lck: Development of an expedient and divergent synthetic route and preliminary SAR

DiMauro, Erin F.; Newcomb, John; Nunes, Joseph J.; Bemis, Jean E.; Boucher, Christina; Buchanan, Joan L.; Buckner, William H.; Cheng, Alan C.; Faust, Theodore; Hsieh, Faye; Huang, Xin; Lee, Josie H.; Marshall, Teresa L.; Martin, Matthew W.; McGowan, David; Schneider, Stephen E.; Turci, Susan M.; White, Ryan D.; Zhu, Xiaotian

doi:10.1016/j.bmcl.2007.01.057

Cited by 44 publications

(16 citation statements)

References 14 publications

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“…Supplementary Figure S1C shows that each of these compounds displayed anti-HIV activity; compound [3] was most remarkable, suppressing HIV replication to undetectable levels in this experiment. This compound, 3-(5,6-diphenylfuro[2,3- d ]pyrimidin-4-ylamino)propan-1-ol (referred to hereafter as DFP-4AP; Figure 3), is structurally related to a class of recently described protein-tyrosine kinase inhibitors built around a 5,6-biarylfuro[2,3- d ]pyrimidine pharmacophore (30). We re-synthesized DFP-4AP and confirmed its structure by NMR and mass spectrometry.…”

Section: Resultsmentioning

confidence: 99%

“…As for Hck, very little inhibition of Lyn was observed with DFP-4A in the presence or absence of Nef. Note that a recent X-ray crystal structure of the Lck kinase domain bound to a related diphenylfuropyrimidine-based inhibitor (30) suggests that the furopyrimidine moiety of DFP-4AP and the active analogs occupy the Hck and Lyn ATP-binding sites (Supplementary Figure S3). Indeed, substitution of the Hck active site “gatekeeper” residue (Thr338) (31), which comes in close contact with the DFP pharmacophore in the Lck crystal structure, with a bulkier methionine dramatically reduced the inhibitory potency of DFP-4AP towards Nef-activated Hck (Supplementary Figure S3).…”

Section: Resultsmentioning

confidence: 99%

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Chemical Library Screens Targeting an HIV-1 Accessory Factor/Host Cell Kinase Complex Identify Novel Antiretroviral Compounds

et al. 2009

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Nef is an HIV-1 accessory protein essential for AIDS progression and an attractive target for drug discovery. Lack of a catalytic function makes Nef difficult to assay in chemical library screens. We developed a high-throughput screening assay for inhibitors of Nef function by coupling it to one of its host cell binding partners, the Src-family kinase Hck. Hck activation is dependent upon Nef in this assay, providing a direct readout of Nef activity in vitro. Using this screen, a unique diphenylfuropyrimidine was identified as a strong inhibitor of Nef-dependent Hck activation. This compound also exhibited remarkable antiretroviral effects, blocking Nef-dependent HIV replication in cell culture. Structurally related analogs were synthesized and shown to exhibit similar Nef-dependent anti-viral activity, identifying the diphenylfuropyrimidine substructure as a new lead for antiretroviral drug development. This study demonstrates that coupling non-catalytic HIV accessory factors with host cell target proteins addressable by high-throughput assays may afford new avenues for the discovery of anti-HIV agents.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Chemical Library Screens Targeting an HIV-1 Accessory Factor/Host Cell Kinase Complex Identify Novel Antiretroviral Compounds

et al. 2009

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“…Thus, selective and potent inhibitors of ACK1 are useful in probing the role of ACK1 in cancer. Pyrazolo pyrimidines and Lck kinase inhibitors have been reported as potent ACK1 inhibitors (DiMauro et al, 2007; Kopecky et al, 2008). In our study, detailed SAR supported by the speculated interaction between the diazepine ring amide and the gatekeeper threonine, led to compound B19 as the most potent and selective compound for ACK1.…”

Section: Discussionmentioning

confidence: 99%

High-Throughput Kinase Profiling: A More Efficient Approach toward the Discovery of New Kinase Inhibitors

Miduturu

Deng

Kwiatkowski

et al. 2011

Chemistry & Biology

109

101

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SUMMARY Selective protein kinase inhibitors have only been developed against a small number of kinase targets. Here we demonstrate that “high-throughput kinase profiling” is an efficient method for the discovery of lead compounds for established as well as unexplored kinase targets. We screened a library of 118 compounds constituting two distinct scaffolds (furan-thiazolidinediones and pyrimido-diazepines) against a panel of 353 kinases. A distinct kinase selectivity profile was observed for each scaffold. Selective inhibitors were identified with submicromolar cellular activity against PIM1, ERK5, ACK1, MPS1/PLK1–3 and Aurora A,B kinases. In addition, we identified potent inhibitors for so far unexplored kinases such as DRAK1, HIPK2 and DCAMKL1 that await further evaluation. This inhibitor-centric approach permits comprehensive assessment of a scaffold of interest and represents an efficient and general strategy for identifying new selective kinase inhibitors.

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“…AIM-100 is the first and the best-studied ACK1 inhibitor, identified in a high throughput screening [18; 20; 50]. A kinase assay performed in the presence of increasing concentrations of AIM-100 revealed that it specifically inhibits ACK1 with an IC 50 of 21 nM but not 30 other kinases, including members of the AKT, AXL, HER, JAK, ERK and PI3K subfamily in vitro [20].…”

Section: Ack1 Inhibitorsmentioning

confidence: 99%

ACK1 tyrosine kinase: Targeted inhibition to block cancer cell proliferation

Mahajan

2013

Cancer Letters

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ACK1 tyrosine kinase, located on chromosome 3q29, is aberrantly activated, amplified or mutated in a wide variety of human cancers. While the deregulated kinase is oncogenic and its activation correlates with progression to metastatic stage, its inhibition causes cell cycle arrest, sensitizes cells to ionizing radiation and induces apoptosis. Oncogenicity of ACK1 is not only due to its ability to promote activation of critical pro-survival kinases and receptors by phosphorylating at distinct tyrosine residues, but also by employing a similar mechanism to eliminate a tumor suppressor from cancer cells. Despite the substantial data supporting the oncogenic role of ACK1, and the potential clinical benefit of blocking ACK1 in metastatic disease, to date ACK1-specific small molecule inhibitors have not been exploited for cancer therapy. This review highlights recent advances that elucidate how cancer cells employ ACK1 kinase to their advantage and discusses some of the novel ACK1 inhibitors that have shown promise in pre-clinical studies.

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Discovery of 4-amino-5,6-biaryl-furo[2,3-d]pyrimidines as inhibitors of Lck: Development of an expedient and divergent synthetic route and preliminary SAR

Cited by 44 publications

References 14 publications

Chemical Library Screens Targeting an HIV-1 Accessory Factor/Host Cell Kinase Complex Identify Novel Antiretroviral Compounds

Chemical Library Screens Targeting an HIV-1 Accessory Factor/Host Cell Kinase Complex Identify Novel Antiretroviral Compounds

High-Throughput Kinase Profiling: A More Efficient Approach toward the Discovery of New Kinase Inhibitors

ACK1 tyrosine kinase: Targeted inhibition to block cancer cell proliferation

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