Extended kinase profile and properties of the protein kinase inhibitor nilotinib

Manley, Paul W.; Drueckes, Peter; Fendrich, Gabriele; Furet, Pascal; Liebetanz, Janis; Martiny-Baron, Georg; Mestan, Jürgen; Trappe, Jörg; Wartmann, Markus; Fabbro, Doriano

doi:10.1016/j.bbapap.2009.11.008

Cited by 204 publications

(189 citation statements)

References 46 publications

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“…17,18 To further demonstrate the role of ZAK in doxorubicin-induced apoptosis of normal cells we employed two multi-kinase inhibitors with high affinity for ZAK, sorafenib (Bayer, K d = 6.3 nM) and nilotinib (Novartis, K d = 3 nM). 24,26 Nilotinib was developed as a secondgeneration inhibitor of BCR-ABL and has been successful in treating chronic myelogenous leukemia (CML) in patients that have developed resistance to imatinib (Gleevec). Nilotinib's binding affinity for ZAK is higher than its affinity for BCR-ABL.…”

Section: Discussionmentioning

confidence: 99%

“…25 Another small molecule kinase inhibitor with a high binding affinity for ZAK is nilotinib (Novartis, K d = 3 nM), which also inhibits breakpoint cluster region-abelson (BCR-ABL) and is currently in clinical use for treatment of chronic myelogenous leukemia. 26 Although the binding affinities of sorafenib and nilotinib for ZAK have been reported, neither agent has been tested for their ability to inhibit ZAK activity.…”

Section: Doxorubicinmentioning

confidence: 99%

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ZAK is required for doxorubicin, a novel ribotoxic stressor, to induce SAPK activation and apoptosis in HaCaT cells

Sauter

Magun

Iordanov

et al. 2010

Cancer Biology & Therapy

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Section: Discussionmentioning

confidence: 99%

Section: Doxorubicinmentioning

confidence: 99%

ZAK is required for doxorubicin, a novel ribotoxic stressor, to induce SAPK activation and apoptosis in HaCaT cells

Sauter

Magun

Iordanov

et al. 2010

Cancer Biology & Therapy

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“…We have developed an irreversible inhibitor of MRK, M443, based on the close proximity of the M443 parental compound nilotinib to cysteine 22 in the model structure of the MRK ATPbinding domain (24). The unique presence of this cysteine at this position in MRK, compared with other nilotinib targets and other MRK-related proteins, suggested that an irreversible inhibitor of MRK could provide high selectivity toward MRK, which is likely to result in reduced off-target effects of a treatment based on this molecule.…”

Section: Discussionmentioning

confidence: 99%

“…Figure 2A shows that preincubation of these cells with the different drugs led to various levels of MRK inhibition. Among the inhibitors, we selected nilotinib, which had been previously shown by Manley and colleagues to bind with very high affinity to MRK (24).This study also included a model of the MRK active site bound to nilotinib, based on the corresponding structure of nilotinib bound to its original target cAbl. We noticed that the pyridine ring in nilotinib was located in close proximity to cysteine 22 in MRK, suggesting the possibility of designing a nilotinib derivative that can covalently interact with MRK.…”

Section: Design Of An Irreversible Inhibitor Of Mrkmentioning

confidence: 99%

Pharmacological Inhibition of the Protein Kinase MRK/ZAK Radiosensitizes Medulloblastoma

Markowitz

Powell

Tran

et al. 2016

Molecular Cancer Therapeutics

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Medulloblastoma is a cerebellar tumor and the most common pediatric brain malignancy. Radiotherapy is part of the standard care for this tumor, but its effectiveness is accompanied by significant neurocognitive sequelae due to the deleterious effects of radiation on the developing brain. We have previously shown that the protein kinase MRK/ZAK protects tumor cells from radiation-induced cell death by regulating cell-cycle arrest after ionizing radiation. Here, we show that siRNA-mediated MRK depletion sensitizes medulloblastoma primary cells to radiation. We have, therefore, designed and tested a specific small molecule inhibitor of MRK, M443, which binds to MRK in an irreversible fashion and inhibits its activity. We found that M443 strongly radiosensitizes UW228 medulloblastoma cells as well as UI226 patient-derived primary cells, whereas it does not affect the response to radiation of normal brain cells. M443 also inhibits radiation-induced activation of both p38 and Chk2, two proteins that act downstream of MRK and are involved in DNA damage-induced cell-cycle arrest. Importantly, in an animal model of medulloblastoma that employs orthotopic implantation of primary patientderived UI226 cells in nude mice, M443 in combination with radiation achieved a synergistic increase in survival. We hypothesize that combining radiotherapy with M443 will allow us to lower the radiation dose while maintaining therapeutic efficacy, thereby minimizing radiation-induced side effects.

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“…30 L-783277 was found to inhibit MEK2 with an IC 50 of 15 nM, which is in good agreement with the activity originally reported by the Merck group. 29 Activity was also observed at the cellular level, where L-783277 inhibited VEGFR2 autophosphorylation 27 with an IC 50 of 57 nM.…”

mentioning

confidence: 91%

Kinase Inhibition by Deoxy Analogues of the Resorcylic Lactone L-783277

Liniger

Neuhaus

Hofmann

et al. 2010

ACS Med. Chem. Lett.

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The natural product L-783277 is a resorcylic lactone type covalent kinase inhibitor. We have prepared the 5 0 -deoxy analogue of L-783277 (1) in a stereoselective fashion. Remarkably, this analogue retains almost the full kinase inhibitory potential of natural L-783277, with low nanomolar IC 50 values against the most sensitive kinases, and it exhibits essentially the same selectivity profile (within the panel of 39 kinases investigated). In contrast, removal of both the 4 0 -and the 5 0 -hydroxyl groups leads to a more significant reduction in kinase inhibitory activity and so does a change in the geometry of the C7 0 -C8 0 double bond in 1 from Z to E. These findings offer new perspectives for the design of second generation resorcylic lactone-based kinase inhibitors.

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Extended kinase profile and properties of the protein kinase inhibitor nilotinib

Cited by 204 publications

References 46 publications

ZAK is required for doxorubicin, a novel ribotoxic stressor, to induce SAPK activation and apoptosis in HaCaT cells

ZAK is required for doxorubicin, a novel ribotoxic stressor, to induce SAPK activation and apoptosis in HaCaT cells

Pharmacological Inhibition of the Protein Kinase MRK/ZAK Radiosensitizes Medulloblastoma

Kinase Inhibition by Deoxy Analogues of the Resorcylic Lactone L-783277

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