NMS-P937, a 4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline derivative as potent and selective Polo-like kinase 1 inhibitor

Beria, Italo; Bossi, R.; Brasca, Maria Gabriella; Caruso, Michele; Ceccarelli, Walter; Fachin, Gabriele; Fasolini, Marina; Forte, Barbara; Fiorentini, Francesco; Pesenti, Enrico; Pezzetta, Daniele; Posteri, Helena; Scolaro, Alessandra; Depaolini, Stefania Re; Valsasina, Barbara

doi:10.1016/j.bmcl.2011.03.054

Cited by 80 publications

(52 citation statements)

References 13 publications

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“…Evaluation of the selectivity of inhibitors (IC 50 s) against a panel of kinases was performed using a radiometric assay format as previously described (32). All assays were performed in house, with the exception of TRKB and TRKC, for which IC 50 s were extrapolated from percentage inhibition values at 10 and 100 nmol/L of inhibitor in duplicate obtained using the SelectScreen Kinase Profiling Services from Life Technologies using the equation:…”

Section: Kinase Biochemical Profilingmentioning

confidence: 99%

Entrectinib, a Pan–TRK, ROS1, and ALK Inhibitor with Activity in Multiple Molecularly Defined Cancer Indications

Ardini

Menichincheri

Banfi

et al. 2016

Molecular Cancer Therapeutics

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Activated ALK and ROS1 tyrosine kinases, resulting from chromosomal rearrangements, occur in a subset of non-small cell lung cancers (NSCLC) as well as other tumor types and their oncogenic relevance as actionable targets has been demonstrated by the efficacy of selective kinase inhibitors such as crizotinib, ceritinib, and alectinib. More recently, low-frequency rearrangements of TRK kinases have been described in NSCLC, colorectal carcinoma, glioblastoma, and Spitzoid melanoma. Entrectinib, whose discovery and preclinical characterization are reported herein, is a novel, potent inhibitor of ALK, ROS1, and, importantly, of TRK family kinases, which shows promise for therapy of tumors bearing oncogenic forms of these proteins. Proliferation profiling against over 200 human tumor cell lines revealed that entrectinib is exquisitely potent in vitro against lines that are dependent on the drug's pharmacologic targets. Oral administration of entrectinib to tumor-bearing mice induced regression in relevant human xenograft tumors, including the TRKA-dependent colorectal carcinoma KM12, ROS1-driven tumors, and several ALK-dependent models of different tissue origins, including a model of brain-localized lung cancer metastasis. Entrectinib is currently showing great promise in phase I/II clinical trials, including the first documented objective responses to a TRK inhibitor in colorectal carcinoma and in NSCLC. The drug is, thus, potentially suited to the therapy of several molecularly defined cancer settings, especially that of TRK-dependent tumors, for which no approved drugs are currently available.

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Section: Kinase Biochemical Profilingmentioning

confidence: 99%

Entrectinib, a Pan–TRK, ROS1, and ALK Inhibitor with Activity in Multiple Molecularly Defined Cancer Indications

Ardini

Menichincheri

Banfi

et al. 2016

Molecular Cancer Therapeutics

Self Cite

248

191

View full text Add to dashboard Cite

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“…An explanation for the excellent selectivity profile of NMS-P937 is its binding mode in the ATP pocket as evident in the X-ray cocrystal structure of the PLK1 kinase domain and NMS-P937, described by Beria and colleagues (24). Briefly, the compound binds to the ATP pocket of the PLK1 kinase domain in the active conformation (type I inhibitor) and hydrogen bonds are formed with key residues in the kinase hinge region.…”

Section: Kinase Inhibitionmentioning

confidence: 99%

NMS-P937, an Orally Available, Specific Small-Molecule Polo-like Kinase 1 Inhibitor with Antitumor Activity in Solid and Hematologic Malignancies

Valsasina

Beria

Alli

et al. 2012

Molecular Cancer Therapeutics

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Polo-like kinase 1 (PLK1) is a serine/threonine protein kinase considered to be the master player of cell-cycle regulation during mitosis. It is indeed involved in centrosome maturation, bipolar spindle formation, chromosome separation, and cytokinesis. PLK1 is overexpressed in a variety of human tumors and its overexpression often correlates with poor prognosis. Although five different PLKs are described in humans, depletion or inhibition of kinase activity of PLK1 is sufficient to induce cell-cycle arrest and apoptosis in cancer cell lines and in xenograft tumor models. NMS-P937 is a novel, orally available PLK1-specific inhibitor. The compound shows high potency in proliferation assays having low nanomolar activity on a large number of cell lines, both from solid and hematologic tumors. NMS-P937 potently causes a mitotic cell-cycle arrest followed by apoptosis in cancer cell lines and inhibits xenograft tumor growth with clear PLK1-related mechanism of action at well-tolerated doses in mice after oral administration. In addition, NMS-P937 shows potential for combination in clinical settings with approved cytotoxic drugs, causing tumor regression in HT29 human colon adenocarcinoma xenografts upon combination with irinotecan and prolonged survival of animals in a disseminated model of acute myelogenous leukemia in combination with cytarabine. NMS-P937, with its favorable pharmacologic parameters, good oral bioavailability in rodent and nonrodent species, and proven antitumor activity in different preclinical models using a variety of dosing regimens, potentially provides a high degree of flexibility in dosing schedules and warrants investigation in clinical settings.

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“…NMS-P937 is an ATP-competitive compound that binds the ATP-pocket of PLK1, not including the Thr210 phosphorylation site. 25 The inhibitory effect of the compound is unlinked to the Thr210 phosphorylation level of PLK1, as demonstrated by the initial increase of Thr210 phosphorylation levels in response to NMS-P937 43 and our observation that PLK1 phosphorylation levels, in contrast to total PLK1 protein levels, are not correlated to sensitivity to NMS-P937. In line with the effective concentrations found in this study, Valsasina et al showed that NMS-P937 inhibited proliferation of a range of solid tumor and leukemia cell lines at mid-nanomolar concentrations.…”

Section: Discussionmentioning

confidence: 71%

Inhibiting Polo-like kinase 1 causes growth reduction and apoptosis in pediatric acute lymphoblastic leukemia cells

et al. 2013

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This study investigated Polo-like kinase 1, a mitotic regulator often over-expressed in solid tumors and adult hematopoietic malignancies, as a potential new target in the treatment of pediatric acute lymphoblastic leukemia. Polo-like kinase 1 protein and Thr210 phosphorylation levels were higher in pediatric acute lymphoblastic leukemia (n=172) than in normal bone marrow mononuclear cells (n=10) (P<0.0001). High Polo-like kinase 1 protein phosphorylation, but not expression, was associated with a lower probability of event-free survival (P=0.042) and was a borderline significant prognostic factor (P=0.065) in a multivariate analysis including age and initial white blood cell count. Polo-like kinase 1 was necessary for leukemic cell survival, since short hairpin-mediated Polo-like kinase 1 knockdown in acute lymphoblastic leukemia cell lines inhibited cell proliferation by G2/M cell cycle arrest and induced apoptosis through caspase-3 and poly (ADP-ribose) polymerase cleavage. Primary patient cells with a high Polo-like kinase 1 protein expression were sensitive to the Polo-like kinase 1-specific inhibitor NMS-P937 in vitro, whereas cells with a low expression and normal bone marrow cells were resistant. This sensitivity was likely not caused by Polo-like kinase 1 mutations, since only one new mutation (Ser335Arg) was found by 454-sequencing of 38 pediatric acute lymphoblastic leukemia cases. This mutation did not affect Polo-like kinase 1 expression or NMS-P937 sensitivity. Together, these results indicate a pivotal role for Polo-like kinase 1 in pediatric acute lymphoblastic leukemia and show potential for Polo-like kinase 1-inhibiting drugs as an addition to current treatment strategies for cases expressing high Polo-like kinase 1 levels. ABSTRACTinhibitor highly selective for PLK1 and the first orally administered selective PLK1 inhibitor entering phase I clinical trials 25 (clinicaltrials.gov identifier: NCT01014429). This study shows the potential of PLK1-targeting therapeutics in the treatment of childhood ALL, and indicates their value for further clinical evaluation. Methods Cell linesCell lines (DSMZ, Braunschweig, Germany) were cultured in RPMI+Glutamax with pen-strep, fungizone (Life Technologies, Bleiswijk, The Netherlands) and 10% or 20% fetal calf serum (Integro, Zaandam, The Netherlands), at 37ºC and 5% CO 2 .

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NMS-P937, a 4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline derivative as potent and selective Polo-like kinase 1 inhibitor

Cited by 80 publications

References 13 publications

Entrectinib, a Pan–TRK, ROS1, and ALK Inhibitor with Activity in Multiple Molecularly Defined Cancer Indications

Entrectinib, a Pan–TRK, ROS1, and ALK Inhibitor with Activity in Multiple Molecularly Defined Cancer Indications

NMS-P937, an Orally Available, Specific Small-Molecule Polo-like Kinase 1 Inhibitor with Antitumor Activity in Solid and Hematologic Malignancies

Inhibiting Polo-like kinase 1 causes growth reduction and apoptosis in pediatric acute lymphoblastic leukemia cells

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