BI 6727, A Polo-like Kinase Inhibitor with Improved Pharmacokinetic Profile and Broad Antitumor Activity

Rudolph, Dorothea; Steegmaier, Martin; Hoffmann, M.; Grauert, Matthias; Baum, Anke; Quant, Jens; Haslinger, Christian; Garin‐Chesa, Pilar; Adolf, Günther R.

doi:10.1158/1078-0432.ccr-08-2445

Cited by 340 publications

(402 citation statements)

References 46 publications

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“…In addition, tissue culture experiments show that cells treated with MLN0905 undergo a strong mitotic arrest followed by subsequent apoptosis (10), phenotypes consistently showed to be associated with PLK1 inhibition (using both small-molecule and genetic knockdown approaches; refs. [11][12][13][14]. Tissue culture cell viability experiments show that MLN0905 yields LD 50 values in the double-digit nanomolar range for solid tumor cell lines (10).…”

Section: Introductionmentioning

confidence: 99%

MLN0905, a Small-Molecule PLK1 Inhibitor, Induces Antitumor Responses in Human Models of Diffuse Large B-cell Lymphoma

Shi¹,

Lasky²,

Shinde³

et al. 2012

Molecular Cancer Therapeutics

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Diffuse large B-cell lymphoma (DLBCL) is the most common of the non-Hodgkin lymphomas, accounting for up to 30% of all newly diagnosed lymphoma cases. Current treatment options for this disease are effective, but not always curative; therefore, experimental therapies continue to be investigated. We have discovered an experimental, potent, and selective small-molecule inhibitor of PLK1, MLN0905, which inhibits cell proliferation in a broad range of human tumor cells including DLBCL cell lines. In our report, we explored the pharmacokinetic, pharmacodynamic, and antitumor properties of MLN0905 in DLBCL xenograft models grown in mice. These studies indicate that MLN0905 modulates the pharmacodynamic biomarker phosphorylated histone H3 (pHisH3) in tumor tissue. The antitumor activity of MLN0905 was evaluated in three human subcutaneous DLBCL xenograft models, OCI LY-10, OCI LY-19, and PHTX-22L (primary lymphoma). In each model, MLN0905 yielded significant antitumor activity on both a continuous (daily) and intermittent dosing schedule, underscoring dosing flexibility. The antitumor activity of MLN0905 was also evaluated in a disseminated xenograft (OCI LY-19) model to better mimic human DLBCL disease. In the disseminated model, MLN0905 induced a highly significant survival advantage. Finally, MLN0905 was combined with a standard-of-care agent, rituximab, in the disseminated OCI LY-19 xenograft model. Combining rituximab and MLN0905 provided both a synergistic antitumor effect and a synergistic survival advantage. Our findings indicate that PLK1 inhibition leads to pharmacodynamic pHisH3 modulation and significant antitumor activity in multiple DLBCL models. These data strongly suggest evaluating PLK1 inhibitors as DLBCL anticancer agents in the clinic. Mol Cancer Ther; 11(9); 2045-53. Ó2012 AACR.

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Section: Introductionmentioning

confidence: 99%

MLN0905, a Small-Molecule PLK1 Inhibitor, Induces Antitumor Responses in Human Models of Diffuse Large B-cell Lymphoma

Shi¹,

Lasky²,

Shinde³

et al. 2012

Molecular Cancer Therapeutics

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“…The reason for clinical anticancer activity of volasertib, in contrast to the first-generation Plk1 inhibitor BI2536, which has similar potency on Plk1, is likely due to the fact that volasertib has a large volume of distribution and a long half-life in humans of up to 110 hours. Such sustained exposure conceivably is able to cause mitotic arrest of proliferating cancer cells as they progress into mitosis and also sustained SAC activation for induction of apoptosis (42,43).…”

Section: Discussionmentioning

confidence: 99%

A Novel Eg5 Inhibitor (LY2523355) Causes Mitotic Arrest and Apoptosis in Cancer Cells and Shows Potent Antitumor Activity in Xenograft Tumor Models

Fan

Horn

et al. 2015

Molecular Cancer Therapeutics

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Intervention of cancer cell mitosis by antitubulin drugs is among the most effective cancer chemotherapies. However, antitubulin drugs have dose-limiting side effects due to important functions of microtubules in resting normal cells and are often rendered ineffective by rapid emergence of resistance. Antimitotic agents with different mechanisms of action and improved safety profiles are needed as new treatment options. Mitosis-specific kinesin Eg5 represents an attractive anticancer target for discovering such new antimitotic agents, because Eg5 is essential only in mitotic progression and has no roles in resting, nondividing cells. Here, we show that a novel selective Eg5 inhibitor, LY2523355, has broad target-mediated anticancer activity in vitro and in vivo. LY2523355 arrests cancer cells at mitosis and causes rapid cell death that requires sustained spindle-assembly checkpoint (SAC) activation with a required threshold concentration. In vivo efficacy of LY2523355 is highly dose/schedule-dependent, achieving complete remission in a number of xenograft tumor models, including patient-derived xenograft (PDX) tumor models. We further establish that histone-H3 phosphorylation of tumor and proliferating skin cells is a promising pharmacodynamic biomarker for in vivo anticancer activity of LY2523355.

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“…Due to its high specificity for PLK1, NMS-P937 may be preferred over less specific compounds like GW843682X, BI 2536 and BI 6727, which are known to also target PLK2/3 and other kinases. 44,49,50 A phase I trial with NMS-P937 in adults with advanced solid tumors has recently been completed (clinicaltrials.gov identifier: NCT01014429).…”

Section: Discussionmentioning

confidence: 99%

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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BI 6727, A Polo-like Kinase Inhibitor with Improved Pharmacokinetic Profile and Broad Antitumor Activity

Cited by 340 publications

References 46 publications

MLN0905, a Small-Molecule PLK1 Inhibitor, Induces Antitumor Responses in Human Models of Diffuse Large B-cell Lymphoma

MLN0905, a Small-Molecule PLK1 Inhibitor, Induces Antitumor Responses in Human Models of Diffuse Large B-cell Lymphoma

A Novel Eg5 Inhibitor (LY2523355) Causes Mitotic Arrest and Apoptosis in Cancer Cells and Shows Potent Antitumor Activity in Xenograft Tumor Models

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

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