The advent of molecularly targeted drug discovery has facilitated the identification of a new generation of anti-mitotic therapies that target proteins with specific functions in mitosis. The exquisite selectivity for mitosis and the distinct ways in which these new agents interfere with mitosis provides the potential to not only overcome certain limitations of current tubulin-targeted anti-mitotic drugs, but to expand the scope of clinical efficacy that those drugs have established. The development of these new anti-mitotic drugs as targeted therapies faces significant challenges; nevertheless, these potential therapies also serve as unique tools to dissect the molecular mechanisms of the mitotic-checkpoint response.

Targeted anti-mitotic therapies: can we improve on tubulin agents?

Polo-like kinase 1 (PLK1) plays key roles in the regulation of mitotic progression, including mitotic entry, spindle formation, chromosome segregation, and cytokinesis. PLK1 expression and activity are strongly linked to proliferating cells. Many studies have shown that PLK1 expression is elevated in a variety of tumors, and high expression often correlates with poor prognosis. Using a variety of methods, including small-molecule inhibition of PLK1 function and/or activity, apoptosis in cancer cell lines, cell cycle arrest in normal cell lines, and antitumor activity in vivo have been observed. In the present study, we have examined the in vitro biological activity of a novel and selective thiophene benzimidazole ATP-competitive inhibitor of PLK1 and PLK3 (5-(5,6-dimethoxy-1H-benzimidazol-1-yl)-3-{[2-(trifluoromethyl)-benzyl]oxy}thiophene-2-carboxamide, called compound 1). Compound 1 has low nanomolar activity against the PLK1 and PLK3 enzymes and potently inhibits the proliferation of a wide variety of tumor cell lines. In the lung adenocarcinoma cell line NCI-H460, compound 1 induces a transient G(2)-M arrest, mitotic spindle defects, and a multinucleate phenotype resulting in apoptosis, whereas normal human diploid fibroblasts arrest in G(2)-M and show little apoptosis. We also describe a cellular mechanistic assay that was developed to identify potent intracellular inhibitors of PLK1. In addition to its potential as a therapeutic agent for treating cancer, compound 1 is also a useful tool molecule for further investigation of the biological functions of PLK1 and PLK3.

https://mct.aacrjournals.org/content/molcanther/6/2/450.full.pdf

In vitro biological activity of a novel small-molecule inhibitor of polo-like kinase 1

Polo-like kinase 1 (Plk1) is a conserved serine/threonine kinase that plays an essential role in regulating the many processes involved in mitotic entry and progression. In humans, Plk1 is expressed primarily during late G(2) and M phases and, in conjunction with Cdk1/cyclin B1, acts as master regulatory kinases for the myriad protein substrates involved in mitosis. Plk1 overexpression is strongly associated with cancer and has been correlated with poor prognosis in a broad range of human tumor types. We have identified a potent, selective, reversible, ATP-competitive inhibitor of Plk1, GSK461364A, capable of inhibiting cell growth of most proliferating cancer cell lines tested. We observe distinct cell cycle effects of GSK461364A depending on the dose used. The predominant phenotype for cells treated with GSK461364A is prometaphase arrest with characteristic collapsed polar polo spindle. At high concentrations, GSK461364A delays mitotic entry in G(2) followed by gradual progression into terminal mitosis; in some cell lines, this correlates with decreased apoptosis. Cell culture growth inhibition by GSK461364A can be cytostatic or cytotoxic but leads to tumor regression in xenograft tumor models under proper dose scheduling. Finally, we describe pharmacodynamic biomarkers of GSK461364A activity (pHH3 and Plk1) that are currently being evaluated in human cancer clinical trials.

https://cancerres.aacrjournals.org/content/canres/69/17/6969.full.pdf

Distinct Concentration-Dependent Effects of the Polo-like Kinase 1-Specific Inhibitor GSK461364A,Including Differential Effect on Apoptosis

https://www.jto.org/article/S1556-0864(15)30553-0/pdf

The Efficacy and Safety of BI 2536, a Novel Plk-1 Inhibitor, in Patients with Stage IIIB/IV Non-small Cell Lung Cancer Who Had Relapsed after, or Failed, Chemotherapy Results from an Open-Label, Randomized Phase II Clinical Trial

Purpose We conducted a first-in-man (to our knowledge) phase I study to determine the dose-limiting toxicities (DLTs), characterize the pharmacokinetic profile, and document any antitumor activity of ON 01910.Na, a new chemical entity that arrests cancer cells in G2/M by modulating mitotic regulatory pathways including polo-like kinase 1 (Plk1). Patients and Methods Patients had solid tumors refractory to standard therapy. ON 01910.Na was administered as a 2-hour infusion on days 1, 4, 8, 11, 15, and 18 in 28-day cycles. The starting dose was 80 mg, and an accelerated titration schedule (single-patient cohorts) was used for escalation. Pharmacokinetics were studied on days 1 and 15 of cycle 1. Results Twenty patients (11 women and nine men; age 46 to 73 years) were enrolled onto the study. Dose levels of 80, 160, 320, 480, 800, 1,280, 2,080, and 3,120 mg were evaluated in single-patient cohorts. A DLT and additional grade 2 toxicities made the 4,370-mg dose (n = 6) not tolerable, and the next lower dose c...

https://ascopubs.org/doi/pdf/10.1200/JCO.2008.17.9788

Phase I Study of ON 01910.Na, a Novel Modulator of the Polo-Like Kinase 1 Pathway, in Adult Patients With Solid Tumors

3069 Background: BI 2536 is a novel highly potent and selective inhibitor of the serine-threonine Polo-like kinase 1 (Plk1), a key regulator of cell cycle progression. Objectives of this trial were...

A phase I study of two administration schedules of the Polo-like kinase 1 inhibitor BI 2536 in patients with advanced solid tumors

2038 Background: BI 2536 is a novel highly potent and selective inhibitor of the serine-threonine kinase polo-like kinase 1 (Plk1), which is a key regulator of cell cycle progression. Objectives of...

A phase I repeated dose escalation study of the Polo-like kinase 1 inhibitor BI 2536 in patients with advanced solid tumours

M146 Architect/alinity tumormarker assays: Can results be used mutually interchangeably?

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A phase I study of two administration schedules of the Polo-like kinase 1 inhibitor BI 2536 in patients with advanced solid tumors

A phase I repeated dose escalation study of the Polo-like kinase 1 inhibitor BI 2536 in patients with advanced solid tumours

M146 Architect/alinity tumormarker assays: Can results be used mutually interchangeably?