Movers and SHAKERS
Polo-like kinases inhibitors are novel drug targets of cancer therapeutics
We will lose an estimated 9.6 million people due to cancer this year according to the World Health Organization. The report, published in September, also says that cancer is now the second leading cause of death across the globe.
Doctors today are turning to Polo-like kinases in order to develop anti-cancer drugs.
According to an article in the health journal Molecular Cell , “about 150 kinase-targeted drugs are currently being tested in clinical trials, followed by many kinase-specific inhibitors advancing in preclinical stage of drug development."
Translational Oncology highlighted the importance of targeting PLK1 and the homology of various isoform of PLK in a 2017 article saying “PLK1 overexpression has been shown to occur in a wide range of tumors, prompting research and development of PLK1 inhibitors for the treatment of cancer”
The article went on to say, “in humans, five members of the family—PLK1, PLK2, PLK3, PLK4, and PLK5—have been identified, and although a certain degree of homology is observed among the family members, depletion of PLK1 activity is not rescued by the other orthologues and is sufficient to trigger mitotic block and apoptosis of tumor cells.”
It continued stating, “drugs interfering with the normal progression of mitosis such as the taxanes and vinca alkaloids are amongst the most successful chemotherapeutic compounds currently used for anti-cancer treatment. PLK1 is a master regulator of mitosis that is expressed in all proliferating cells and overexpressed in a number of malignant tumors.”
An article in Molecular Cancer Therapeutics journal underlined the unselective profile of suspended PLK inhibitors “BI-2536 and BI-6727” versus selective profile of next generation inhibitors (NMS-P937, Onvansertib) saying, “BI-2536 and BI-6727 are in fact highly potent inhibitors of not only on PLK1, but also on PLK2 and PLK3.”
It also said, “a PLK1 specific inhibitor such as NMS-P937 might show a better long-term safety profile. NMS-P937 with its unique PLK1 selectivity profile coupled with oral bioavailability warrants systematic clinical evaluation.”
Third generation PLK inhibitor (NMS-P937, Onvansertib) is currently being evaluated in human clinical trials. Data from these trials was reported at the American Society of Hematology (ASH) meeting abstract in December 2018. Preliminary efficacy in the evaluable population showed over 80% patient benefit. No drug-related deaths or SAEs have been reported to-date.
Another compound demonstrated selective inhibition of PLK1: “CYC140 selectivity towards PLK1 was tested in vitro in a panel of over 250 kinases. Short pulse treatments of CYC140 were optimized to quantify the maximal difference in cytotoxicity between esophageal cell lines from malignant and non-malignant tissue.” (These data were presented at 28th EORTC-NCI-AACR Molecular Targets and Cancer Therapeutics Symposium).
Despite several programs under development, a complete understanding of Plk1 biology/mechanism is yet to be fully achieved. The relative success with PLK1 inhibitors in preclinical models has not translated well into clinical success.
In 2015, BioMed Research International summarized clinical failures in PLK inhibitor space as, “the essentially of PLK1 for normal cell cycle progression and mitosis has raised lingering questions regarding the targeting value of PLK-1 in cancer chemotherapy.”
The article also stated, “small molecule inhibitors for PLK1 showed substantial inhibitory potential against tumor and induced apoptosis of cancer cells. However, these inhibitors also show a high load of adverse effects, including bone marrow suppression, neutropenia, and heart disease.”
Second generation PLK inhibitor showed limited clinical benefit as stated in an article published on Leukemia journal.
It said clinical development of a PLK1 inhibitor BI 2536 was halted because, “one of the first PLK inhibitors to be developed was BI 2536. Unfortunately, Phase 2 trials in patients with relapsed/refractory solid tumors including 12 non-small-cell lung cancer (NSCLC), 13 small-cell lung cancer, 14 chemotherapy-naïve pancreatic cancer, 15 and relapsed/refractory acute myeloid leukemia (AML) demonstrated that BI 2536 had modest, if any, clinical activity”
Second generation inhibitor volasertib was generated with improved “potency, selectivity, ability to inhibit cell proliferation in vitro, ef?cacy in xenograft models of cancer, drug metabolism and pharmacokinetics (PK) characteristics”
A Nature Medicine article stated the serious adverse events related to PLK inhibitors, “the main reported adverse effects of these inhibitors are hematological alterations such as anemia, neutropenia, and thrombocytopenia, as well as gastrointestinal events, which are probably a consequence of the essential role of PLK1 in the cell cycle. Nonetheless, our data suggest that caution should be taken when using PLK1 inhibitors, as they may have cardiovascular side effects such as hypotension, hemorrhage, and aneurysm, especially with extended treatment or in hypertensive patients. “
The company developing volasertib suspended clinical trials telling the European Medicines Agency in 2018, “Boehringer Ingelheim has taken the decision to generally discontinue development of volasertib. The decision has been taken based on strategic considerations.”
According to a 2017 article published in Translational Oncology, “research should also be directed towards understanding the mechanisms of PLK1 and designing additional next generations of specific, potent PLK1 inhibitors to target cancer. Therefore, the main point of focus is that the small molecule inhibitor should display maximum selectivity and molecular specificity against targets in addition to validation of the essentiality of the target for normal cells in order to minimize side effects.”
A 2012 article in Molecular Cancer Therapeutics journal says, “NMS-P937 (Onvansertib) with its unique PLK1 selectivity profile coupled with oral bioavailability warrants systematic clinical evaluation.”
The presentation at the EORTC-NCI-AACR Molecular Targets and Cancer Therapeutics Symposium stated, “CYC140 selectivity towards PLK1 was tested in vitro in a panel of over 250 kinases” and “maximal difference in cytotoxicity between esophageal cell lines from malignant and non-malignant tissue.”
Lessons learned from previous clinical failures could lead to improved strategies directed toward a valuable target for treatment of cancer. As stated on 2017 Nature Medicine article, “a better understanding of the physiological requirements for PLK1 in different tissues, either as an essential cell cycle kinase or as a RhoA regulator, will undoubtedly improve future therapeutic strategies aimed at inhibiting this kinase in human disease.”
"World Health Organization Cancer detail” Sept. 12th 2018
“World Cancer Report 2014”, Bernard W. Stewart & Christopher P. Wild, World Health Organization
“Kinase-targeted cancer therapies: progress, challenges and future directions”, Khushwant S. Bhullar et al., Mol Cancer, 2018.
“PLK1, A Potential Target for Cancer Therapy”, Zhixian Liu. et al., Translational Oncology, Feb. 2017, 10, 22–32
“PLK1 regulates contraction of postmitotic smooth muscle cells and is required for vascular homeostasis” Guillermo de Carcer. et al., Nature Medicine Volume 23, Number 8, Jul. 10th 2017
“Phase I dose escalation study of NMS-1286937, an orally available Polo-Like Kinase 1 inhibitor, in patients with advanced or metastatic solid tumors” Valsasina B. et al. Molecular Cancer Therapeutics Feb. 7th 2012
“PLK-1 Targeted Inhibitors and Their Potential against Tumorigenesis” Shiv Kumar and Jaebong Kim, BioMed Research International, May 14 2015
“Phase 1b Safety, Preliminary Anti-Leukemic Activity and Biomarker Analyses of the Polo-like Kinase 1 (PLK1) Inhibitor, Onvansertib (NMS-P937), in Combination with Low-Dose Cytarabine or Decitabine in Patients with Relapsed/Refractory Acute Myeloid Leukemia” Amer Zeidan et al. ASH abstract, Dec. 3rd 2018
European Medicines Agency, Jan. 30 2018