onvansertib (PCM-075)

The 90% ethanol-aqueous extract of C. asiatica whole plant, which was prepared at room temperature, contained ten bioactive compounds including rutin, quercetin, kaempferol, chlorogenic acid, fisetin, apigenin, asiatic acid, fumaric acid, betulinic acid and ursolic acid identified by UHPLC method. As our findings, rutin was identified as a promising PLK-1 inhibitor that exhibited significant docking score -13.07 and high stability within the binding pockets of PLK-1 protein as compared to control drug onvansertib. Furthermore, experimental validation is urgently needed for future translational research to develop rutin as potent PLK-1 inhibitor for treating cancer.

P1/2, N=50, Active, not recruiting, Antonio Giordano, MD | Trial primary completion date: Feb 2026 --> Dec 2026

These findings suggest that combining PLK1 inhibition with radiation may improve therapeutic response for HPV- HNSCC via MMP10, offering a novel approach to overcome radiation resistance.

We detected the expression of PLK1 in pancreatic cancer tissues and cell lines and study the effects of PLK1 and Gemcitabine on cell viability and apoptosis of GEM-resistant pancreatic cancer PANC-1 cells and Gemcitabine sensitive BxPC-3 cells; Using inhibitors or siRNA, we further investigate the effects of PLK1 on ERK1/2, AKT1, and pro-apoptotic genes PUMA, Bim, and Noxa; We finally investigated the effect of the combined onvansertib and Gemcitabine on the growth of PANC-1 subcutaneous transplant tumors in nude mice and explored its possible mechanism of action...BI2536 (a PLK1 kinase inhibitor) treatment recures the Gemcitabine sensitivity in the PLK -transfected BxPC-3 cells by upregulation of Bim and Noxa expression in vitro...Targeting PLK1 sensitizes PDAC cells to gemcitabine in vitro and in vivo. This indicates that combination therapy with PLK1 inhibitor may overcome gemcitabine resistance, offering a promising new therapeutic option for the treatment of gemcitabine-resistant human pancreatic cancer.

It is well-established that pyruvate dehydrogenase kinase (PDK)-mediated phosphorylation of PDH leads to its inactivation and that dichloroacetic acid (DCA), a PDK inhibitor, has been investigated in preclinical and early clinical studies as a potential therapeutic agent for lung cancer. This study aims to elucidate how PLK1-associated activity drives the metabolic reprogramming from OXPHOS to glycolysis during cellular transformation, thereby contributing to lung carcinogenesis. Our results provide support for a clinical trial to evaluate the efficacy of Onvansertib plus DCA in treating lung cancer.

A recent phase I trial reported a 44% partial response rate of onvansertib, a PLK1 inhibitor, in the treatment of patients with KRAS-mutated metastatic colorectal cancer, indicating that PLK1 inhibitor might be suitable for the treatment of this specific subtype of cancer. This review summarizes the results of preclinical experiments and clinical trials of PLK1 inhibitors, with colorectal cancer as a focus, in hope of facilitating future investigations in this research field.

PLN-5 showed nanomolar inhibitory potency against PLK1 (IC50 = 2.07 ± 0.13 nM) and NRP1 (IC50 = 5.15 ± 0.24 nM), exceeding the positive controls onvansertib and EG00229 by approximately 9-fold and 124-fold, respectively...Importantly, MTT assays showed that PLN-5 had significant antiproliferative activity (IC50 = 0.27 ± 0.02 μM) against human lung cancer cells, with no significant inhibitory effect on normal lung cells. In conclusion, these results demonstrate the therapeutic potential of PLN-5 as a dual-targeting antitumor agent that warrants further development.

The activity of the combinations of onvansertib, an inhibitor of polo-like kinase 1, with gemcitabine or carboplatin was tested using patient-derived xenografts of high-grade serous ovarian carcinoma resistant to cisplatin (DDP). The molecular mechanism underlying the efficacy of the combinations suggests a higher induction of DNA damage which seems plausible considering that, in both cases, gemcitabine and carboplatin, respectively, interfere with DNA metabolism and induce alkylation damage. The results suggest that the combinations of onvansertib/gemcitabine and onvansertib/carboplatin are safe and were shown to be of therapeutic value in the platinum-resistant setting of ovarian carcinoma, strongly supporting their clinical translatability.

The combination of onvansertib with paclitaxel demonstrated a synergistic effect in cell proliferation inhibition via inducing cell apoptosis and DNA damage. Our results provide preclinical evidence that onvansertib may be an effective strategy to treat USC and deserves further evaluation in animal models and clinical trials.

P2, N=113, Active, not recruiting, Cardiff Oncology | Recruiting --> Active, not recruiting

Plk1 is involved in the development of resistances to chemotherapeutics such as doxorubicin, Taxol, and gemcitabine. In summary, these results suggest that onvansertib is causing cells within the spheroid to halt at a certain phase of the cell cycle in accordance with previous literature. Our findings suggest the S phase is likely interrupted, with observed alterations in cell cycle control proteins and PC lipid abundance.

Onvansertib treatment for 4 weeks significantly reduced tumor growth in LKB1fl/flp53fl/fl mice. Given these promising pre-clinical results, further studies are needed to evaluate the clinical translatability of onvansertib combined with paclitaxel as an effective treatment for endometrial cancer.