Finally, the contributing role of KIFC1 and the inhibitory effect of TRIM37 on EC development and metastasis was verified in a nude mouse xenograft model. Our study elucidated that KIFC1 depends on TRIM37-mediated reduced ubiquitination degradation of PLK4 to promote centrosome amplification and EC progression, thus providing a potential prognostic marker and promising therapeutic target for EC in the future.

P1, N=13, Completed, University Health Network, Toronto | Active, not recruiting --> Completed

NL13, a novel PLK4-targeted curcumin analogue, exerts promising anticancer properties against prostate cancer by disrupting the PLK4-AKT-CCNB1/CDK1 and apoptosis pathways. NL13 represents a promising new agent for prostate cancer therapy.

P2, N=15, Active, not recruiting, Canadian Cancer Trials Group | Trial completion date: Dec 2022 --> Dec 2024

Uterine LMS with DNA repair defects is sensitive to PLK4 inhibition because of the effects of chromosome missegregation and increased DNA damage. Loss-of-function BRCA2 alterations or pharmacological inhibition of ATM enhanced the efficacy of PLK4 inhibitor. Genomic profiling of an advanced-stage or recurrent uterine LMS may guide therapy.

P1, N=13, Active, not recruiting, University Health Network, Toronto | Trial completion date: Mar 2024 --> Jun 2024 | Trial primary completion date: Jun 2021 --> Jun 2024

In contrast to the regulation of PLK4 by SCFβ-TrCP, the interaction between PLK4 and DCAF1 is independent of PLK4 kinase activity and mediated by polo-boxes 1 and 2 of PLK4, suggesting that DCAF1 promotes PLK4 ubiquitylation independently of β-TrCP. Thus, the SCFSlimb/β-TrCP pathway, targeting PLK4 for ubiquitylation based on its phosphorylation state and CRL4DCAF1, which ubiquitylates PLK4 by binding to the conserved PB1-PB2 domain, appear to be complementary ways to control PLK4 abundance to prevent centriole overduplication.

P1, N=80, Recruiting, Repare Therapeutics | Not yet recruiting --> Recruiting

Furthermore, HIV-1 WT, but not its Vpr mutant, induces multiple centrosomes and aneuploidy in human primary CD4+ T cells. We propose that the Vpr•VprBP•Plk4 complex serves as a molecular link that connects HIV-1 infection to oncogenesis and that inhibiting the Vpr C-terminal motif may reduce the occurrence of HIV-1-associated cancers.

Tumor PLK4 immunohistochemistry score >3 was linked with shortened disease-free survival (p = 0.026) and overall survival (p = 0.028) and independently predicted poorer disease-free survival (hazard ratio: 2.797; p = 0.040). Tumor PLK4 reflects extrathyroidal invasion, higher tumor stage and shortened survival in PTC.

Increased PLK4 levels in cells with C-Nap1 and Rootletin knock-out resulted with distanced CRs and CRCs in interphase, while Nek2 knock-out inhibited separation of CRCs in prometaphase, providing functional evidence for the binding of CRC structures with centrosomal linker proteins. Taken together, these results suggest a cell cycle dependent model for PLK4 induced centrosome amplification which occurs in 2 consecutive cell cycles: (i) CR state in the first cell cycle, and (ii) CRC state in the second cell cycle.

In our previous studies, we showed that inhibition of Polo-like Kinase 4 (PLK4) by a novel drug, CFI-400945 significantly enhances the anticancer effects of radiotherapy (RT) compared to single treatment alone...Our data suggest that PLK4 is a promising target for enhancing the anticancer effects of RT in TNBC that, at least in part, is modulated by the overamplification of centrioles. These results support further mechanistic and translational studies of anti-PLK4 agents and RT as an anticancer combination treatment strategy.

P1/2, N=72, Recruiting, Treadwell Therapeutics, Inc | Trial completion date: Jan 2024 --> Jan 2026 | Trial primary completion date: Jan 2024 --> Jan 2026

P2, N=51, Active, not recruiting, Canadian Cancer Trials Group | Trial completion date: Jun 2024 --> Dec 2025 | Trial primary completion date: Dec 2023 --> Dec 2024

A tumor PLK4 IHC score > 6 or > 3 associates with shortened DFS and OS in EC patients who undergo surgical resection.

Additionally, the expression of PLK4 protein exhibited a positive correlation with AKT1 phosphorylation in glioma patient tissues. These findings highlight the pivotal role of PLK4-mediated phosphorylation of AKT1 in glioma tumorigenesis and dysregulation of glucose metabolism.

P1, N=80, Not yet recruiting, Repare Therapeutics

P1, N=13, Active, not recruiting, University Health Network, Toronto | Trial completion date: Dec 2023 --> Mar 2024

As such, numerous small-molecule inhibitors with distinct chemical scaffolds targeting PLK4 have been extensively investigated for the treatment of different human cancers, with several undergoing clinical evaluation (e.g., CFI-400945). Here, we review the structure, distribution, and biological functions of PLK4, encapsulate its intricate regulatory mechanisms of expression, and highlighting its multifaceted roles in cancer development and metastasis. Moreover, the recent advancements of PLK4 inhibitors in patent or literature are summarized, and their therapeutic potential as monotherapies or combination therapies with other anticancer agents are also discussed.

Similarly, knockdown of PLK4 reduced the centrosomal distribution of CCDC85C. Our results suggest that Cd activates ROS-GCLM pathway that triggers the expression of and binding between CCDC85C and PLK4, and promotes the translocation of CCDC85C-PLK4 complex to the centrosomes, which eventually leads to CA.

P1/2, N=72, Recruiting, Treadwell Therapeutics, Inc

Dose-limiting toxicity was enteritis/colitis. A monotherapy and combination therapy study with a newer crystal form of CFI-400945 in patients with AML, MDS and chronic myelomonocytic leukemia (CMML) is ongoing (NCT04730258).

No abstract available

In vivo, PLK4 inhibition also induced cytokine and chemokine expression in mouse recipients and its combination with anti-CD47 antibody, which inhibited the "don't-eat-me" signal in macrophages, synergistically reduced leukemic burden and prolonged animal survival. The study shed important light on the pathogenetic role of PLK4 and might lead to novel therapeutic strategies in TP53 mutated AML.

ConclusionOur data indicate that HDAC inhibitor Chidamide significantly synergizes GL-V9-induced cell growth inhibition, apoptosis, and cell cycle arrest in AML, and the underlying mechanism by suppressing the expression of ESPL1 and PLK4, the key regulators of cell division and proliferation. Our results also provide a potential chemotherapy-free option for AML patients.

P1/2, N=72, Recruiting, Treadwell Therapeutics, Inc | Phase classification: P1b/2 --> P1/2

No abstract available

Background: CFI-400945 is a potent, selective, orally administered, first-in-class inhibitor of the serine/threonine kinase Polo-like kinase 4 (PLK4), a unique Polo-like kinase family member, that is a conserved upstream regulator of centriole duplication. CFI-400945 has been generally well tolerated in this difficult to treat patient population, including patients whose disease progressed on or following venetoclax based therapies. Three of 6 evaluable patients with AML achieved a response (MLFS=2, CRi=1) at the 96mg dose. PK characteristics support daily dosing of CFI-400945 and PD studies are ongoing.

PLK4 expression and pathways that were highly correlated with PLK4 expression levels were upregulated in patients with LUAD with the TP53 mutation. (4) PLK4 expression affects the survival of patients with LUAD and is a potential therapeutic target for LUAD with TP53 mutations.

At the cellular level, it presented excellent antiproliferative activity against breast cancer cells. Taken together, these results suggest that compound 8h has potential value in the further research of PLK4-targeted anticancer drugs.

P2, N=51, Active, not recruiting, Canadian Cancer Trials Group | Trial completion date: Jun 2023 --> Jun 2024 | Trial primary completion date: Jun 2023 --> Dec 2023

Subsequently, centrinone plus sorafenib reduced cell viability, promoted cell apoptosis, facilitated cell cycle at G2/M phase and repressed Wnt/β-catenin signaling more effectively compared with centrinone or sorafenib monotherapy in C643 and 8305c cells (all P < .05). PLK4 inhibitor exhibits antitumor effect and synergizes sorafenib via arresting cell cycle and inactivating Wnt/β-catenin pathway in ATC.

Moreover, SP27 showed 149% bioavailability after intraperitoneal administration in PK studies and potent antitumor efficacy in vivo. The discovery of SP27 demonstrated the practicality and importance of PLK4 PROTAC and paved the way for studying PLK4-dependent biological functions and treat TRIM37-amplified breast cancer.

Our findings reveal that downregulation of PLK4-induced autophagy contributes to tumor dormancy and autophagy inhibition leads to apoptosis of CRC dormant cells. Our study is the first to report that downregulation PLK4 induced autophagy is an early event in CRC dormancy and highlights autophagy inhibitor as a potential therapeutic target for dormant cell elimination.

To examine the therapeutic mechanisms, transcriptome analyses were performed and differentially expressed genes (DEGs) induced by PLK4 inhibitor CFI-400945 were examined in TP53 mutated AML cell line (KO52)... The observations supported a novel PLK4/PRMT5/EZH2/H3K27me3 axis that might account for the anti-leukemiceffects of PLK4 inhibition on TP53 mutated AML. Acknowledgements: This research was supported by Health@InnoHK, Innovation and Technology Commission of the HKSAR, Theme- based Research Scheme (T12-702/20-N), HMRF (08191906), Li Shu Fan Medical Foundation, Ying Wan Leung Research Fund and Collaborative Research Fund (C7028-19G), and Tang King Ying Research Fund.

We identify a previously unknown role for NUAK1 in regulating accurate centrosome duplication and show that loss of NUAK1 triggers genomic instability. The latter activity is conserved in primary fibroblasts, raising the possibility of undesirable genotoxic effects of NUAK1 inhibition.

Consequently, the combination of drugs that induce polyploidy with the BCL-2 inhibitor Venetoclax is highly synergistic and safe against xenograft and PDX models. We show that B cell lymphomas are ill-equipped for acute, therapy-induced polyploidy and that BCL-2 inhibition further enhances the removal of polyploid lymphoma cells.

In cell viability assays, selective PLK4 inhibitors were potent in the parental G95 cells and lost activity in L95 cells, unlike less selective inhibitors whose potency did not depend on PLK4. Oral dosing of a selective PLK4 inhibitor resulted in tumor growth inhibition in TRIM37 high xenograft tumors with no body weight loss.In summary, we have discovered that highly selective small molecule inhibitors of PLK4 confirm the potential of the synthetic lethal impact in treating tumors with high levels of TRIM37.

These findings demonstrated that targeting PLK4 can induce apoptosis, G2/M and ER stress in AML cells.

Interestingly, immune cell infiltration analysis showed that the dendritic cells, macrophages, and so forth might play important role in HCC progress. In brief, we provides a roadmap for screening functional genes related to HCC invasion and metastasis in vivo, which may provide new potential targets for the treatment of HCC.

In the K562 cells xenograft mouse model, a 20 mg/kg/day dosage treatment obviously suppressed tumor progression. As a potential and novel PLK4-targeted candidate drug for CML, compound B43 is undergoing extensive preclinical safety evaluation.