P1, N=29, Terminated, Repare Therapeutics | Active, not recruiting --> Terminated; Sponsor decided to terminate study early

Various compounds, such as CFI-400945, centrinone B, and others have been developed to inhibit PLK4 activity...Clinical studies have been initiated with some of these compounds in cancer patients, including those with breast cancer. This manuscript discusses the role of PLK4 as a promising therapeutic target in breast cancer, one of the most common causes of morbidity and mortality in women.

Further, several small-molecule PLK4 inhibitors such as centrinone, YLZ-F5, CFI-400945, and RP-1664 have demonstrated efficacy in targeting PLK4...In this review, we provide a comprehensive overview of the known functions of PLK4 in skin cancer. Additionally, we discuss potential mechanistic insights into PLK4's involvement in skin cancer progression by extrapolating evidence from studies in other cancer types including colorectal cancer, thyroid cancer, lymphomas, leukemia, etc., while identifying gaps for future research.

P2, N=15, Active, not recruiting, Canadian Cancer Trials Group | Trial completion date: Jun 2025 --> Dec 2025

The selective PLK4 inhibitor CFI-400945 exhibits dual anti-tumor activity by promoting terminal differentiation and suppressing proliferation. Our study identifies PLK4 as a potential molecular switch governing NB differentiation and a promising therapeutic target to overcome resistance to 13-cis RA.

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

Notably, despite activation of the DDR responses, DNA damage persisted for 24 or more hours after RT. While some of these observations were cell-line dependent (emphasizing known molecular heterogeneity of TNBC), we highlight that canonical DDR pathways activity in response to RT might be inefficient and modulated by drugs, such as CFI-400945-a cancer cell vulnerability that warrants further investigations for better understanding the biology of TNBC, its responses to treatment and novel drug development.

Furthermore, compound 34b exhibited acceptable in vivo pharmacokinetic properties with the oral bioavailability of 22.1 %. Overall, compound 34b exhibited potent anti-neuroblastoma activities and acceptable pharmacokinetic properties, which served as a favorable lead compound targeting PLK4.

Further, small molecule inhibition of PLK4 activity with centrinone, a specific and reversible inhibitor, and CFI-400945, an ATP-competitive inhibitor, decreased cell viability, proliferation, and clonogenic survival of human cSCC and BCC cells...Overall, this study suggested that PLK4 is a potential therapeutic target and a biomarker for NMSC management. However, additional studies are needed to validate and expand these findings in additional model systems.

P1, N=29, Active, not recruiting, Repare Therapeutics | Recruiting --> Active, not recruiting | N=80 --> 29 | Trial completion date: Jan 2027 --> Oct 2025 | Trial primary completion date: Jan 2027 --> Sep 2025

P1/2, N=72, Active, not recruiting, Treadwell Therapeutics, Inc | Recruiting --> Active, not recruiting

RP-1664 disrupts centriole biogenesis in cancer cells, modulates pharmacodynamic readouts of PLK4 activity in xenograft tumor tissues, and is efficacious in multiple TRIM37-amplified xenograft models. This first-in-class clinical candidate is currently being evaluated in Phase 1 clinical trials (NCT06232408) for treatment of advanced solid tumors.