pidnarulex (CX-5461)

When combined with cisplatin, CX-5461 enhances the sensitivity of cervical cancer cells to this chemotherapeutic agent. In conclusion, CX-5461 demonstrates potential therapeutic value for cervical cancer, particularly as a new strategy for patients with primary or platinum-resistant disease.

Interfering with TFEB improved the sensitivity of cancer cells to both CX-5461 and gemcitabine. Our findings suggest that TFEB provides broad protection against the stress caused by chemotherapeutic drugs, representing a promising target for intercepting chemoresistance and improving the efficacy of anticancer agents.

P1/2, N=50, Recruiting, National Cancer Institute (NCI) | Not yet recruiting --> Recruiting | Trial completion date: Sep 2027 --> Jan 2030 | Initiation date: Mar 2026 --> Oct 2026 | Trial primary completion date: Sep 2027 --> Jan 2030

P1, N=36, Recruiting, National Cancer Institute (NCI) | Not yet recruiting --> Recruiting | Initiation date: Mar 2026 --> Oct 2026

P1, N=36, Not yet recruiting, National Cancer Institute (NCI) | Trial completion date: Mar 2027 --> Jan 2028 | Trial primary completion date: Mar 2027 --> Jan 2028

P1/2, N=50, Not yet recruiting, National Cancer Institute (NCI) | Initiation date: Dec 2025 --> Mar 2026

P1/2, N=86, Not yet recruiting, National Cancer Institute (NCI) | Initiation date: Dec 2025 --> Mar 2026

P1, N=36, Not yet recruiting, National Cancer Institute (NCI) | Initiation date: Dec 2025 --> Mar 2026

Our study examined two "first-in-class" RNA Pol I inhibitors, CX-5461 and BMH-21, which differentially regulate NK cell-activating and inhibitory ligand expression in MM. This effect was modulated by Lenalidomide and Panobinostat. Moreover, RNA Pol I inhibition enhanced Daratumumab-mediated antibody-dependent cellular cytotoxicity (ADCC) of NK cells against MM, uncovering novel immuno-mediated antitumor mechanisms.

This is particularly important given that several clinical trials, including a Phase Ib study of CX-5461 in patients with solid tumours [ NCT04890613 ] and a National Cancer Institute sponsored Phase I trial [ NCT06606990 ] are currently enrolling patients. These ongoing and planned clinical efforts highlight both the therapeutic promise of CX-5461 and the importance of evaluating this agent within rigorous and clinically relevant frameworks.

To investigate the therapeutic potential of three G4 ligands-pidnarulex, APTO-253, and BRACO-19-a high-throughput drug combination screen was conducted in thirty-one multi-cell type tumor spheroids derived from patient tumors and established cancer cell lines. Brightfield imaging corroborated enhanced spheroid growth suppression from synergistic combinations. These findings underscore the context-dependent activity of G4 ligands and support the use of integrated functional and imaging-based approaches to characterize potential therapeutic combinations in physiologically relevant 3D cancer models.

In this study, we examine the response of HGSOC cells to standard of care cisplatin chemotherapy and to the RNA Polymerase I transcription inhibitor CX-5461/Pidnarulex, two drugs that elicit a potent DNA damage response and growth arrest. Mechanistically, we demonstrate that senescent HGSOC cells have altered expression of regulators of iron metabolism leading to intracellular iron overload that underpins this targetable vulnerability. Together, we highlight elevated levels of iron as a TIS biomarker in HGSOC and the potential of inducing ferroptosis to eradicate residual HGSOC cells following initial therapy.