Pidnarulex

Pidnarulex: CX-5461

G-quadruplex (stabilizer): Pidnarulex (CX-5461), a synthetically derived small molecule, is supplied as a lyophilized drug with intravenous (IV) administration.

Home
Pidnarulex

Introduction

In cancer research and therapy, "synthetic lethality" (SL) has emerged as an innovative treatment approach, particularly in targeting cancer within the genome. In this concept, the loss of a single gene does not lead to cell death, but when the corresponding dependent gene also loses function, it triggers cellular apoptosis. CX-5461 is the first small molecule drug that primarily targets the stabilization of G-quadruplexes (G4). G4 structures are special nucleic acid formations rich in guanine sequences and are widely present in the promoter regions and telomeres of genes. These structures are closely related to the activation of various oncogenes, including MYC, RAS, c-KIT, and BCL-2.

The main mechanism of action for CX-5461 is to stabilize G4 structures, which prevents the normal replication of DNA, leading to stalled replication forks and subsequent DNA damage, thus causing genomic instability and tumor cell death. This process highlights the potential of CX-5461 in cancer therapy, particularly in tumors with BRCA mutations or other homologous recombination repair deficiencies. Studies indicate that CX-5461 is significantly more effective against these tumors compared to existing PARP inhibitors and platinum-based chemotherapies.

Pidnarulex (CX-5461) has demonstrated the potential to convert “cold tumors” into “hot tumors” by altering the tumor microenvironment, thereby enhancing the therapeutic response to immune checkpoint inhibitors (ICIs). In addition to its direct cytotoxic effects, CX-5461 also possesses important immunomodulatory functions. The drug can activate the tumor microenvironment (TME) by inducing DNA breaks through the stabilization of G4 structures, resulting in the production of abundant cytosolic DNA fragments. These fragments activate the cGAS-STING signaling pathway, which is an innate immune sensing mechanism. When this pathway is activated, it induces the release of type I interferons and other pro-inflammatory cytokines, encouraging the immune system to effectively recognize and attack tumor cells. Furthermore, CX-5461 can convert the tumor microenvironment from a "cold" state to a "hot" state, further enhancing the tumor's sensitivity to immunotherapy (such as PD-1/PD-L1 inhibitors).

Preclinical model studies show that CX-5461 exhibits significant efficacy against BRCA-related tumors, and it remains effective against tumors that have developed resistance to PARP inhibitors. This demonstrates its potential as a possible rescue therapy. In human clinical trials, the results of CX-5461 as a monotherapy have shown encouraging trends, with nearly 70% of advanced cancer patients responding positively to the drug, especially those who were refractory to chemotherapy, targeted therapy, and immunotherapy.

Currently, CX-5461 is being explored in combination with other therapies, including combination therapy with the PARP inhibitor Talazoparib. This collaboration shows promise in further modifying the tumor microenvironment and enhancing the efficacy of immunotherapy. As a result, CX-5461 is positioned as a potentially transformative cancer treatment option, especially in facing the challenges of treatment resistance.

Synthetic lethality is defined as the combination of two non-lethal mutations that result in cell death. G-quadruplexes (G4) are higher-order DNA and RNA structures formed from guanine-rich sequences, and present in rapidly dividing cancer cells.

A. CX-5461 is a G4-stabilizing agent, which can stabilize the folded conformation and lead to replication fork stalling and unreplicated chromosomal areas. In turn, CX-5461 causes DNA breaks and triggers cellular DNA-repair mechanisms.

B. However, in cancer cells with defective homologous recombination (HR), such as BRCA1/2-deficient cells, double-strand breaks cannot be efficiently repaired due to the HR defect. This concept A+B is known as synthetic lethality.