The targeted delivery of radionuclides, cytotoxic drugs and pro-inflammatory cytokines into malignant tissue is gaining ground in the field of anticancer treatments. Low molecular weight molecules used as targeting agents are emerging as attractive alternatives to antibody-based drug delivery. These agents promise to improve the therapeutic index and overall efficacy of drugs with a negligible immunogenic risk. Furthermore, their pharmacokinetics is easier to modulate. Targeting a cancer-associated protein With the support of the Marie Curie programme, researchers of the LDC4PCaTher project developed a novel drug delivery vehicle targeting the bone marrow tyrosine kinase in chromosome X (BMX) protein. BMX is overexpressed in prostate tumour cells and is also associated with cancer pathophysiology. “Our goal was to maximise drug efficacy into the tumour while causing minimal damage to healthy cells,″ explains Marie Curie fellow Dr João Seixas. Most of the existing inhibitors are promiscuous and lack selectivity towards BMX. In addition, the ligand-drug conjugates often have an unstable chemical conjugation, which causes the cytotoxic cargo to be released in circulation, leading to undesired toxicity. To address these issues and understand how to improve sensitivity and specificity, LDC4PCaTher scientists investigated analogues of one of the most potent commercial BMX inhibitors. They designed a structure activity relationship and determined which modifications are amenable to chemical conjugation without interfering with the ligand binding characteristics. The physicochemical properties of the ligands such as solubility, lipophilicity, and membrane permeability were determined. In addition, scientists evaluated ligand interaction with the target protein using state-of-the-art techniques. This led to the identification of promising compounds with increased potency towards BMX. “Since BMX is a cytoplasmic protein we devised a strategy to ensure that the ligand-drug conjugation system could only be specifically cleaved inside the cancer cell, releasing the cytotoxic agent specifically in the tumour site,″ emphasises Dr Seixas. Furthermore, scientists obtained the first X-ray structure of BMX with a covalent inhibitor, which highlighted structural features paramount for the future development of BMX ligands. The crystallisation experiments also helped scientists identify the region of the molecule suitable for the attachment of new modalities such as cytotoxic agents and diagnostic tracers for imaging purposes. The future of BMX inhibitors According to Dr Seixas, the exquisite selectivity towards TEC kinases was “the most significant achievement of the project,″ and helped produce novel ligands with a selective inhibition profile. Over the years, the FDA has approved a number of broad kinase inhibitors such as ibrutinib for the treatment of chronic lymphocytic leukaemia (CLL) and other lymphocytic disorders. Second generation inhibitors with increased selectivity have also been recently introduced to tackle mantle cell leukaemia. The LDC4PCaTher project identified a new family of molecules that given their selectivity profile are currently in the process of being patented to allow future commercial exploitation. In view of the future, Dr Seixas is confident that “these selective inhibitors may become useful tools for the treatment of different conditions where TEC family of kinases play a prominent role such as CLL.″ The LDC4PCaTher approach, however, goes beyond prostate cancer therapy and can be used for any disease with deregulated transduction pathways.
LDC4PCaTher, bone marrow tyrosine kinase in chromosome X (BMX), prostate cancer, ligand, inhibitor, cytotoxic, chronic lymphocytic leukaemia (CLL)