11 новых молекулярных мишеней к 2025 году расширяют возможности лечения редких заболеваний и рака

Eleven newly identified molecular targets are reshaping the pharmaceutical landscape by 2025, expanding treatment options for rare diseases and cancer. These first-in-class therapies introduce novel approaches for conditions ranging from bronchiectasis and immunoglobulin A (IgA) nephropathy to Barth syndrome. In a review published in Nature Reviews Drug Discovery, Sorin Avram, PhD, head of the Department of Computational Chemistry, “Coriolan Dragulescu” Institute of Chemistry, Timișoara, Romania, and colleagues highlighted the year’s most significant advances. Innovation Shift According to the authors, developing new drugs is becoming increasingly challenging because many well-defined molecular targets have already been successfully exploited therapeutically. As a result, future advances will largely depend on the identification of new molecular targets and biological pathways. The review identified 2025 as the landmark year for first-in-class therapy. Among 94 drugs with well-defined mechanisms of action approved for the first time in the US, EU, Japan, and China, 10 targeted 11 molecular structures for which no approved therapies had previously existed. In other words, roughly 1 in every 10 newly approved drugs acted on an entirely new molecular target. The newly identified molecular targets include two kinases, five additional enzymes, one tumor-associated antigen, one bacterial neurotoxin, and, for the first time, the phospholipid cardiolipin. These targets were modulated by six small molecules, three monoclonal antibodies, and one peptide. The review also highlighted another milestone. China approved first-in-class therapies directed at entirely new molecular targets for the first time, highlighting the country’s growing role in biopharmaceutical innovation. Small Molecules Six of the newly approved therapies are small molecules, including three classic enzyme inhibitors. Brensocatib is a reversible inhibitor of dipeptidyl peptidase 1, which reduces the activation of neutrophil serine proteases and limits inflammatory tissue damage in patients with bronchiectasis unrelated to cystic fibrosis. Defactinib targets focal adhesion kinase 1 and tyrosine kinase 2. In combination with the mitogen-activated protein kinase kinase inhibitor avutometinib, it has been approved for the treatment of KRAS-mutated low-grade serous ovarian cancer. Together, these agents inhibit the signaling pathways that drive tumor growth and treatment resistance. Olgotrelvir has a distinct dual mechanism of action. Following metabolic activation, it inhibits cathepsin L, reducing SARS-CoV-2 entry into host cells. Its active metabolite also inhibits the main viral protease, which is essential for processing viral polyproteins. By targeting both viral entry and replication, olgotrelvir acts at two critical stages of the viral life cycle. Mitochondrial Therapy The authors highlighted doxecitine and doxribtimine as particularly noteworthy because they represent the first disease-modifying treatments for mitochondrial thymidine kinase 2 (TK2) deficiency. The two pyrimidine nucleosides serve as substrates for cytosolic deoxycytidine kinase and thymidine kinase 1, respectively. Following phosphorylation, the compounds enter the mitochondria, where they replenish the nucleotide pool required for mitochondrial DNA synthesis. This restores mitochondrial DNA replication, improves oxidative phosphorylation and ATP production, and addresses the underlying molecular defects. For patients with the rare disorder caused by TK2 deficiency, these therapies provide the first targeted treatment. Dual Mechanism Dordaviprone introduced a novel mechanism of action in neurooncology. The drug triggers apoptosis in cancer cells through a dual mechanism: It hyperactivates the mitochondrial protease ClpP to disrupt energy metabolism and antagonizes the dopamine D2 receptor to activate the integrated stress response. Dordaviprone is the first FDA-approved systemic therapy for adult and pediatric patients with recurrent or progressive diffuse midline glioma harboring the H3K27M mutation, a disease for which treatment options have been extremely limited. New Antibodies Three of the 11 newly identified molecular targets were targeted by monoclonal antibodies. Narsoplimab selectively inhibits mannan-binding lectin-associated serine protease 2, blocking the activation of the lectin complement pathway and reducing inflammatory damage in conditions such as hematopoietic stem cell transplantation-associated thrombotic microangiopathy. Sibeprenlimab is a humanized monoclonal antibody that binds to and blocks A PRoliferation-Inducing Ligand, reducing levels of serum galactose-deficient IgA1 (Gd-IgA1). The drug represents the first targeted disease-modifying therapy. Gd-IgA1 acts as the primary pathogenic trigger for IgA nephropathy, the most common form of primary glomerulonephritis. Developed in China, siltartoxatug (Sintetol) is the world’s first recombinant monoclonal antibody targeting the tetanus neurotoxin of Clostridium tetani. It serves as a viable alternative to traditional plasma-based options for passive tetanus immunization. First Phospholipid Elamipretide was the first cardiolipin-directed therapy. By binding to cardiolipin, a vital phospholipid in the inner mitochondrial membrane, it prevents oxidative damage, preserves structural integrity, and stabilizes mitochondrial function. This drug has been approved for Barth syndrome, a rare inherited disorder of phospholipid metabolism characterized by cardiomyopathy, skeletal muscle myopathy, and severe exercise intolerance. Elamipretide targets the underlying disease mechanism rather than simply treating symptoms, offering a new therapeutic option for conditions with limited treatment options. Rare Diseases According to the authors, the distribution of first-in-class therapies is particularly striking. Seven of the 11 newly identified molecular targets have been linked to therapies for rare diseases, reinforcing a trend that has emerged in recent years. Although many therapeutic opportunities for common diseases have already been explored, rare diseases continue to offer considerable potential for pharmaceutical innovation. The review also highlighted a geopolitical shift in drug development. First-in-class therapies directed at entirely new molecular targets have received their initial approval in China, highlighting the country’s growing role in biopharmaceutical research and development. This story was translated from Medscape’s German edition.