Targeting conventionally intractable cancer-driving proteins: What has been achieved recently?

Recent Advances in Cancer Treatment Drugs: The Developmental Journey from Preclinical Discovery to Market Approval

The oncology landscape is undergoing a profound paradigm shift from broad-spectrum cytotoxic chemotherapies to highly selective, mechanism-driven precision medicine. This report systematically reviews the structural development, validation pathways, and regulatory mechanisms of next-generation oncology therapeutics. Modern precision oncology focuses on the targetable oncogenic drivers of malignant transformation—including epidermal growth factor receptor (EGFR) exon 20 insertions, human epidermal growth factor receptor 2 (HER2) mutations, Kirsten rat sarcoma virus oncogene (KRAS) G12C, and estrogen receptor 1 (ESR1) mutations—via small-molecule kinase inhibitors, antibody-drug conjugates (ADCs) featuring stable linkers and topoisomerase I payloads, and proteolysis-targeting chimeras (PROTACs). We highlight clinical milestones and regulatory approvals from 2025 and 2026, including the landmark PROTAC vepdegestrant, bispecific antibodies such as zenocutuzumab, and novel combinations like teclistamab with daratumumab.

TARGETED PROTEIN DEGRADATION WITH PROTACS IN CANCER THERAPY: MECHANISMS, CLINICAL ADVANCES, CHALLENGES, AND FUTURE PERSPECTIVES

Targeted protein degradation (TPD) has emerged as one of the most transformational approaches in current drug development, fundamentally challenging the long-standing assumption that small compounds must only inhibit their protein targets. Among TPD methods, proteolysis-targeting chimeras (PROTACs) have attracted considerable attention from both academic researchers and clinicians, giving a catalytic mechanism that permits the total removal of disease-driving proteins rather than just reducing their activity. This thorough analysis investigates the molecular basis of PROTAC technology, tracking its progression from an elegant intellectual notion to a clinically approved treatment platform. We discuss the molecular machinery of the ubiquitin - proteas ome system that PROTACs exploit, analyze the structural design principles underlying effective degrader molecules, and provide a detailed survey of the current clinical landscape,including the landmark progression of vepdegestrant (ARV-471) through Phase III clinical evaluation, culminating in U.S. Food and Drug Administration (FDA) approval on May 1, 2026.

Targeting KRAS in Cancer: Advances in Precision Oncology and Drug Development

KRAS is among the most commonly mutated oncogenes in human cancers, driving tumour initiation, progression, and therapeutic resistance through dysregulation of multiple signalling pathways. For many years, KRAS was regarded as an undruggable target because of its high affinity for guanosine nucleotides and the absence of suitable drug-binding pockets. Recent advances in structural biology and medicinal chemistry have fundamentally changed this perspective, enabled the development of mutation-specific inhibitors and established KRAS as a clinically actionable target in precision oncology. The discovery of the switch-II binding pocket facilitated the design of selective covalent inhibitors targeting KRAS G12C, leading to the clinical approval of sotorasib and adagrasib for selected patients with KRAS G12C-mutated malignancies. These breakthroughs have validated direct KRAS inhibition as an effective therapeutic strategy. However, durable clinical responses remain limited by intrinsic and acquired resistance, pathway reactivation, tumour heterogeneity, and the lack of effective therapies for non-G12C KRAS mutations.

Exploring the landscape of targetable alterations in patients with glioblastoma.

Advancing Cancer Therapy: Nano-Therapeutics for Precision Targeting of the Tumor Microenvironment.

Cancer remains one of the most challenging diseases to treat effectively, primarily due to the complex and adaptive nature of the tumour microenvironment. Traditional therapies often fail to target the TME adequately, leading to resistance and relapse. Recent advancements in nanotechnology have opened new avenues for targeted cancer therapy, offering innovative solutions to overcome these challenges. This review provides a comprehensive overview of nano-therapeutics designed to target the TME, highlighting their mechanisms, current progress, and prospects. By emphasizing the relationship between nanotherapeutics and different TME constituents, such as immune cells, stromal cells, and extracellular matrix, we want to clarify how these innovative techniques might improve therapeutic efficacy and reduce side effects. The potential of combining nano-therapeutics with conventional treatments is also explored, emphasizing a multi-faceted strategy in the fight against cancer.

Therapeutic oligonucleotides revisited: Focus on siRNA and antisense technologies

Oligonucleotide therapeutics have demonstrated unique advantages, including the capacity to target traditionally undruggable disease targets and achieve prolonged pharmacological effects that can last up to months. This fast-evolving drug modality has been gaining momentum over the past two decades, evidenced by regulatory approval on multiple entities which mostly target liver. Nevertheless, further extending its application to extrahepatic targets is largely confined by corresponding delivery systems. This review first provides a concise overview of the mechanistic principles underlying oligonucleotide function and commonly employed chemical modification techniques. It then highlights recent advancements in receptor-mediated delivery systems for extrahepatic targeting, and dual-targeting oligonucleotide engagement strategies encompassing design principles and outcomes in complex disease condition. Finally, we discuss key challenges and future directions in the field. Collectively, ongoing innovations in chemical modification and delivery technologies are expected to broaden the therapeutic scope of oligonucleotide agents, paving the way for improved clinical outcomes across a wider range of diseases.