In the past 25 years, kinase drug discovery has grown into one of the most thriving areas in pharmaceutical research and development. What began as a field dominated by ATP-competitive small molecules has diversified into a broad therapeutic landscape that includes allosteric and covalent inhibitors, activators, proximity-induced modulators, targeted protein degraders and antibody-based therapies, with more than 150 regulatory approvals so far worldwide. In this Review, we provide a comprehensive analysis of the current kinase therapeutic landscape, including more than 2,100 kinase-targeting agents that have entered clinical development in more than 23,000 clinical trials. We cover drug platforms, new targeting approaches, the expanding target spectrum, approvals and clinical trends. Nearly half of the canonical human protein kinases have at least one clinical-stage agent, placing kinases among the most intensively explored drug target classes. Nevertheless, development remains highly concentrated around a small set of blockbuster kinase targets, such as EGFR. We also examine the features associated with successful kinase-targeting agents and causes of agent discontinuations and regulatory withdrawal. Over the past 25 years, kinase drug discovery has been one of the most active areas in pharmaceutical research and development. This article provides a comprehensive analysis of the kinase therapeutic landscape, covering drug platforms, new targeting approaches, the expanding target spectrum, approvals and clinical trends.
Immunotherapy has transformed cancer treatment, enabling durable responses and long-term survival in many patients. However, widespread use remains limited by refractory indications, immune-related toxicities and acquired resistance. Complications such as cytokine release syndrome, immune-related adverse events, infusion-related reactions and on-target, off-tumour toxicities have emerged as specific safety concerns. Approaches that can direct immunotherapy to the tumour microenvironment (TME), such as intratumoural administration, have only partially mitigated these risks and present additional logistical and technical barriers. Conditional biologics, in which proteins are engineered to become active in response to tumour-associated signals or in the TME, enable the uncoupling of efficacy from toxicity. By enhancing tumour accumulation, targeting activity to a particular cell type and minimizing off-target effects, conditional activation offers a potential strategy to expand the therapeutic window of cancer therapeutics. This Review provides a comprehensive overview of the mechanisms, applications, challenges and future directions of this approach, while assessing completed and ongoing clinical trials. Conditional biologics (CBs) — protein therapeutics engineered to selectively activate within the tumour microenvironment — have the potential to increase the potency and limit the off-target adverse effects of cancer immunotherapies. This Review describes the design principles and activation mechanisms of CBs, assesses those being investigated in the clinic, and addresses ongoing challenges and future directions for the field.
Histone post-translational modifications, such as methylation, acetylation, phosphorylation and ubiquitination, have fundamental roles in regulating chromatin structure and gene expression. Histone methylation was once considered a static modification until the discovery of the histone lysine demethylase LSD1 (KDM1A), more than two decades ago. Since then, numerous KDMs in two main enzyme classes have been identified. Their diverse roles in regulating gene expression, metabolism, immune responses and disease pathogenesis have been extensively studied and small-molecule inhibitors have been developed. KDMs exert context-dependent functions as either oncogenes or tumour suppressors, which complicates their therapeutic targeting. As we enter the third decade of investigations into histone demethylation, unlocking the full therapeutic potential of inhibiting KDMs will require a deeper understanding of their biology, substrate specificity, interaction networks and regulatory crosstalk. In this Review, we discuss the functions of KDMs in metabolic and immune regulation and their roles in cancer and other diseases. We describe the landscape of KDM inhibitors, especially LSD1 inhibitors, which are the most advanced demethylase inhibitors in clinical trials. We highlight the need for more potent and selective KDM inhibitors, biomarkers of therapeutic response, novel combinatorial treatments and innovative drug discovery strategies. Histone lysine demethylases regulate gene expression and chromatin structure and help to integrate epigenetics with metabolic and immune responses. This Review discusses the diverse contributions of these demethylases to disease pathogenesis, particularly cancer, and the efforts underway to target them with small molecules.
A decade has passed since the initial description of cytosine base editors in 2016. This new class of gene editors, utilizing DNA damage intermediates beyond double-stranded DNA breaks, fundamentally shifted the paradigm of gene editing from stochastic disruption to precise chemical correction. Since then, the field has rapidly matured, with the development of optimized base editors with improved editing efficiency, targeting scope, precision and specificity, as well as the subsequent generation of adenine base editors and prime editors. Base editors have not only become widely used research tools but have served as foundational platforms for biotechnology companies developing human therapies. Today, base editors are being deployed in trials for a diverse list of indications including sickle cell disease, alpha-1 antitrypsin deficiency, inborn errors of metabolism, leukaemias and cardiovascular indications. This Review critically examines the ‘bench-to-bedside’ trajectory of base editors, detailing their mechanistic evolution and expanding role in treating human disease. Base editing, a gene editing technology capable of installing point mutations with high efficiency and precision, was first reported a decade ago. This Review examines the evolution of base editors and their road to clinical translation, highlighting key advances, ongoing challenges and the current clinical trial landscape.
Immune cell engagers (ICEs) offer a promising approach for achieving deep depletion of pathogenic B cell populations in systemic autoimmune diseases. Their modular design enables the recruitment of T cells, natural killer cells, γδ T cells or myeloid cells to eliminate B cells, plasmablasts and long-lived plasma cells. Use of ICEs in haematological malignancies has established the therapeutic potential of targeting the lineage antigens of B cells and plasma cells, and informed understanding of resistance, treatment-associated toxicity and incomplete target-cell depletion. However, applications in autoimmune diseases present distinct challenges, including disease-specific B cell heterogeneity, pharmacokinetic limitations, effector-cell dysfunction and the risk of cytokine release syndrome. Despite these challenges, early clinical reports using CD19-directed and B cell maturation antigen-directed T cell engagers have shown sustained improvements in several systemic autoimmune diseases. In this Review, we discuss the principles guiding ICE development for autoimmune diseases, including target selection, engager architecture, effector-cell recruitment and safety. We also consider emerging strategies, including CD8-biased T cell engagement, co-stimulatory multispecific formats, and natural killer or γδ T cell recruitment, to improve safety and durability of response. ICEs could ultimately provide an off-the-shelf alternative to chimeric antigen receptor T cell therapies, enabling sustained immune reprogramming in patients with refractory autoimmune diseases. Immune cell engagers are emerging as a strategy for deep B cell depletion in autoimmune diseases. This Review examines their mechanisms, clinical development and next-generation designs, including T cell, natural killer cell and γδ T cell-engaging formats, and considers lessons from haematological malignancies to improve efficacy, safety and durability of immune modulation.
