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Evaluation of the implementation effectiveness of accelerated drug marketing registration procedures in China: lessons from the 2016–2024 regulatory review

IF 6.5 2区医学 Q1 PHARMACOLOGY & PHARMACY

Drug Discovery Today

Pub Date : 2025-04-10 DOI: 10.1016/j.drudis.2025.104353

Yipeng Lan , Li Wang , Xiaofeng Lin , Yiqing Wu , Zhe Huang

China has implemented accelerated drug marketing registration procedures (ADMRPs) since 2016, including priority review and approval (PRA), conditional approval (CA), and breakthrough therapy drugs (BTDs). This study analyzed the characteristics of drugs approved by ADMRPs from 2016 to 2024 and explored the implementation effectiveness of these procedures. Overall, 922 drugs were approved for marketing through five ADMRPs (or procedure combinations): PRA (759, 82.3%), CA (12, 1.3%), CA + PRA (108, 11.7%), BTD + PRA (23, 2.5%), and BTD + CA + PRA (20, 2.2%). Drugs approved through the different procedures differed widely in terms of drug attributes and clinical uses, clinical trial design, and drug registration and marketing. Implementing ADMRPs has demonstrated excellent results in accelerating the development and marketing of clinically value-driven drugs.

引用次数: 0

The spindle assembly checkpoint: Molecular mechanisms and kinase-targeted drug discovery

IF 6.5 2区医学 Q1 PHARMACOLOGY & PHARMACY

Drug Discovery Today

Pub Date : 2025-04-10 DOI: 10.1016/j.drudis.2025.104355

Inês Lima , Fernanda Borges , António Pombinho , Daniel Chavarria

The spindle assembly checkpoint (SAC) is a surveillance mechanism required for the fidelity of chromosome segregation, ensuring that anaphase is not initiated until all chromosomes are properly attached to the mitotic spindle. In cancer cells, SAC inactivation leads to aneuploidy beyond the cell’s adaptation, culminating in cell death. This review provides a concise overview of the SAC signaling process and properties. Recent drug discovery strategies to selectively target kinases, particularly Aurora B and monopolar spindle kinase (MPS1), aimed at developing innovative anticancer agents able to override SAC are also presented.

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Selective imaging probes for differential detection of pathological tau polymorphs in tauopathies

IF 6.5 2区医学 Q1 PHARMACOLOGY & PHARMACY

Drug Discovery Today

Pub Date : 2025-04-10 DOI: 10.1016/j.drudis.2025.104352

Nicolò Bisi, Luca Pinzi, Giulio Rastelli

Tauopathies, including Alzheimer’s disease (AD), Pick’s disease (PiD), progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD), are characterized by the misfolding and pathological aggregation of the tau protein, leading to neurodegeneration. Although the pathogenesis of these diseases is still a matter for debate, the formation of amyloid inclusions still represents the only histopathological hallmark available. Tau inclusions are not the same in terms of structure and morphology, and different tauopathies are characterized by different polymorphs. Remarkably, the selective detection of these polymorphs is crucial for differential diagnosis, disease monitoring and evaluation of the potential harmfulness of polymorphs, with a significant impact on drug discovery. This review discusses recent advances in the development of imaging probes designed for the selective detection of pathological tau forms associated with specific tauopathies. We explore the application of compounds that can target tau polymorphs characteristic of AD, PiD, PSP and CBD. In particular, we focus on discussing the probes’ selectivity and sensitivity in distinguishing between the different tauopathy-associated polymorphs in preclinical settings. The progress and the weaknesses in this field are discussed, to guide the researchers in identifying accurate and potent probes for the selective diagnosis of these different neurodegenerative diseases.

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引用次数: 0

Every Compound a Candidate: experience-led risk-taking approaches to accelerate small-molecule drug discovery

IF 6.5 2区医学 Q1 PHARMACOLOGY & PHARMACY

Drug Discovery Today

Pub Date : 2025-04-08 DOI: 10.1016/j.drudis.2025.104354

Dermot F. McGinnity , Jerome Meneyrol , Christophe Boldron , Craig Johnstone

Despite progress, small-molecule drug discovery remains slow and costly. A paradigm shift is underway by leveraging artificial intelligence (AI) and machine learning (ML); however, these technological advances are necessary but not sufficient. Performance indicators from our partnered portfolio include timelines for data turnaround (5-day) and candidate delivery (2.9 versus 4.0 years for industry). Together with optimised processes and effective decision-making, improved translational predictivity is required. Progressing more compounds through downstream in vitro and in vivo models will rapidly reveal translational thresholds or crucial blockers for compound progression, with humans and machines actively learning from such data. We advocate for more experience-led risk-taking and a mindset shift toward an Every Compound a Candidate strategy, which aims to deliver drug candidates in <2 years.

引用次数: 0

Pathogenic TDP-43 in amyotrophic lateral sclerosis

IF 6.5 2区医学 Q1 PHARMACOLOGY & PHARMACY

Drug Discovery Today

Pub Date : 2025-04-04 DOI: 10.1016/j.drudis.2025.104351

Zhao Zhong Chong, Nizar Souayah

The aberrant expression of the transactive response DNA-binding protein of 43 kDa (TDP-43) has been closely associated with amyotrophic lateral sclerosis (ALS). Cytoplasmic inclusions containing TDP-43 can be found in the brain and spinal cord in up to 97% of ALS cases. Mutations in the TARDBP gene promote the nuclear export of TDP-43, increase cytoplasmic aggregation, and predispose TDP-43 to post-translational modifications. Cleavage of TDP-43 and the resulting C- and N-terminal fragments also contribute to the development of ALS. Cellularly, the resulting impairment of autophagy and mitochondria aggravates cellular damage and neurodegeneration. Given the contribution of pathogenic TDP-43 to the development of ALS, elucidating the mechanisms related to TDP-43 will facilitate finding therapeutic targets for the disease.

引用次数: 0

The connection between Bayesian networks and adverse outcome pathway (AOP) networks and how to use it for predicting drug toxicity

IF 6.5 2区医学 Q1 PHARMACOLOGY & PHARMACY

Drug Discovery Today

Pub Date : 2025-04-03 DOI: 10.1016/j.drudis.2025.104350

Dong Wang , Ayako Suzuki , Weida Tong

There is significant interest in combining adverse outcome pathways (AOPs) with Bayesian networks (BNs) because of their shared representation using directed acyclic graphs (DAGs). However, it has not been verified empirically whether AOP networks are mathematically congruent with BNs. Furthermore, important properties for BNs, such as Markov blankets, have not been emphasized, which is a missed opportunity for simplifying and optimizing the model. Here, we summarize the connection between AOP networks and BNs and explore the implications for toxicity modeling. We also present a case study in drug-related liver toxicity. Our results confirm that AOP networks are congruent mathematically with BNs, with incorporation of the mathematical properties of BN leading to significantly simplified and more efficient models.

将不良后果路径（AOPs）与贝叶斯网络（BNs）结合起来引起了人们极大的兴趣，因为它们共同使用有向无环图（DAGs）表示。然而，AOP 网络与贝叶斯网络在数学上是否一致尚未得到经验验证。此外，BN 的重要属性（如马尔可夫空白）也未得到强调，这就错失了简化和优化模型的机会。在此，我们总结了 AOP 网络与 BN 之间的联系，并探讨了其对毒性建模的影响。我们还介绍了一个与药物相关的肝脏毒性案例研究。我们的研究结果证实，AOP 网络与 BN 在数学上是一致的，结合 BN 的数学特性可以大大简化模型并提高其效率。

引用次数: 0

Overview of new indications for novel drugs approved in China between 2018 and 2024

IF 6.5 2区医学 Q1 PHARMACOLOGY & PHARMACY

Drug Discovery Today

Pub Date : 2025-04-01 DOI: 10.1016/j.drudis.2025.104342

Yang Xu , Qixiang Guo , Ziqi Chen , Yunpeng Liu , Yue Yang

Since China’s regulatory reforms were initiated in 2015, the development of new indications for novel drugs has become an important trend. Between 2018 and 2024, China’s National Medical Products Administration (NMPA) approved 313 new indications for 151 novel drugs. This cross-sectional study comprehensively depicts the landscape of China’s new indications for novel drugs, including the characteristics of approvals, quality, and quantity of clinical trial evidence. The quality characteristics of the efficacy evidence for new indications were affected by the treatment areas and conditional approval programs. The efficacy of a novel drug for a new indication can be demonstrated by one pivotal trial or one pivotal trial plus supportive evidence in most cases.

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The Six Ds of Exponentials and drug discovery: A path toward reversing Eroom’s law

IF 6.5 2区医学 Q1 PHARMACOLOGY & PHARMACY

Drug Discovery Today

Pub Date : 2025-04-01 DOI: 10.1016/j.drudis.2025.104341

Alexander Tropsha , Holli-Joi Martin , Artem Cherkasov

Many technological sectors underwent recent exponential growth because of digital disruption, a phenomenon Peter Diamantis characterized as the ‘Six Ds of Exponentials’: digitization, deception, disruption, demonetization, dematerialization, and democratization. In contrast, drug discovery has been marked by rising costs and modest growth, if any, of annual drug approvals. We argue that the exponential growth of drug discovery can be also achieved through digital disruption brought by data expansion, mature artificial intelligence (AI), automation of experiments, public–private partnerships, and open science. We detected the emergence of all ‘Six Ds of Exponentials’ within modern drug discovery and discuss how each of the ‘Six Ds’ can further empower the field and forcefully address the societal demand for novel, potent, affordable, and accessible medicines.

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Covalent inhibitors possessing autophagy-modulating capabilities: charting novel avenues in drug design and discovery

IF 6.5 2区医学 Q1 PHARMACOLOGY & PHARMACY

Drug Discovery Today

Pub Date : 2025-04-01 DOI: 10.1016/j.drudis.2025.104347

Yutong Wang , Shiyu Luo , Hongbao Sun , Shuai Huang , Lianhai Shan , Jifa Zhang

Autophagy is a crucial cellular process in degrading damaged organelles and maintaining cellular homeostasis. By forming irreversible bonds with specific proteins, covalent inhibitors present a distinct advantage in regulating autophagy and its related pathways. These inhibitors can provide sustained modulation of autophagy at lower doses, improving therapeutic efficacy while minimizing adverse effects. We discuss their mechanisms, including how they affect autophagy-related enzymes and pathways, and their potential applications in the treatment of cancers and other autophagy-related disorders. Studying autophagy-related pathway targets will provide new insights for the development of covalent inhibitors and enhance therapeutic strategies for complex conditions.

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IRE1α-mediated UPR activation in gastrointestinal cancers: Adaptive mechanisms and therapeutic potential

IF 6.5 2区医学 Q1 PHARMACOLOGY & PHARMACY

Drug Discovery Today

Pub Date : 2025-04-01 DOI: 10.1016/j.drudis.2025.104335

Valappan Veetil Soumya , Baby Jisna , Davis Anu , Chevookaren Francis Binoy , Thekkekara Devassy Babu

The endoplasmic reticulum (ER) plays a crucial role in protein synthesis, folding and quality control. Disruptions in these processes lead to ER stress (ERS) and activate the unfolded protein response (UPR) to restore cellular homeostasis. In gastrointestinal cancers, inositol-requiring enzyme 1α (IRE1α) is a key regulator of the UPR, enabling cancer cells to adapt to hostile conditions such as hypoxia, oxidative stress and chemotherapy. Elevated IRE1α activity supports tumor survival, progression and metastasis by mitigating ERS-induced apoptosis. However, targeting IRE1α signaling presents a promising therapeutic strategy by impairing cancer cell adaptation to stress, offering promising therapeutic opportunities for gastrointestinal cancers.

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