作者: Qu, Zihan ; Amarasinghe, Ovini ; Cullers, Clayton C ; Putt, Karson S. ; Dong, Jiajun ; Mason, Emily R ; Putt, Karson S ; Cullers, Clayton C. ; Zhang, Zhong-Yin ; Chu, Shaoyou ; Lin, Jianping ; Miao, Jinmin ; Mason, Emily R.

Src Homology 2-containing Inositol 5'-Phosphatase-1 (SHIP-1), encoded by INPP5D, has been identified as an Alzheimer's disease (AD) risk-associated gene through recent genetic and epigenetic studies. SHIP-1 confers AD risk by inhibiting the TREM2 cascade and reducing beneficial microglial cellular processes, including phagocytosis. While several small molecules have been reported to modulate SHIP-1 activity, their limited selectivity and efficacy in advanced models restricted their potential as therapeutic agents or probes for biological studies. Herein, we validated and implemented a high-throughput screening platform to explore new chemotypes that can modulate the phosphatase activity of SHIP-1. We screened 49,260 central nervous system (CNS)-penetrate compounds sourced from commercial vendors using the malachite green-based assay for anti-SHIP-1 activity. Through analysis, prioritization, and validation of the screening hits, we identified three novel types of scaffolds that inhibit the SHIP-1 phosphatase activity with IC₅₀s as low as 46.6 µM. To improve the inhibitory activity of these promising hits, we carried out structure-activity relationship (SAR) studies, resulting in a lead molecule SP3-12 that inhibits SHIP-1 with an IC₅₀ value of 6.1 μM. Kinetic analyses of SP3-12 revealed that its inhibition mechanism is competitive, with a K_i value of 3.2 µM for SHIP-1 and a 7-fold selectivity over SHIP-2. Furthermore, results from testing in a microglial phagocytosis/cell health high content assay indicated that SP3-12 could effectively activate phagocytosis in human microglial clone 3 (HMC3) cells, with an EC₅₀ of 2.0 µM, without cytotoxicity in the dose range. Given its potency, selectivity, and cellular activity, SP3-12 emerges as a promising small molecule inhibitor with potential for investigating the biological functions of SHIP-1.

2024-10-02·EXPERT OPINION ON THERAPEUTIC PATENTS

Caspase inhibitors: a review on recently patented compounds (2016–2023)

Review

作者: Kasana, Shivani ; Patel, Preeti ; Jain, Shweta ; Vaidya, Ankur ; Kumar, Shivam ; Sahu, Sanjeev ; Kurmi, Balak Das

INTRODUCTION:

Caspases are a family of protease enzymes that play a crucial role in apoptosis. Dysregulation of caspase activity has been implicated in various pathological conditions, making caspases an important focus of research in understanding cell death mechanisms and developing therapeutic strategies for diseases associated with abnormal apoptosis.

AREAS COVERED:

It is a comprehensive review of caspase inhibitors that have been comprising recently granted patents from 2016 to 2023. It includes peptide and non-peptide caspase inhibitors with their application for different diseases.

EXPERT OPINION:

This review categorizes and analyses recently patented caspase inhibitors on various diseases. Diseases linked to caspase dysregulation, including neurodegenerative disorders, and autoimmune conditions, are highlighted to accentuate the therapeutic relevance of the patented caspase inhibitors. This paper serves as a valuable resource for researchers, clinicians, and pharmaceutical developers seeking an up-to-date understanding of recently patented caspase inhibitors. The integration of recent patented compounds, structural insights, and mechanistic details provides a holistic view of the progress in caspase inhibitor research and its potential impact on addressing various diseases.

2024-10-01·NEUROCHEMISTRY INTERNATIONAL

Caspase-1 inhibitor CZL80 protects against acute seizures via amplifying the inhibitory neural transmission

Article

作者: Liu, Yao ; Gong, Yiwei ; Zhang, Shuo ; Cui, Sunliang ; Xu, Cenglin ; Tang, Yingying ; Chen, Zhong ; Wang, Yi

Current anti-seizure medications (ASDs) primarily target ion channels or neurotransmissions; however, their practicability is limited by unwanted side-effects and pharmacoresistance. Cumulative evidence has proposed pro-inflammatory caspase-1 as a potential target for developing ASDs. In this study, we showed that the small-molecular caspase-1 inhibitor CZL80 can prevent seizures in various models including the maximal electroshock (MES), the pentylenetetrazol (PTZ), and the amygdaloid kindled models. Specifically, we discovered that CZL80 prevented death, reduced the duration of generalized seizures, and increased the threshold of generalized seizures in a dose-dependent manner in the MES model. In the PTZ model, CZL80 decreased the seizure stages, prolonged the latency to stage 4 seizures, and decreased the death rate. And in amygdaloid kindled rats, CZL80 inhibited the seizure stages, shortened the durations of both generalized seizures and after-discharges. And the anti-seizure efficacy of CZL80 was diminished in caspase-1 knockout mice. In vitro electrophysiology recordings revealed that CZL80 was able to decreased the excitability of glutamatergic pyramidal neurons, as denoted by reducing the spontaneous neuronal firings and increasing the rheobase injected currents to elicit action potentials. Furthermore, CZL80 was able to increase the amplitudes of inhibitory post-synaptic currents (IPSC), while the excitatory post-synaptic currents (EPSC) were not influenced. Lastly, daily administration of CZL80 for 3 weeks did not influence the normal locomotor functions in mice. In sum, our results highlighted CZL80 as a potential anti-seizure therapy with therapeutic significance.

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适应症	最高研发状态	国家/地区	公司	日期
结肠炎	临床前	美国	Elgia Therapeutics, Inc.初创企业	2024-07-12
炎症	临床前	美国	Elgia Therapeutics, Inc.初创企业	2024-07-12
炎症性肠病	临床前	美国	Elgia Therapeutics, Inc.初创企业	2024-07-12
神经炎症	临床前	美国	Elgia Therapeutics, Inc.初创企业	2024-07-12