Discovery of NLRP3 inhibitors using machine learning: Identification of a hit compound to treat NLRP3 activation-driven diseases.

NLRP3 is vital in developing many human diseases as one of the most critical inflammasomes. Developing related inhibitors has been instrumental in advancing the development of therapies for associated diseases. To date, there are no NLRP3 inhibitors on the market. This study identified a series of NLRP3 inhibitors using the self-developed machine learning model. Among them, CSC-6 was validated as the hit molecule with optimal activity and significantly inhibited IL-1ß secreted by PMA-THP-1 cells (IC50 = 2.3 ± 0.38 µM). The results show that CSC-6 specifically binds NLRP3 and inhibits NLRP3 activation by blocking ASC oligomerization during NLRP3 assembly. In vivo experiments have demonstrated that CSC-6 effectively reduces the symptoms of NLRP3 overactivation-mediated sepsis and Gout in mouse models. Importantly, CSC-6 has lower cytotoxicity and exhibits better stability in human-derived liver microsomes, which is more favorable for the drug to maintain its efficacy in vivo for longer. The discovery of CSC-6 may contribute to the design and discovery of related NLRP3 inhibitors.

NSD3: Advances in cancer therapeutic potential and inhibitors research.

Nuclear receptor-binding SET domain 3, otherwise known as NSD3, is a member of the group of lysine methyltransferases and is involved in a variety of cellular processes, including transcriptional regulation, DNA damage repair, non-histone related functions and several others. NSD3 gene is mutated or loss of function in a variety of cancers, including breast, lung, pancreatic, and osteosarcoma. These mutations produce dysfunction of the corresponding tumor tissue proteins, leading to tumorigenesis, progression, chemoresistance, and unfavorable prognosis, which suggests that the development of NSD3 probe molecules is important for understanding the specific role of NSD3 in disease and drug discovery. In recent years, NSD3 has been increasingly reported, demonstrating that this target is a very hot epigenetic target. However, the number of NSD3 inhibitors available for cancer therapy is limited and none of the drugs that target NSD3 are currently available on the market. In addition, there are very few reviews describing NSD3. Within this review, we highlight the role of NSD3 in tumorigenesis and the development of NSD3 targeted small-molecule inhibitors over the last decade. We hope that this publication can serve as a guide for the development of potential drug candidates for various diseases in the field of epigenetics, especially for the NSD3 target.

The structure-based optimization of 3-substituted indolin-2-one derivatives as potent and isoform-selective c-Jun N-terminal kinase 3 (JNK3) inhibitors and biological evaluation.

An indolin-2-(4-thiazolidinone) scaffold was previously shown to be a novel chemotype for JNK3 inhibition. However, more in vivo applications were limited due to the unconfirmed configuration and poor physicochemical properties. Here, the indolin-2-(4-thiazolidinone) scaffold validated the absolute configuration; substituents on the scaffold were optimized. Extensive structure activity relationship (SAR) studies were performed using kinase activity assays, thus leading to potent and highly selective JNK3 inhibitors with neuroprotective activity and good oral bioavailability. One lead compound, A53, was a potent and selective JNK3 inhibitor (IC50 = 78 nM) that had significant inhibition (>80% at 1 µM) to only JNK3 in a 398-kinase panel. A53 had low inhibition against JNK3 and high stability (t1/2(α) = 0.98 h, t1/2(ß) = 2.74 h) during oral administration. A modeling study of A53 in human JNK3 showed that the indolin-2-(4-thiazolidinone)-based JNK3 inhibitor with a 5-position-substituted hydrophilic group offered improved kinase inhibition.

Discovery of pterostilbene analogs as novel NLRP3 inflammasome inhibitors for potential treatment of DSS-induced colitis in mice.

The pterostilbene skeleton is a promising chemical scaffold that exerts anti-inflammatory, anti-depressant, and anti-tumor effects. In this study, we aim to reduce in vivo and in vitro toxicity of compound 32 (preliminary work) and maintain its biological activity. A series of novel pterostilbene derivatives (D1-D43) were designed and synthesized, and their anti-inflammatory activities were screened. All compounds were screened to evaluate their inhibitory effect on LPS/Nigericin-induced IL-1ß production and pyroptosis. The structure-activity relationships was deduced, and finally 1-((E)-4-(2-ethoxyethoxy)styryl)-3,5-dimethoxy-2-((E)-2-nitrovinyl)benzene (D22) was found to be a low-toxic compound with most potent inhibitory efficacy (against IL-1ß: IC50 = 2.41 µM). Preliminary mechanism studies showed that compound D22 may affect the assembly of NLRP3 inflammasome by targeting NLRP3 protein, thereby inhibiting the activation of NLRP3 inflammasome. The in vivo anti-inflammatory activity indicated that compound D22 had significant therapeutic effects on DSS-induced mouse acute colitis models.