21:I[432972,["/_next/static/chunks/bb923814e1f4d2e9.js","/_next/static/chunks/dd3ee9f5b7716ca6.js","/_next/static/chunks/4204a0ae82542ca8.js","/_next/static/chunks/1270dead247da766.js","/_next/static/chunks/6e1aa89a642f40be.js","/_next/static/chunks/2d7aa753e81324a8.js","/_next/static/chunks/8ffd0b71567920d8.js","/_next/static/chunks/67ea6dfd21f16c5f.js","/_next/static/chunks/24eb4379f68013fd.js","/_next/static/chunks/b8cd775ffdf935bd.js","/_next/static/chunks/983103cd9eb7b428.js","/_next/static/chunks/263f2cdcb9aa2341.js","/_next/static/chunks/294b9525248c8e5f.js"],"default"] 22:T48f,Concomitant inhibition of PARP and PI3K pathways has been recognized as a promising strategy for cancer therapy, which may expand the clinical utility of PARP inhibitors. Herein, we report the discovery of dual PARP/PI3K inhibitors that merge the pharmacophores of PARP and PI3K inhibitors. Among them, compound 15 stands out as the most promising candidate with potent inhibitory activities against both PARP-1/2 and PI3Kα/δ with pIC₅₀ values greater than 8. Compound 15 displayed superior antiproliferative profiles against both BRCA-deficient and BRCA-proficient cancer cells in cellular assays. The prominent synergistic effects produced by the concomitant inhibition of the two targets were elucidated by comprehensive biochemical and cellular mechanistic studies. In vivo, 15 showed more efficacious antitumor activity than the corresponding drug combination (Olaparib + BKM120) in the MDA-MB-468 xenograft model with a tumor growth inhibitory rate of 73.4% without causing observable toxic effects. All of the results indicate that 15, a first potent dual PARP/PI3K inhibitor, is a highly effective anticancer compound.23:T467,Indoleamine 2,3-dioxygenase-1 (IDO1) plays an important role in tumor immune escape. However, unsatisfactory clinical efficacies of selective IDO1 inhibitors have impeded their further development, suggesting that they do not exert sufficient antitumor effects by selectively inhibiting IDO1. IDO2, an isoenzyme of IDO1, is overexpressed in some human tumors, and emerging evidence suggests that concomitant inhibition of IDO1/2 may have synergistic effects in cancer treatment, revealing a promising cancer immunotherapeutic strategy. Herein, we describe the discovery of compound 4t, the first inhibitor targeting both IDO1/2 that has excellent in vitro inhibitory activity (IDO1 IC₅₀ = 28 nM and IDO2 IC₅₀ = 144 nM). Notably, 4t (TGI = 69.7%) exhibited significantly stronger in vivo antitumor potency than epacadostat (TGI = 49.4%) in CT26 xenograft mouse models, highlighting the advantages of IDO1/2 dual inhibitors for tumor immunotherapy. Preliminary mechanistic studies in vivo further identified that 4t exerts its antitumor effect by inhibiting IDO1/2.24:T43b,Aggregation of amyloid β-peptide (Aβ) is closely related to the pathology of Alzheimer's disease (AD). In this pathology, the beginning stage is characterized by excessive accumulation of Aβ monomers due to imbalanced Aβ in the process of clearance. The Aβ peptide exists in many forms such as soluble and insoluble Aβ species, both of which coexist during the progression of AD and contribute to AD pathology. Thus, probes capable of monitoring all Aβ species are highly desirable. While there are several fluorescent probes for detecting insoluble Aβ, it is still challenging to monitor all Aβ forms by using probes. Here, we describe a near-infrared fluorescent chemical probe, termed AD-1, developed through complexation of curcumin analogues with a stabilizer, which has good photophysical properties and shows high binding to all Aβ species in solution tests. Furthermore, AD-1 exhibited good blood-brain barrier penetrating ability and low cytotoxicity. More importantly, it was successfully applied to 4-month-young APP/PS1 mice imaging noninvasively.

#	Concept	H-Index	Publications	Citations
1	Medicine	2	2	45
2	Pharmacology	2	2	45
3	Natural Sciences	1	1	14
4	Biochemistry	1	1	14
5	Chemical Biology	1	1	14

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