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Small molecule drug conjugates are an emerging targeted therapy for cancer treatment. Building upon the overexpressed prostate-specific membrane antigen (PSMA) in prostate cancer, we herein report the design and synthesis of a novel PSMA-PI3K small molecule drug conjugate 1. Conjugate 1 demonstrates potent inhibition against PI3K with an IC50 value of 0.40 nM and simultaneously targets PSMA, giving rise to selective growth inhibition activity for PSMA-positive cancer cells. Conjugate 1 also potently inhibits the phosphorylation of PI3K main downstream effectors and arrests the cell cycle in the G0/G1 phase in PSMA-positive 22Rv1 prostate cancer cells. Further in vivo evaluation shows that conjugate 1 has favorable efficacy and tolerability in a 22Rv1 xenograft model, demonstrating its potential application in targeted cancer therapy.

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Photopharmacology is an emerging approach for achieving light-controlled drug activity. Herein, we design and synthesize a novel series of photoswitchable PI3K inhibitors by replacing a sulfonamide moiety with an azo group in a 4-methylquinazoline-based scaffold. Through structure-activity relationship studies, compound 6g is identified to be effectively switched between its trans- and cis-configuration under irradiation with proper wavelengths. Molecular docking studies show the cis-isomer of 6g is favorable to bind to the PI3K target, supporting compound 6g in the PSS365 (cis-isomer enriched) was more potent than that in the PSSdark (trans-isomer dominated) in PI3K enzymatic assay, cell antiproliferative assay, Western blotting analysis on PI3K downstream effectors, cell cycle analysis, colony formation assay, and wound-healing assay. Relative to the cis-isomer, the trans-isomer is more metabolically stable and shows good pharmacokinetic properties in mice. Moreover, compound 6g inhibits tumor growth in nude mice and a zebrafish HGC-27 xenograft model.

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Proteolysis targeting chimeria (PROTAC) degrades target proteins by utilizing the ubiquitin-proteasome pathway, subverting the concept of traditional small molecule inhibitors. Among the common mutation targets of non-small cell lung cancer (NSCLC), PROTAC technology has successfully achieved the effective degradation of kirsten rat sarcoma viral oncogene homolog (KRAS), epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK ) and other proteins in preclinical studies. PROTAC drugs with their unique event-driven advantages, are expected to overcome acquired drug resistance caused by small molecule inhibitors and show good therapeutic potential for undruggable targets, thereby providing a new strategy for the treatment of NSCLC.
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A synthetic protocol based on Cp*CoIII-catalyzed C-H amidation/annulation of 2-aryl-1H-imidazoles with 1,4,2-dioxazol-5-ones was developed to give imidazo[1,2-c]quinazoline derivatives with broad substrate scope in moderate to good yields. The method has good prospects of application in the synthesis of imidazo[1,2-c]quinazoline drugs.

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With the rapid development of nanotechnology, new types of fluorescent nanomaterials (FNMs) have been springing up in the past two decades. The nanometer scale endows FNMs with unique optical properties which play a critical role in their applications in bioimaging and fluorescence-dependent detections. However, since low selectivity as well as low photoluminescence efficiency of fluorescent nanomaterials hinders their applications in imaging and detection to some extent, scientists are still in search of synthesizing new FNMs with better properties. In this review, a variety of fluorescent nanoparticles are summarized including semiconductor quantum dots, carbon dots, carbon nanoparticles, carbon nanotubes, graphene-based nanomaterials, noble metal nanoparticles, silica nanoparticles, phosphors and organic frameworks. We highlight the recent advances of the latest developments in the synthesis of FNMs and their applications in the biomedical field in recent years. Furthermore, the main theories, methods, and limitations of the synthesis and applications of FNMs have been reviewed and discussed. In addition, challenges in synthesis and biomedical applications are systematically summarized as well. The future directions and perspectives of FNMs in clinical applications are also presented.