Abstract Fibroblast growth factor receptor (FGFR) inhibitors are emerged as an important class of targeted therapies in oncology, targeting key pathways associated with tumor growth, angiogenesis, and resistance to conventional treatments. FIIN‐2, the first irreversible covalent pan‐FGFR inhibitor, has shown promise in overcoming resistance due to gatekeeper mutations; however, its selectivity and molecular mechanisms in tumors remain poorly understood. In this study, an FIIN‐2 chemical probe is designed and synthesized to identify both established and novel targets in hepatocellular carcinoma (HCC) via chemoproteomic profiling. An integrative multi‐omics approach, including chemoproteomic, phosphoproteomic, transcriptomic, and proteomic analyses, is utilized to elucidate the full spectrum of target proteins, signaling pathways, and downstream effectors regulated by FIIN‐2 in HCC. Notably, adenosine monophosphate‐activated protein kinase α1 (AMPKα1) is identified as a novel target of FIIN‐2, with Cys185 identified as its covalent binding site. These findings reveal that FIIN‐2 can induce autophagy by directly binding to and activating AMPKα1, influencing its anti‐tumor activity in HCC cells. Overall, this study greatly advances the understanding of FIIN‐2′s on‐ and off‐target effects, offering a comprehensive view of its molecular mechanisms in cancer cells. The integrative multi‐omics approach provides a valuable framework for the development and optimization of covalent kinase inhibitors.

Fibroblast growth factor receptors (FGFRs) represent promising therapeutic targets in various malignancies, yet the clinical application of FGFR covalent inhibitors has been impeded by several significant challenges, including unquantifiable target engagement, undefined off-target effects, and the emergence of drug resistance. In this study, we designed and synthesized a series of FGFR activity-based probes (ABPs) derived from FIIN-2, a pioneering selective, next-generation irreversible covalent FGFR inhibitor with demonstrated efficacy against gatekeeper mutations. Among them, FP1 exhibited comparable inhibitory potency to FIIN-2. FP1 could facilitate precise in vitro and in situ labeling and visualization of both FGFR1-4 and their mutants. Utilizing FP1, we successfully mapped the target spectrum of FIIN-2 in MDA-MB-453 cells through activity-based protein profiling (ABPP), and established a robust framework for employing our probe as a generalizable tool to systematically evaluate the on- and off-target activities of prospective FGFR covalent inhibitors. Overall, the FGFR ABP offers a promising strategy for elucidating the engagement of FGFR, profiling the target specificity and mechanisms of covalent FGFR inhibitors, and offering potential avenues for overcoming drug resistance.

Aberrant signaling via fibroblast growth factor 19 (FGF19)/fibroblast growth factor receptor 4 (FGFR4) has been identified as a driver of tumorigenesis and the development of many solid tumors, making FGFR4 is a promising target for anticancer therapy. Herein, we designed and synthesized a series of bis-acrylamide covalent FGFR4 inhibitors and evaluated their inhibitory activity against FGFRs, FGFR4 mutants, and their antitumor activity. CXF-007, verified by mass spectrometry and crystal structures to form covalent bonds with Cys552 of FGFR4 and Cys488 of FGFR1, exhibited stronger selectivity and potent inhibitory activity for FGFR4 and FGFR4 cysteine mutants. Moreover, CXF-007 exhibited significant antitumor activity in hepatocellular carcinoma cell lines and breast cancer cell lines through sustained inhibition of the FGFR4 signaling pathway. In summary, our study highlights a novel covalent FGFR4 inhibitor, CXF-007, which has the potential to overcome drug-induced FGFR4 mutations and might provide a new strategy for future anticancer drug discovery.

Mercury is a highly toxic heavy metal and it poses a serious threat to the natural environment and human health. Thus, selective detection of trace mercury (e.g. inorganic mercury and methylmercury) in the environment is critical yet challenging. Herein, we describe the rational design and facile synthesis of a new triphenylamine-based phenylboronic acid fluorescent probe (TPA-PBA) for selective detection of Hg2+ and CH3Hg+. Due to the inherent specificity of the displacement reaction between phenylboronic acid and mercury, this probe exhibits exceptionally high selectivity towards Hg2+/CH3Hg+ against other tested ions with ppb-level sensitivity. More importantly, the probe TPA-PBA is effective and selective in detecting Hg2+/CH3Hg+ in tap water and real-world groundwater, indicating its potential practical applications in in situ and online mercury detection in real-world scenarios. With TPA-PBA based test strips Hg2+ can be distinguished from CH3Hg+ by the naked eye. This study could accelerate the development of low-cost, highly efficient and selective fluorescent probes for rapid trace mercury detection.

Because of the electron-rich property of indoles, direct functionalization strategies towards indoles generally involve electrophilic substitutions. In this paper, an efficient protocol for nucleophilic hydroxylation, halogenation and esterification of indoles via the aromatic Pummerer process was developed. With the advantages of readily accessible starting materials, simple operation and mild conditions, this protocol should be of interest to synthetic scientists.

Macrocyclization proves a useful strategy for obtaining artificial supramolecular hosts via reducing the degrees of freedom of the corresponding precursors. However, synthesis of receptor containing multiple macrocycles is challenging. In this contribution, we describe the rational design and synthesis of a new class of organometallic trimacrocyclic hexasubstituted benzenes 1 and 2 via either metal–ligand coordination or dynamic covalent chemistry strategies. Such class of constructs feature a benzene core fused by three identical metallomacrocycles with high symmetry and interesting physiochemical property, as inferred from the NMR, mass spectrometry, cyclic voltammetry and DFT calculations. Trimacrocycle 2 bearing one ferrocene unit in each sub–macrocycle was found able to selectively capture bromide and iodide, as evidenced by NMR spectroscopy, DFT calculations, as well as molecular dynamics simulations. Thus, we hope this study will somewhat accelerate the development of complex functional host–guest systems for species of interest.

The fibroblast growth factor 19 (FGF19)/fibroblast growth factor receptor 4 (FGFR4) signaling pathways play critical roles in a variety of cancers, such as hepatocellular carcinoma (HCC). FGFR4 is recognized as a promising target to treat HCC. Currently, all FGFR covalent inhibitors target one of the two cysteines (Cys477 and Cys552). Here, we designed and synthesized a dual-warhead covalent FGFR4 inhibitor, CXF-009, targeting Cys477 and Cys552 of FGFR4. We report the cocrystal structure of FGFR4 with CXF-009, which exhibits a dual-warhead covalent binding mode. CXF-009 exhibited stronger selectivity for FGFR4 than FGFR1-3 and other kinases. CXF-009 can also potently inhibit the single cystine mutants, FGFR4(C477A) and FGFR4(C552A), of FGFR4. In summary, our study provides a dual-warhead covalent FGFR4 inhibitor that can covalently target two cysteines of FGFR4. CXF-009, to our knowledge, is the first reported inhibitor that forms dual-warhead covalent bonds with two cysteine residues in FGFR4. CXF-009 also has the potential to overcome drug induced resistant FGFR4 mutations and might serve as a lead compound for future anticancer drug discovery.

Androgen receptor (AR) and histone deacetylase 6 (HDAC6) are important targets for cancer therapy. Given that both AR antagonists and HDAC6 inhibitors modulate AR signaling, a novel AR/HDAC6 dual inhibitor is investigated for its anticancer effects in castration-resistant prostate cancer (CRPC). Zeta55 inhibits nuclear translocation of AR and suppresses androgen-induced PSA and TMPRSS2 expression. Meanwhile, Zeta55 selectively inhibits HDAC6 activity, leading to AR degradation. Zeta55 reduces the growth of AR-overexpressing VCaP prostate cancer cells both in vitro and in a CRPC xenograft model. These results provide preclinical proof of principle for Zeta55 as a promising therapeutic in prostate cancer treatment.

Calix[4]pyrrole 1 can form host-guest complexes with certain thallium salts, for example, TlF, not only in the gas phase but also in solution and in the solid state. The complexation of TlF by calix[4]pyrrole 1 was found to promote self-assembly and the formation of well-defined and highly ordered fibrous supramolecular morphologies, as revealed by polarizing microscopy and scanning electron microscopy. The findings reported here serve to broaden the scope of cationic substrates that may be complexed as ion pairs by calix[4]pyrrole receptors while setting the stage for the development of new hosts for thallium(I) salts.

Empagliflozin is an effective sodium glucose cotransporter-2 (SGLT2) inhibitor to improve glycemic control in adults with type 2 diabetes. During the manufacture of empagliflozin, three unknown impurities were discovered in pilot batches ranging from 0.05 % to 0.15 % by LC analysis. These unknown impurities were isolated from the crystallization mother liquor by column chromatography and semi-preparative LC, and their structures were elucidated by comprehensive analysis of HRMS, 1D-NMR (1H, 13C) and 2D-NMR (1H-1H COSY, HSQC, HMBC) spectroscopy data. The plausible mechanistic pathways to the formation of these three impurities were also discussed.

We report what to our knowledge is the smallest bis-calix[4]pyrrole (2). It proved capable of trapping fluoride anions exclusively relative to other anions (Cl-, Br-, SCN-, NO3-, H2PO4-, HSO4-, SO42-, and HP2O73-; tetrabutylammonium salts), as confirmed by 1H NMR spectroscopy (CDCl3), X-ray diffraction analysis, DFT calculations, and molecular dynamics simulations. The F- selectivity is ascribed to the small size of the cavity in 2.

A novel supramolecular conjugate was conveniently fabricated by the non-covalent interaction between 4-amido-1,8-naphthalimide bridged permethyl-β-cyclodextrins and tetrasodium tetraphenylporphyrintetrasulfonate, which was comprehensively characterized by the methods of UV–Vis, NMR, AFM, and TEM, respectively. Significantly, the efficient excited energy transfer process from 4-amido-1,8-naphthalimide to porphyrin was investigated, showing that efficiency of excited energy transfer is high to 99% within the artificial nanoassembly.

Here the synthetic utility of fluoroacetate dehalogenase RPA1163 is explored for the production of enantiomerically pure (R)-α-fluorocarboxylic acids and (R)-α-hydroxylcarboxylic acids via kinetic ...

Biochemical and structural studies provide information on the mode of action of FGF401 as a selective, reversible covalent inhibitor of FGFR4. Kinase and proliferation assays reveal that FGF401 has the ability to overcome gatekeeper mutations in FGFR4.

Fibroblast growth factor receptors (FGFRs) are a family of receptor tyrosine kinases expressed on the cell membrane that play crucial roles in both developmental and adult cells. Dysregulation of FGFRs has been implicated in a wide variety of cancers, such as urothelial carcinoma, hepatocellular carcinoma, ovarian cancer and lung adenocarcinoma. Due to their functional importance, FGFRs have been considered as promising drug targets for the therapy of various cancers. Multiple small molecule inhibitors targeting this family of kinases have been developed, and some of them are in clinical trials. Furthermore, the pan-FGFR inhibitor erdafitinib (JNJ-42756493) has recently been approved by the U.S. Food and Drug Administration (FDA) for the treatment of metastatic or unresectable urothelial carcinoma (mUC). This review summarizes the structure of FGFR, especially its kinase domain, and the development of small molecule FGFR inhibitors.

The classic Pummerer reaction involves an α-substituted sulfide via an elimination/addition of a thionium ion. In this paper, we reported a remote para- or ortho-benzyl nucleophilic functionalization using an aromatic Pummerer process. A plausible mechanism involving a quinone thionium intermediate was proposed to explain this reaction.

The chemical compound LY2874455 has the potential to overcome drug resistance driven by FGFR gatekeeper mutations. X-ray crystallographic studies provide the structural explanation for why this compound is effective against the FGFR gatekeeper mutations.

A convenient synthesis of 3-chloro-α-carbolines by the condensation of vinamidinium salt with 2-indolinones via two steps is reported. This protocol has the advantages of readily available starting materials, high yields and easy workup.