Synthesis and Biological Evaluation of 2,4,6-Trihydroxychalcone Derivatives as Novel Protein Tyrosine Phosphatase 1B Inhibitors

A series of 2,4,6‐trihydroxychalcone derivatives were synthesized and identified as reversible and competitive protein tyrosine phosphatase (PTP) 1B inhibitors with IC₅₀ values in the micromolar range. Compound 4a had the greatest in vitro inhibition activity against PTP1B (IC₅₀ = 0.27 ± 0.01 μm ) and the best selectivity (6.9‐fold) for PTP1B relative to T‐cell protein tyrosine phosphatases. The compounds identified herein provide a foundation on which to design specific inhibitors of PTP1B and other PTPs.     

Anthraquinone Derivatives as Potent Inhibitors of c-Met Kinase and the Extracellular Signaling Pathway

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Tyrosine Kinase Inhibitors in Preclinical Development

Due to the limited efficacy of cytotoxic chemotherapy in the treatment of advanced malignancy and its excessive toxicity precluding its use in chemoprevention, new therapeutic and preventive strategies have been sought. One of the most interesting of these new approaches is the manipulation of signal transduction pathways. Among the approaches being considered to eventuate such a strategy is the inhibition of autophosphorylation, a critical first step in the signal transduction pathways of many cell surface receptor tyrosine kinases, as well as of non-receptor tyrosine kinases. This article is intended to review those tyrosine kinase inhibitors that are currently in preclinical development, for which there are data to support consideration for their use in chemoprevention or cancer treatment. We will focus upon those agents that have received attention in the past several years.     

Structure-Guided Design of Novel l-Cysteine Derivatives as Potent KSP Inhibitors

l-cysteine derivatives as selective KSP inhibitors. Here, we report further optimizations using docking modeling in the L5 allosteric binding site, which led to the discovery of several high affinity derivatives with two fused phenyl rings in the trityl group giving low nanomolar range KSP ATPase inhibition. The representative derivatives potently inhibited cell growth of HCT116 cells in correlation with KSP inhibitory activities and significantly suppressed tumor growth in the xenograft model in vivo.     

Novel Aminomethylindole Derivatives as Inhibitors of pp60c‐Src Tyrosine Kinase: Synthesis and Biological Activity

The pp60^c‐Src is one of the ubiquitously expressed Src family kinases and has important functions in malignant cells, including regulation of cell division, growth factor signaling, and movement. Therefore, investigating new small molecule inhibitors of pp60^c‐Src is important to discover and develop novel therapeutics for cancer and metastasis. Moreover, some of the small molecule inhibitors that do not qualify for therapeutic use may become very useful tool to explore the role of Src kinase in normal cells as well as in a variety of disease models. Our continuous efforts to find novel inhibitors of pp60^c‐Src aimed for therapeutic and research use, we synthesized newly designed aminomethylindole derivatives as novel small molecule inhibitors and investigated their inhibitory effect on pp60^c‐Src tyrosine kinase. Here, we report one potential inhibitor of the pp60^c‐Src from five active molecules of all nine compounds, which were synthesized and screened for the biological activity of the molecules against pp60^c‐Src target.     

荧光检测技术在蛋白酪氨酸激酶抑制剂高通量筛选中的应用

介绍荧光共振能量转移技术、荧光偏振免疫分析技术、荧光素酶-激酶检测技术和毛细管电泳-激光诱导荧光技术在酪氨酸激酶抑制剂高通量筛选模型中的应用情况。蛋白酪氨酸激酶与多种疾病的发生和发展密切相关,通过高通量筛选寻找其抑制剂已成为新药研发的热点之一。荧光检测技术因具有灵敏、易于检测、适于微量化和安全性高等优势,在药物的高通量筛选中被广泛使用。     

Synthesis and Biological Evaluation of Kojic Acid Derivatives Containing 1,2,4‐triazole as Potent Tyrosinase Inhibitors

A series of 5‐substituted‐3‐[5‐hydroxy‐4‐pyrone‐2‐yl‐methymercapto]‐4‐amino‐1,2,4‐triazole derivatives were synthesized by nucleophilic substitution reaction of 5‐hydroxy‐2‐chloromethyl ‐4H‐pyran‐4‐one with 5‐substituted‐3‐mercapto‐4‐amino‐1,2,4‐triazole, and their inhibitory effects on mushroom tyrosinase were evaluated. The results indicated that most of the synthesized compounds exhibited significant inhibitory activity. Specifically, 5‐(4‐chlorophenyl)‐3‐[5‐hydroxy‐4‐pyrone‐2‐yl‐methymercapto]‐4‐amino‐1,2,4‐triazole ( 6j ) exhibited the most potent tyrosinase inhibitory activity with IC₅₀ value of 4.50 ± 0.34 μm . The kinetic studies of the compound ( 6j ) demonstrated that the inhibitory effects of the compound on the tyrosinase were belonging to competitive inhibitors. Meanwhile, the structure–activity relationship was also discussed.     

Discovery of Novel 17-Phenylethylaminegeldanamycin Derivatives as Potent Hsp90 Inhibitors

Twenty-six 17-phenylethylamine-modified geldanamycin derivatives were synthesized and evaluated for antiproliferation activity in human cancer cell lines, LNCaP and MDA-MB-231. Five derivatives ( 2j , 2q , 2v , 2x , and 2y ) showed excellent in vitro antitumor activities. Among them, compound 2y was the most potent lead, with IC₅₀ values of 0.27 ± 0.11 and 0.86 ± 0.23 μm for LNCaP and MDA-MB-231, respectively. In particular, compound 2y was more active than its precursor geldanamycin against LNCap cells. Liver injury test in mice demonstrated that 2y group showed no significant difference for serum alanine aminotransferase (ALT) activity versus vehicle control, indicating that 2y was a promising antitumor candidate. Preliminary structure–activity relationship (SAR) and molecular dynamics (MD) simulations of this new series of geldanamycin derivatives were also investigated, suggesting a theoretical model of 17-phenylethylaminegeldanamycins binding to Hsp90.     

Evaluation of New Indole and Bromoindole Derivatives as pp60c‐Src Tyrosine Kinase Inhibitors

A series of N‐benzyl‐indole‐3‐imine‐, amine derivatives and their 5‐bromo congeners were synthesized and their biological activity were evaluated against the pp60^c‐Src tyrosine kinase target. To afford the imine derivatives, aldehydes were reacted with substituted benzylamines and the corresponding amine derivatives were obtained by NaBH₄ reduction of these imines. Except insoluble N‐benzyl‐indole‐3‐imine derivatives, all the derivatives showed some activity against the kinase target. Screening of these compounds for their biological activity revealed that among N‐benzyl‐indole derivatives, those bearing 5‐bromo substitution have the enhanced potency, where the amine derivatives were more active than imines.     

Anti-Angiogenic Activity of Selected Receptor Tyrosine Kinase Inhibitors, PD166285 and PD173074: Implications for Combination Treatment with Photodynamic Therapy

Angiogenesis, the formation of new blood vessels from an existing vasculature, is requisite for tumor growth. It entails intercellular coordination of endothelial and tumor cells through angiogenic growth factor signaling. Interruption of these events has implications in the suppression of tumor growth. PD166285, a broad-spectrum receptor tyrosine kinase (RTK) inhibitor, and PD173074, a selective FGFR₁TK inhibitor, were evaluated for their anti-angiogenic activity and anti-tumor efficacy in combination with photodynamic therapy (PDT). To evaluate the anti-angiogenic and anti-tumor activities of these compounds, RTK assays, in vitro tumor cell growth and microcapillary formation assays, in vivo murine angiogenesis and anti-tumor efficacy studies utilizing RTK inhibitors in combination with photodynamic therapy were performed. PD166285 inhibited PDGFR--, EGFR-, and FGFR₁TKs and c-src TK by 50% (IC₅₀) at concentrations between 7–85nM. PD173074 displayed selective inhibitory activity towards FGFR₁TK at 26nM. PD173074 demonstrated (>100 fold) selective growth inhibitory action towards human umbilical vein endothelial cells compared with a panel of tumor cell lines. Both PD166285 and PD173074 (at 10nM) inhibited the formation of microcapillaries on Matrigel-coated plastic. In vivo anti-angiogenesis studies in mice revealed that oral administration (p.o.) of either PD166285 (1–25 mg/kg) or PD173074 (25–100 mg/kg) generated dose dependent inhibition of angiogenesis. Against a murine mammary 16c tumor, significantly prolonged tumor regressions were achieved with daily p.o. doses of PD166285 (5–10 mg/kg) or PD173074 (30–60 mg/kg) following PDT compared with PDT alone (p<0.001). Many long-term survivors were also noted in combination treatment groups. PD166285 and PD173074 displayed potent anti-angiogenic and anti-tumor activity and prolonged the duration of anti-tumor response to PDT. Interference in membrane signal transduction by inhibitors of specific RTKs (e.g. FGFR₁TK) should result in new chemotherapeutic agents having the ability to limit tumor angiogenesis and regrowth following cytoreductive treatments such as PDT.     

Structural Insights for Design of Potent Spleen Tyrosine Kinase Inhibitors from Crystallographic Analysis of Three Inhibitor Complexes

Spleen tyrosine kinase is considered an attractive drug target for the treatment of allergic and antibody mediated autoimmune diseases. We have determined the co‐crystal structures of spleen tyrosine kinase complexed with three known inhibitors: YM193306, a 7‐azaindole derivative and R406. The cis‐cyclohexyldiamino moiety of YM193306 is forming four hydrophobically shielded polar interactions with the spleen tyrosine kinase protein and is therefore crucial for the high potency of this inhibitor. Its primary amino group is inducing a conformational change of the spleen tyrosine kinase DFG Asp side chain. The crystal structure of the 7‐azaindole derivative bound to spleen tyrosine kinase is the first demonstration of a 2‐substituted 7‐azaindole bound to a protein kinase. Its indole‐amide substituent is tightly packed between the N‐ and C‐terminal kinase lobes. The co‐crystal structure of the spleen tyrosine kinase–R406 complex shows two main differences to the previously reported structure of spleen tyrosine kinase soaked with R406: (i) the side chain of the highly conserved Lys is disordered and not forming a hydrogen bond to R406 and (ii) the DFG Asp side chain is pointing away from and not towards R406. The novel protein–ligand interactions and protein conformational changes revealed in these structures guide the rational design and structure‐based optimization of second‐generation spleen tyrosine kinase inhibitors.     

NMR-Based Design and Evaluation of Novel Bidentate Inhibitors of the Protein Tyrosine Phosphatase YopH

We describe the use of a furanyl salicyl nitroxide derivative (‘spin-labeled’ compound), as a paramagnetic phosphotyrosine mimetic, to carry out a second-site screening by NMR against the PTPase YopH from Yersinia pestis. Using such a fragment-based screening approach we identified several small molecules targeting YopH that bind at sites adjacent to the spin-labeled compound. These second-site fragments were subsequently used to design and synthesize bidentate YopH inhibitors with submicromolar in vitro inhibition, selectivity against the human PTPase PTP1B, and cellular activity against Y. pseudotuberculosis. These initial compounds could result useful in elucidating the structural determinants necessary for YopH inhibition and may help in the design of even more active, selective and cell permeable compounds for the development of novel therapies against Yersiniae.     

Highly Selective and Potent Thiophenes as PI3K Inhibitors with Oral Antitumor Activity

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General Ser/Thr Kinases Pharmacophore Approach for Selective Kinase Inhibitors Search as Exemplified by Design of Potent and Selective Aurora A Inhibitors

A general pharmachophore model for various types of Ser/Thr kinases was developed. Search for the molecules fitting to this pharmacophore among ASINEX proprietary library revealed a number of compounds, which were tested and appeared to possess some activity against several Ser/Thr kinases such as Aurora A, Aurora B and Haspin. The possibility of performing the fine‐tuning of the general Ser/Thr pharmacophore to desired types of kinase to get active and selective inhibitors was exemplified by Aurora A kinase. As a result, several hits in 3–5 nm range of activity against Aurora A kinase with rather good selectivity and ADME properties were obtained.     

Pyridopyrimidinone Derivatives as Potent and Selective c-Jun N-Terminal Kinase (JNK) Inhibitors

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