The water-soluble peptidylhydroxamic acid FN439 is a broad-spectrum inhibitor of human matrix metalloproteinases. 4-Abz-Gly-Pro-D-Leu-D-Ala-NHOH retains its activity even after prolonged incubation with pronase or human granulocyte elastase. FN 439 inhibits interstitial and granulocyte collagenases, granulocyte gelatinase and skin fibroblast stromelysin with IC?? of 1 · 10?? M, 3 · 10?? M and 1.5 · 10?? M, respectively. 

水溶性肽基羥肟酸FN439是一種廣譜的人基質(zhì)金屬蛋白酶抑制劑。4-Abz-Gly-Pro-D-Leu-D-Ala-NHOH即使在與pronase或人粒細(xì)胞彈性酶長時間孵育后仍保持其活性。FN 439抑制間質(zhì)和粒細(xì)胞膠原酶，粒細(xì)胞明膠酶和皮膚成纖維細(xì)胞基質(zhì)酶，IC??分別為1·10??M, 3·10??M和1.5·10??M。

很多蛋白在細(xì)胞中非常容易被降解，或被標(biāo)記，進(jìn)而被選擇性地破壞。但含有部分D型氨基酸的多肽則顯示了很強(qiáng)的抵抗蛋白酶降解能力。

1.Synergistic Effect of the Combination of Novel Suberoylanilide Hydroxamic Acid Derivatives with Cisplatin on Anti-proliferation of Human Cancer Cells.
Xie R, Shi J, Cheng C, Yun F, Liu X, Tang P, Wu X, Yang M, Yuan Q1. Med Chem. 2016 Apr 4. [Epub ahead of print]
A novel, green, and atom-economical boric acid catalyzed direct amidation without the use of any coupling agents for the preparation of suberoylanilide hydroxamic acid (SAHA) and SAHA-based inhibitors targeting anti-proliferation of cancer cells is provided. The new SAHA-based inhibitor B123, when used alone, exhibited higher anti-proliferative activities than SAHA or Cisplatin against a number of human cancer cells. We have examined the effect of combination of these SAHA-based inhibitors with Cisplatin. We found synergistic effects of the combination of SAHA-based inhibitors with Cisplatin over a wide range of concentrations against human liver cancer cells HepG2 and two human lung cancer cell lines H1299 and H460. This synergism leads to up to 8-fold of dose reduction for Cisplatin in the combination with our synthesized inhibitor B123 against H1299.
2.Disarming an Electrophilic Warhead: Retaining Potency in Tyrosine Kinase Inhibitor (TKI)-Resistant CML Lines While Circumventing Pharmacokinetic Liabilities.
Ali AM1,2, Gómez-Biagi RF1, Rosa DA1, Lai PS1, Heaton WL3, Park JS1, Eiring AM4, Vellore NA4, de Araujo ED1, Ball DP1, Shouksmith AE1, Patel AB4, Deininger MW4, O'Hare T4, Gunning PT5. ChemMedChem. 2016 Mar 30. doi: 10.1002/cmdc.201600021. [Epub ahead of print]
Pharmacologic blockade of the activation of signal transducer and activator of transcription?3 (STAT3) in tyrosine kinase inhibitor (TKI)-resistant chronic myeloid leukemia (CML) cell lines characterized by kinase-independent resistance was shown to re-sensitize CML cells to TKI therapy, suggesting that STAT3 inhibitors in combination with TKIs are an effective combinatorial therapeutic for the treatment of CML. Benzoic acid- and hydroxamic acid-based STAT3 inhibitors SH-4-054 and SH-5-007, developed previously in our laboratory, demonstrated promising activity against these resistant CML cell lines. However, pharmacokinetic studies in murine models (CD-1 mice) revealed that both SH-4-054 and SH-5-007 are susceptible to glutathione conjugation at the para position of the pentafluorophenyl group via nucleophilic aromatic substitution (SN Ar). To determine whether the electrophilicity of the pentafluorophenyl sulfonamide could be tempered, an in-depth structure-activity relationship (SAR) study of the SH-4-054 scaffold was conducted.
3.Unprecedented binding mode of hydroxamate-based inhibitors of glutamate carboxypeptidase II: structural characterization and biological activity.
Novakova Z, Wozniak K, Jancarik A, Rais R, Wu Y, Pavlicek J, Ferraris DV, Havlinova B, Ptacek J, Vavra J, Hin N, Rojas C, Majer P, Slusher BS, Tsukamoto T, Barinka C. J Med Chem. 2016 Apr 13. [Epub ahead of print]
Inhibition of glutamate carboxypeptidase II (GCPII) is effective in preclinical models of neurological disorders associated with excessive activation of glutamatergic systems. Here we report synthesis, structural characterization and biological activity of new hydroxamic acid-based inhibitors with nanomolar affinity for human GCPII. Crystal structures of GCPII/hydroxamate complexes revealed an unprecedented binding mode in which the putative P1' glutarate occupies the spacious entrance funnel, rather than the conserved glutamate-binding S1' pocket. This unique binding mode provides a mechanistic explanation for the structure-activity relationship data, most notably the lack of enantiospecificity and the tolerance for bulky/hydrophobic functions as substituents of a canonical glutarate moiety. The in vivo pharmacokinetics profile of one of the inhibitors will be presented along with analgesic efficacy data from the rat chronic constrictive injury model of neuropathic pain.
4.Histone deacetylase inhibitor-induced cancer stem cells exhibit high pentose phosphate pathway metabolism.
Debeb BG1,2, Lacerda L1,2, Larson R1,2, Wolfe AR1,2, Krishnamurthy S3,2, Reuben JM4,2, Ueno NT5,2, Gilcrease M3, Woodward WA1,2. Oncotarget. 2016 Apr 7. doi: 10.18632/oncotarget.8631. [Epub ahead of print]
PURPOSE: We recently demonstrated that histone deacetylase (HDAC) inhibitors can "reprogram" differentiated triple-negative breast cancer cells to become quiescent stem-like cancer cells. We hypothesized that the metabolic state of such cells differs from that of their differentiated progeny.