102359-00-2Relevant articles and documents
Novel Human Aminopeptidase N Inhibitors: Discovery and Optimization of Subsite Binding Interactions
Lee, Jisook,Vinh, Natalie B.,Drinkwater, Nyssa,Yang, Wei,Kannan Sivaraman, Komagal,Schembri, Luke S.,Gazdik, Michelle,Grin, Peter M.,Butler, Georgina S.,Overall, Christopher M.,Charman, Susan A.,McGowan, Sheena,Scammells, Peter J.
, p. 7185 - 7209 (2019/08/28)
Aminopeptidase N (APN/CD13) is a zinc-dependent M1 aminopeptidase that contributes to cancer progression by promoting angiogenesis, metastasis, and tumor invasion. We have previously identified hydroxamic acid-containing analogues that are potent inhibitors of the APN homologue from the malarial parasite Plasmodium falciparum M1 aminopeptidase (PfA-M1). Herein, we describe the rationale that underpins the repurposing of PfA-M1 inhibitors as novel APN inhibitors. A series of novel hydroxamic acid analogues were developed using a structure-based design approach and evaluated their inhibition activities against APN. N-(2-(Hydroxyamino)-2-oxo-1-(3′,4′,5′-trifluoro-[1,1′-biphenyl]-4-yl)ethyl)-4-(methylsulfonamido)benzamide (6ad) proved to be an extremely potent inhibitor of APN activity in vitro, selective against other zinc-dependent enzymes such as matrix metalloproteases, and possessed limited cytotoxicity against Ad293 cells and favorable physicochemical and metabolic stability properties. The combined results indicate that compound 6ad may be a useful lead for the development of anticancer agents.
Synthesis, anti-lung cancer activity and molecular docking study of 3-methylene-2-oxoindoline-5-carboxamide derivatives
Ai, Juntao,Lv, Meng,Li, Xiaohui,Chen, Zhuo,Hu, Gaoyun,Li, Qianbin
, p. 161 - 170 (2018/04/17)
A series of 3-methylene-2-oxoindoline-5-carboxamide derivatives were synthesized in appreciable yield by using 4-aminobenzoic acid as a starting material. The preliminary biological test results showed that most compounds displayed potent inhibitory activity against proliferation of human lung adenocarcinoma epithelial cell line (A549) in MTT assay. Compound 6l displayed the highest potency (IC50 = 3.0 μM). The western blot analysis demonstrated a correlation between anti-proliferative activity of active compounds and blockade of the phosphorylation of extracellular signal-regulated kinases (ERK1/2). The docking study also provides new insights into further optimization of 3-methylene-2-oxoindoline-5-carboxamide derivatives for the discovery of more potent RAF/MEK/ERK pathway regulators as anti-lung cancer agents.
SMYD INHIBITORS
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Paragraph 0952; 0955-0957, (2017/07/18)
The present disclosure provides carboxamides and sulfonamides having Formula (I): and the pharmaceutically acceptable salts and solvates thereof, wherein A, Y, B, X, and Z are defined as set forth in the specification. The present disclosure is also directed to the use of compounds of Formula (I) to treat a disorder responsive to the blockade of SMYD proteins such as SMYD3 or SMYD2. Compounds of the present disclosure are especially useful for treating cancer.