- Development of novel ACK1/TNK2 inhibitors using a fragment-based approach
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The tyrosine kinase ACK1, a critical signal transducer regulating survival of hormone-refractory cancers, is an important therapeutic target, for which there are no selective inhibitors in clinical trials to date. This work reports the discovery of novel and potent inhibitors for ACK1 tyrosine kinase (also known as TNK2) using an innovative fragment-based approach. Focused libraries were designed and synthesized by selecting fragments from reported ACK inhibitors to create hybrid structures in a mix and match process. The hybrid library was screened by enzyme-linked immunosorbent assay-based kinase inhibition and 33P HotSpot assays. Systematic structure-activity relationship studies led to the identification of compound (R)-9b, which shows potent in vitro (IC50 = 56 nM, n = 3, 33P HotSpot assay) and in vivo (IC50 1/2 > 6 h).
- Lawrence, Harshani R.,Mahajan, Kiran,Luo, Yunting,Zhang, Daniel,Tindall, Nathan,Huseyin, Miles,Gevariya, Harsukh,Kazi, Sakib,Ozcan, Sevil,Mahajan, Nupam P.,Lawrence, Nicholas J.
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- [...] aromatic amines acetylcholine esterase inhibitor synthesis and use (by machine translation)
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The present invention provides a formula for the (I) or (II) [...] aromatic amines of the acetylcholine esterase inhibitor and its pharmaceutically acceptable salt or a stereoisomer thereof, a process for their preparation and its in the preparation of acetylcholine esterase inhibitors and treatment of Alzheimer's disease and/or myasthenic application of the medicament, type definition of each group in the specification. The invention of aromatic amine derivatives as [...] of acetylcholine esterase inhibitors with micromolar level to nanomolar inhibiting activity, has further developed into an anti-Alzheimer's disease possibility of drug. (by machine translation)
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Paragraph 0087; 0089; 0091; 0092
(2018/10/19)
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- INHIBITORS OF ACK1/TNK2 TYROSINE KINASE
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Described are cancer therapies and anti-cancer compounds. In particular, disclosed are ihibitors of Ack1 tyrosine kinase and their use in the treatment of cancer. Methods of screening for new Ack1 tyrosine kinase inhibitors are also disclosed. In specifc example, compound having Formula I through IV are disclosed.
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- Piperidine derivatives
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STR1 The invention provides piperidine derivatives of general formula (I) or an acid-addition salt thereof, in which R represents an optionally substituted alkyl, cycloalkyl, aryl or heterocyclyl group: R1 represents an optionally substituted alkyl, alkenyl, akynyl, cycloalkyl, aryl or heterocyclyl group; m represents an integer from 0 to 3; and each of R2 and R3 is independently selected from a group consisting of hydrogen atoms, alkyl and phenyl groups; with the proviso that R does not represent a 4-tert-butylphenyl group; processes for their preparation; compositions containing such compounds and their use as fungicides.
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