- Small-molecule inhibitor of protein kinase A as well as preparation method and application thereof
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The invention discloses a small-molecule inhibitor of histone kinase A. The small-molecule inhibitor comprises an H89 isoquinoline precursor structure, the specific molecular formula is CxHyAzNmOnS, and in the molecular formula, x is 20 or 21, y is 20 or 22, A is F, z is 0 or 1, m is 3 or 4, and n is 2 or 4. The invention further provides small-molecule inhibitors HF89, HFC and HN89, and a PET tracer [ C] HF. The invention also provides a preparation method and an application of the related small-molecule inhibitor. A new feasible scheme is provided for early diagnosis, treatment, curative effect evaluation and the like of tumors.
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Paragraph 0055; 0061-0062
(2020/07/02)
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- Comprehensive structure-activity-relationship of azaindoles as highly potent FLT3 inhibitors
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Acute myeloid leukemia (AML) is characterized by fast progression and low survival rates, in which Fms-like tyrosine kinase 3 (FLT3) receptor mutations have been identified as a driver mutation in cancer progression in a subgroup of AML patients. Clinical trials have shown emergence of drug resistant mutants, emphasizing the ongoing need for new chemical matter to enable the treatment of this disease. Here, we present the discovery and topological structure-activity relationship (SAR) study of analogs of isoquinolinesulfonamide H-89, a well-known PKA inhibitor, as FLT3 inhibitors. Surprisingly, we found that the SAR was not consistent with the observed binding mode of H-89 in PKA. Matched molecular pair analysis resulted in the identification of highly active sub-nanomolar azaindoles as novel FLT3-inhibitors. Structure based modelling using the FLT3 crystal structure suggested an alternative, flipped binding orientation of the new inhibitors.
- Grimm, Sebastian H.,Gagestein, Berend,Keijzer, Jordi F.,Liu, Nora,Wijdeven, Ruud H.,Lenselink, Eelke B.,Tuin, Adriaan W.,van den Nieuwendijk, Adrianus M.C.H.,van Westen, Gerard J.P.,van Boeckel, Constant A.A.,Overkleeft, Herman S.,Neefjes, Jacques,van der Stelt, Mario
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supporting information
p. 692 - 699
(2019/01/22)
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- Compounds for treating central nervous system degenerative diseases or brain tumor and application thereof
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The invention relates to compounds and a medicine composition for treating central nervous system degenerative diseases or brain tumor and application thereof. The compounds have the structure of the formula (see the formula in the description) and can se
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Paragraph 0022
(2017/07/07)
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- A Whole Proteome Inventory of Background Photocrosslinker Binding
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Affinity-based protein profiling (AfBPP) is a widely applied method for the target identification of bioactive molecules. Probes containing photocrosslinkers, such as benzophenones, diazirines, and aryl azides, irreversibly link the molecule of interest t
- Kleiner, Philipp,Heydenreuter, Wolfgang,Stahl, Matthias,Korotkov, Vadim S.,Sieber, Stephan A.
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p. 1396 - 1401
(2017/01/24)
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- Photo-crosslinking of clinically relevant kinases using H89-derived photo-affinity probes
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The profiling of kinases using established proteomics techniques is hampered by their non-covalent mode-of-action. One way to overcome this caveat is the use of probes featuring photo-labelling groups that can be activated by UV irradiation to generate a reactive species that will establish a covalent bond to the enzyme. In this study we have used the well-known kinase inhibitor H89 as a lead for the development of probes for the affinity-based profiling of clinically relevant kinases. A labelling protocol was established for recombinant kinases and more complex protein mixtures using gel-based techniques. We also show that the probes act in a competitive manner with other kinase inhibitors.
- Stolze, Sara C.,Liu, Nora,Wijdeven, Ruud H.,Tuin, Adriaan W.,Van Den Nieuwendijk, Adrianus M. C. H.,Florea, Bogdan I.,Van Der Stelt, Mario,Van Der Marel, Gijsbert A.,Neefjes, Jacques J.,Overkleeft, Herman S.
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p. 1809 - 1817
(2016/06/09)
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- Exploration of N-(2-aminoethyl)piperidine-4-carboxamide as a potential scaffold for development of VEGFR-2, ERK-2 and Abl-1 multikinase inhibitor
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VEGFR, ERK and Abl had been respectively identified as good drug targets, and their crosstalk also had been well elaborated. Multitarget drugs were more advantageous for cancer treatment, however, no inhibitors simultaneously acting on the three proteins were developed due to their structural diversities. Herein, N-(4-((2-(2-(naphthaen-1-yl)acetamido)ethyl)carbamoyl)piperidin-4-yl)-6- (trifluoromethyl)nicotinamide (NEPT, 6a) was discovered as an active scaffold against VEGFR-2, ERK-2 and Abl-1 kinases through the combination of support vector machine, similarity searching and molecular docking. NEPT and its derivatives were synthesized by convenient routine, their in vitro anti-proliferative abilities against human liver cancer cell line HepG2 were preliminarily evaluated. A representative compound 6b showed an IC50 value of 11.3 μM and induced significant HepG2 cells apoptosis. Besides, these compounds displayed better anti-proliferative abilities against K562 cells (a cell line with typical hyperactivity of the above multikinases), for example compound 6b exhibited an IC50 value of 4.5 μM. Based on hepatotoxicity case reports of Abl inhibitors, cytotoxicity of synthetic compounds against normal liver cell lines (QSG7701 and HL7702) was studied, 6b had a similar toxic effect with positive control imatinib, and most compounds showed less than 35% inhibition activities at 100 μM. Molecular docking study disclosed interactions of 6b with VEGFR-2, ERK-2 and Abl-1 kinases, respectively. Our data suggested the biological activities of 6b may derived from collaborative effects of VEGFR-2, ERK-2 and Abl-1 inhibition.
- Jin, Feng,Gao, Dan,Wu, Qin,Liu, Feng,Chen, Yuzong,Tan, Chunyan,Jiang, Yuyang
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p. 5694 - 5706
(2013/09/12)
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- Structure-based design of isoquinoline-5-sulfonamide inhibitors of protein kinase B
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Structure-based drug design of novel isoquinoline-5-sulfonamide inhibitors of PKB as potential antitumour agents was investigated. Constrained pyrrolidine analogues that mimicked the bound conformation of linear prototypes were identified and investigated by co-crystal structure determinations with the related protein PKA. Detailed variation in the binding modes between inhibitors with similar overall conformations was observed. Potent PKB inhibitors from this series inhibited GSK3β phosphorylation in cellular assays, consistent with inhibition of PKB kinase activity in cells.
- Collins, Ian,Caldwell, John,Fonseca, Tatiana,Donald, Alastair,Bavetsias, Vassilios,Hunter, Lisa-Jane K.,Garrett, Michelle D.,Rowlands, Martin G.,Aherne, G. Wynne,Davies, Thomas G.,Berdini, Valerio,Woodhead, Steven J.,Davis, Deborah,Seavers, Lisa C. A.,Wyatt, Paul G.,Workman, Paul,McDonald, Edward
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p. 1255 - 1273
(2007/10/03)
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- PHARMACEUTICAL COMPOUNDS
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The invention provides compounds for the prophylaxis or treatment of a disease state or condition mediated by protein kinase A or protein kinase B, the compounds having the formula (I°), or being salts or solvates thereof. In formula (I°), n is 0 or 1; A and E are alkylene 2-3 carbon atoms in length optionally substituted by R11 and -X-CH(R6)(R7); G is hydrogen when n is 0 and, when n is 1, G is hydrogen or -X-CH(R6)(R7); R1 is an aryl or heteroaryl group having 5-12 ring members; R2 and R4 are selected from hydrogen, R7,R11 and CH(R6)(R7); R3, R3a and R5 are selected from hydrogen, R11 and -X-CH(R6)(R7); or any one pair or any two non-overlapping pairs selected from R2 and R3; R3 and R4; R2 and R5; R3 and R5; R4 and R5; R3 and R8; and R4 and R8 are linked together in a ring and together form an alkylene chain of 1-5 carbon atoms in length which may be optionally substituted by R11 and -X-CH(R6)(R7); or the pair R2 and R4 are linked together in a ring and together form an alkylene chain of 2-5 carbon atoms in length which may be optionally substituted by R11 and -X-CH(R6)(R7); and optionally R3 and R3a may be linked together in a ring and together form an alkylene chain of 1-6 carbon atoms in length which may be optionally substituted by R11 and -X-CH(R6)(R7); or R6 and R7 together with the carbon atom to which they are attached form a cyclic group having 5-12 ring members; X, R6, R7, R8, R9, R10 and R11 are each as defined in claim 1; and wherein the definitions of, A, E, G, X, n and R1 to R11 are subject to the provisos set ou in claim 1.
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Page/Page column 67-68
(2010/02/10)
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- 5-Substituted isoquinoline derivatives
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A compound represented by the following formula (1) or a salt thereof: wherein R1 represents hydrogen atom, a halogen atom and the like; R2 represents hydrogen atom, a halogen atom, a C1-6 alkyl group and the like; and R3 represents —O—X—C(A1)(A11)—C(A2)(A2l)—N(A3l)(A3)(X represents propylene group etc., A11 and A21 represent hydrogen atom, or a C1-6 alkyl group, A31 represents a C1-6 alkyl group substituted with hydroxyl group, or hydrogen atom, and A1, A2, and A3 represent hydrogen atom, a C1-6 alkyl group and the like) and the like, which has an inhibitory activity on the phosphorylation of myosin regulatory light chain, and is useful for treatment of diseases relating to contraction of various cells and the like.
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Page 115-116
(2010/02/10)
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- Protein kinase inhibitors
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Novel isoquinoline derivatives which are useful as inhibitors of protein kinases for experimental, medical, and drug design purposes are disclosed. Preferred compounds which are specific inhibitors of protein kinase B are also disclosed. Furthermore, phar
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Page/Page column 9
(2010/02/05)
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- ISOQUINOLINE-5-SULFONIC ACID AMIDES AS INHIBITORS OF AKT (PROTEIN KINASE B)
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The present invention relates to compounds Formula (I): as inhibitors of AKT activity, which are useful for the treatment of susceptible neoplasms and viral infections.
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- Treatment of amyloidosis associated with Alzheimer disease using modulators of protein phosphorylation
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A method of regulating phosphorylation of proteins involved in controlling processing or function of key proteins found in intracellular neurofibrillary tangles and extracellular amyloid plaques associated with Alzheimer disease comprising introducing an effective amount of a kinase modulator or phosphatase modulator, the modulator capable of increasing or decreasing the rate of proteolytic processing, or modulating the function, of said key proteins.
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- Design of Potent Protein Kinase Inhibitors Using the Bisubstrate Approach
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A new class of serine/threonine protein kinase inhibitors was designed by associating, in the same structure, mimics of both the ATP binding site and a protein substrate.Among the several potent antagonists which were obtained, the most active consists of isoquinoline-5-sulfonamide, as ATP mimic, and Ser-Arg6, as peptidic moiety, bound by a -NH(CH2)2NH(CH2)2CO- linker.This compound, with a Ki of 0.1 μM toward protein kinase C (PKC) and 0.004 μM toward cyclic AMP dependent protein kinase (PKA), is respectively 60- and 750-fold more active than the commercial inhibitor H-7.
- Ricouart, A.,Gesquiere, J. C.,Tartar, A.,Sergheraet, C.
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- Isoquinolinesulfonamide derivatives
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This invention relates to novel isoquinolinesulfonamide derivatives of Formula (I): STR1 wherein A is a C0-10 alkylene group or a C0-10 alkylene group having a C1-10 alkyl group, a phenyl group, a substituted phenyl group
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