scholarly journals DESIGN AND SYNTHESIS OF NOVEL PYRIMIDINE ANALOGS AS ANTI-TUBERCULAR AGENTS TARGETING THYMIDINE KINASE DOMAIN

2021 ◽  
Vol 10 ◽  
Author(s):  
Jainey P. James
Keyword(s):  
Thymidine Kinase ◽  
Kinase Domain ◽  
Design And Synthesis ◽  
Pyrimidine Analogs

Molecular Design of a “Two-in-One” Orthosteric-Allosteric Chimeric Mutant Selective EGFR Inhibitor

2020 ◽  
Author(s):  
Florian Wittlinger ◽  
david heppner ◽  
Ciric To ◽  
Marcel Guenther ◽  
Bo Hee Shin ◽  
...  
Keyword(s):  
Molecular Design ◽  
Growth Factor Receptor ◽  
Kinase Domain ◽  
Egfr Inhibitor ◽  
Allosteric Site ◽  
Generation Agent ◽  
Design And Synthesis ◽  
Activating Mutations ◽  
Allosteric Sites ◽  
Successive Generations

Inhibitors developed to target the epidermal growth factor receptor (EGFR) are an effective therapy for patients with non-small cell lung cancer harbouring drug-sensitive activating mutations in the EGFR kinase domain. Drug resistance due to treatment-acquired mutations within the receptor itself has motivated development of successive generations of inhibitors that bind in the ATP-site, and third-generation agent osimertinib is now a first-line treatment for this disease. More recently, allosteric inhibitors have been developed to overcome the C797S mutation that confers resistance to osimertinib. In this study, we present the rational structure-guided design and synthesis of a mutant-selective EGFR inhibitor that spans the ATPand allosteric sites. The lead compound consists of a pyridinyl imidazole scaffold that binds irreversibly in the orthosteric site fused with a benzylisoindolinedione occupying the allosteric site. The compound potently inhibits enzymatic activity in L858R/T790M/C797S mutant EGFR (4.9 nM), with relative sparing of wild-type EGFR (47 nM). Additionally, this compound achieves cetuximab-independent, mutant-selective cellular efficacy on the L858R and L858R/T790M variants

Molecular Design of a “Two-in-One” Orthosteric-Allosteric Chimeric Mutant Selective EGFR Inhibitor

2020 ◽  
Author(s):  
Florian Wittlinger ◽  
david heppner ◽  
Ciric To ◽  
Marcel Guenther ◽  
Bo Hee Shin ◽  
...  
Keyword(s):  
Molecular Design ◽  
Growth Factor Receptor ◽  
Kinase Domain ◽  
Egfr Inhibitor ◽  
Allosteric Site ◽  
Generation Agent ◽  
Design And Synthesis ◽  
Activating Mutations ◽  
Allosteric Sites ◽  
Successive Generations

Inhibitors developed to target the epidermal growth factor receptor (EGFR) are an effective therapy for patients with non-small cell lung cancer harbouring drug-sensitive activating mutations in the EGFR kinase domain. Drug resistance due to treatment-acquired mutations within the receptor itself has motivated development of successive generations of inhibitors that bind in the ATP-site, and third-generation agent osimertinib is now a first-line treatment for this disease. More recently, allosteric inhibitors have been developed to overcome the C797S mutation that confers resistance to osimertinib. In this study, we present the rational structure-guided design and synthesis of a mutant-selective EGFR inhibitor that spans the ATPand allosteric sites. The lead compound consists of a pyridinyl imidazole scaffold that binds irreversibly in the orthosteric site fused with a benzylisoindolinedione occupying the allosteric site. The compound potently inhibits enzymatic activity in L858R/T790M/C797S mutant EGFR (4.9 nM), with relative sparing of wild-type EGFR (47 nM). Additionally, this compound achieves cetuximab-independent, mutant-selective cellular efficacy on the L858R and L858R/T790M variants

Different affinity of the two forms of human cytosolic thymidine kinase towards pyrimidine analogs

1995 ◽  
Vol 1250 (2) ◽  
pp. 158-162 ◽  
Author(s):  
Birgitte Munch-Petersen ◽  
Gerda Tyrsted ◽  
Lisbeth Cloos ◽  
Rainer A. Beck ◽  
Kurt Eger
Keyword(s):  
Thymidine Kinase ◽  
Pyrimidine Analogs

Design and synthesis of novel pyrimidine analogs as highly selective, non-covalent BTK inhibitors

2018 ◽  
Vol 28 (2) ◽  
pp. 145-151 ◽  
Author(s):  
Wataru Kawahata ◽  
Tokiko Asami ◽  
Takayuki Irie ◽  
Masaaki Sawa
Keyword(s):  
Design And Synthesis ◽  
Pyrimidine Analogs ◽  
Btk Inhibitors

scholarly journals Rational Design and Synthesis of Diverse Pyrimidine Molecules Bearing Sulfonamide Moiety as Novel ERK Inhibitors

2019 ◽  
Vol 20 (22) ◽  
pp. 5592 ◽  
Author(s):  
Halawa ◽  
Eskandrani ◽  
Elgammal ◽  
Hassan ◽  
Hassan ◽  
...  
Keyword(s):  
Map Kinase ◽  
Rational Design ◽  
Binding Pocket ◽  
Kinase Domain ◽  
Effector Proteins ◽  
Cellular Functions ◽  
Oncogenic Signaling ◽  
Design And Synthesis ◽  
Mitogen Activated Protein ◽  
Erk Kinase

Protein kinases orchestrate diverse cellular functions; however, their dysregulation is linked to metabolic dysfunctions, associated with many diseases, including cancer. Mitogen-Activated Protein (MAP) kinase is a notoriously oncogenic signaling pathway in human malignancies, where the extracellular signal-regulated kinases (ERK1/2) are focal serine/threonine kinases in the MAP kinase module with numerous cytosolic and nuclear mitogenic effector proteins. Subsequently, hampering the ERK kinase activity by small molecule inhibitors is a robust strategy to control the malignancies with aberrant MAP kinase signaling cascades. Consequently, new heterocyclic compounds, containing a sulfonamide moiety, were rationally designed, aided by the molecular docking of the starting reactant 1-(4-((4-methylpiperidin-1-yl)sulfonyl)phenyl)ethan-1-one (3) at the ATP binding pocket of the ERK kinase domain, which was relying on the molecular extension tactic. The identities of the synthesized compounds (4–33) were proven by their spectral data and elemental analysis. The target compounds exhibited pronounced anti-proliferative activities against the MCF-7, HepG-2, and HCT-116 cancerous cell lines with potencies reaching a 2.96 μM for the most active compound (22). Moreover, compounds 5, 9, 10b, 22, and 28 displayed a significant G2/M phase arrest and induction of the apoptosis, which was confirmed by the cell cycle analysis and the flow cytometry. Thus, the molecular extension of a small fragment bounded at the ERK kinase domain is a valid tactic for the rational synthesis of the ERK inhibitors to control various human malignancies.

Prostatic Acid Phosphatase (PAP) Differentiated Ultracytochemically from Lysosomal Acid Phosphate in the Rat with a PAP/Specific Substrate, Phosphorylcholine

1975 ◽  
Vol 33 ◽  
pp. 450-451
Author(s):  
W. Allen Shannon ◽  
José A. Serrano ◽  
Hannah L. Wasserkrug ◽  
Anna A. Serrano ◽  
Arnold M. Seligman
Keyword(s):  
Acid Phosphatase ◽  
Phosphate Buffer ◽  
Prostatic Carcinoma ◽  
Prostatic Acid Phosphatase ◽  
Chemotherapeutic Agents ◽  
Specific Substrate ◽  
Acid Phosphate ◽  
Lysosomal Acid ◽  
Design And Synthesis ◽  
New Chemotherapeutic Agents

During the design and synthesis of new chemotherapeutic agents for prostatic carcinoma based on phosphorylated agents which might be enzyme-activated to cytotoxicity, phosphorylcholine, [(CH3)3+NCH2CH2OPO3Ca]Cl-, has been indicated to be a very specific substrate for prostatic acid phosphatase (PAP). This phenomenon has led to the development of specific histochemical and ultracytochemical methods for PAP using modifications of the Gomori lead method for acid phosphatase. Comparative histochemical results in prostate and kidney of the rat have been published earlier with phosphorylcholine (PC) and β-glycerophosphate (βGP). We now report the ultracytochemical results.Minced tissues were fixed in 3% glutaraldehyde-0.1 M phosphate buffered (pH 7.4) for 1.5 hr and rinsed overnight in several changes of 0.05 M phosphate buffer (pH 7.0) containing 7.5% sucrose. Tissues were incubated 30 min to 2 hr in Gomori acid phosphatase medium (2) containing 0.1 M substrate, either PC or βGP.

Tailoring microstructures of materials through biomimetics

1993 ◽  
Vol 51 ◽  
pp. 500-501
Author(s):  
Mehmet Sarikaya ◽  
Ilhan A. Aksay
Keyword(s):  
Chemical Properties ◽  
Design And Synthesis ◽  
Structure Sensitive ◽  
Macro Scale ◽  
Methods Of Synthesis ◽  
Successive Level ◽  
Engineering Materials ◽  
Physical And Chemical ◽  
And Chemical Properties ◽  
Synthesis Of Materials

Biomimetics involves investigation of structure, function, and methods of synthesis of biological composite materials. The goal is to apply this information to the design and synthesis of materials for engineering applications.Properties of engineering materials are structure sensitive through the whole spectrum of dimensions from nanometer to macro scale. The goal in designing and processing of technological materials, therefore, is to control microstructural evolution at each of these dimensions so as to achieve predictable physical and chemical properties. Control at each successive level of dimension, however, is a major challenge as is the retention of integrity between successive levels. Engineering materials are rarely fabricated to achieve more than a few of the desired properties and the synthesis techniques usually involve high temperature or low pressure conditions that are energy inefficient and environmentally damaging.In contrast to human-made materials, organisms synthesize composites whose intricate structures are more controlled at each scale and hierarchical order.

Design and synthesis of azaisoflavones

Planta Medica ◽  
2008 ◽  
Vol 74 (09) ◽  
Author(s):  
B Kang ◽  
YJ Jung ◽  
R Jeon
Keyword(s):  
Design And Synthesis

Computer Modeling-Assisted Design And Synthesis Of Flavonols Derivatives As Proteasome Inhibitors

Planta Medica ◽  
2016 ◽  
Vol 82 (05) ◽  
Author(s):  
KY Orabi ◽  
MS Abaza ◽  
KA ElSayed ◽  
AY Elnagar ◽  
SI Faggal ◽  
...  
Keyword(s):  
Computer Modeling ◽  
Proteasome Inhibitors ◽  
Design And Synthesis
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