- RAS INHIBITORS AND METHODS OF USING THE SAME
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Provided herein are compounds identified as inhibitors of KRAS protein activity that can be used to treat various diseases and disorders, such as cancer.
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Paragraph 000150
(2021/08/06)
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- Design, Synthesis, and Pharmacological Evaluation of First-in-Class Multitarget N-Acylhydrazone Derivatives as Selective HDAC6/8 and PI3Kα Inhibitors
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Targeting histone deacetylases (HDACs) and phosphatidylinositol 3-kinases (PI3Ks) is a very promising approach for cancer treatment. This manuscript describes the design, synthesis, in vitro pharmacological profile, and molecular modeling of a novel class of N-acylhydrazone (NAH) derivatives that act as HDAC6/8 and PI3Kα dual inhibitors. The surprising selectivity for PI3Kα may be related to differences in the conformation in the active site. Cellular studies showed that these compounds act in HDAC6 inhibition and the PI3/K/AKT/mTOR pathway. The compounds that are selective for inhibition of HDAC6/8 and inhibit PI3Kα show potential for the treatment of cancer.
- Alves, Marina A.,Chaves, Lorrane S.,Fernandes, Patrícia D.,Fraga, Carlos A. M.,Guerra, Fabiana S.,Rodrigues, Daniel A.,Sagrillo, Fernanda S.,Sant'Anna, Carlos M. R.,Thota, Sreekanth,de Sena M. Pinheiro, Pedro
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- Design, synthesis and evaluation of novel derivatives of orotic acid amide as potent glucokinase activators
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Background: Glucokinase activators (GKAs) represent a promising opportunity for the treatment of type 2 diabetes due to the fact that glucokinase (GK) is a key regulator of glucose homeostasis. Method: Based on structure-based design strategies, a series of novel orotic acid amide derivatives have been synthesized. Lead optimization led to the discovery of several active compounds via in vitro enzyme assays. Compared to the positive control compound GKA22, compounds 10j, 11h and 11i exhibited identical or even higher activity. Furthermore, docking simulation of compound 11i further demonstrated that the hydrogen atom of amide and the nitrogen atom of pyrimidine both bound to Arg63 via hydrogen bonds. Results: Hydrogen bond interactions were also observed between the two oxygen atoms of 2-methoxy-1-methyl-ethoxy moiety and Thr65. Both ends of the molecule were fixed in allosteric pocket of glucokinase, which was in favour of keeping active conformation.
- Zhang, Leilei,Hu, Shengquan,Lei, Lei,Zhang, Yuliang,Zhang, Lijing,Song, Hongrui,Shen, Zhufang,Feng, Zhiqiang
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p. 252 - 261
(2017/02/15)
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- Mapping the landscape of potentially primordial informational oligomers: Oligo-dipeptides tagged with orotic acid derivatives as recognition elements
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Partner up! Base-pairing properties of oligo-dipeptides tagged with orotic acid and its 2,4- diamino counterpart (see structure) are found to be consistent with previously observed correlations between ΔpKa values and the pairing strength of co
- Zhang, Xuejun,Krishnamurthy, Ramanarayanan
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supporting information; scheme or table
p. 8124 - 8128
(2010/03/01)
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- 4-(PYRAZOL-3-YLAMINO) PYRIMIDINE DERIVATIVES FOR USE IN THE TREATMENT OF CANCER
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A compound of Formula (I); wherein the substituents are as defined in the text for use in modulating insulin-like growth factor 1 receptor activity in a warm blooded animal such as man.
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Page/Page column 208-209
(2008/06/13)
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