Author: "Ishchenko, Alexey" / Publisher: elsevier b.v. - Searchworks@Jio Institute Digital Library Search Results

Author: Zhukovskaya, Evgeniya S., Deyneko, Dina V., Baryshnikova, Oksana V., Belik, Alexei A., Leonidov, Ivan I., Ishchenko, Alexey V., Stefanovich, Sergey Y., Morozov, Vladimir A., and Lazoryak, Bogdan I.
Published: 2019
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Author: Ishchenko, Alexey, Zhang, Lin, Le Brazidec, Jean-Yves, Fan, Junhua, Chong, Jer Hong, Hingway, Aparna, Raditsis, Annie, Singh, Latika, Elenbaas, Brian, Hong, Victor Sukbong, Marcotte, Doug, Silvian, Laura, Enyedy, Istvan, and Chao, Jianhua
Subjects: *SERINE/THREONINE kinases, *CANCER treatment, *KINASE inhibitors, *CANCER cell proliferation, *CRYSTAL structure, *PROTEIN-ligand interactions, *HYDROGEN bonding
Abstract: PIM kinases are implicated in variety of cancers by promoting cell survival and proliferation and are targets of interest for therapeutic intervention. We have identified a low-nanomolar pan-PIM inhibitor (PIM1/2/3 potency 5:14:2 nM) using structure based modeling. The crystal structure of this compound with PIM1 confirmed the predicted binding mode and protein–ligand interactions except those in the acidic ribose pocket. We show the SAR suggesting the importance of having a hydrogen bond donor in this pocket for inhibiting PIM2; however, this interaction is not important for inhibiting PIM1 or PIM3. In addition, we report the discovery of a new class of PIM inhibitors by using computational de novo design tool implemented in MOE software (Chemical Computing Group). These inhibitors have a different interaction profile. [ABSTRACT FROM AUTHOR]
Published: 2015
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Author: Yuan, Jing, Simpson, Robert D., Zhao, Wei, Tice, Colin M., Xu, Zhenrong, Cacatian, Salvacion, Jia, Lanqi, Flaherty, Patrick T., Guo, Joan, Ishchenko, Alexey, Wu, Zhongren, McKeever, Brian M., Scott, Boyd B., Bukhtiyarov, Yuri, Berbaum, Jennifer, Panemangalore, Reshma, Bentley, Ross, Doe, Christopher P., Harrison, Richard K., and McGeehan, Gerard M.
Subjects: *CHEMICAL inhibitors, *DRUG design, *DRUG development, *RENIN, *HYPERTENSION, *X-ray crystallography, *ANTIHYPERTENSIVE agents, *ETHER (Anesthetic)
Abstract: Abstract: Structure-based design led to the discovery of a novel class of renin inhibitors in which an unprecedented phenyl ring filling the S1 site is attached to the phenyl ring filling the S3 pocket. Optimization for several parameters including potency in the presence of human plasma, selectivity against CYP3A4 inhibition and improved rat oral bioavailability led to the identification of 8d which demonstrated antihypertensive efficacy in a transgenic rat model of human hypertension. [Copyright &y& Elsevier]
Published: 2011
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Author: Xu, Zhenrong, Cacatian, Salvacion, Yuan, Jing, Simpson, Robert D., Jia, Lanqi, Zhao, Wei, Tice, Colin M., Flaherty, Patrick T., Guo, Joan, Ishchenko, Alexey, Singh, Suresh B., Wu, Zhongren, McKeever, Brian M., Scott, Boyd B., Bukhtiyarov, Yuri, Berbaum, Jennifer, Mason, Jennifer, Panemangalore, Reshma, Cappiello, Maria Grazia, and Bentley, Ross
Subjects: *BIOAVAILABILITY, *RENIN, *AMINES, *CHEMICAL inhibitors, *DRUG design, *ORAL drug administration, *THERAPEUTICS, *HYPERTENSION, *LABORATORY rats
Abstract: Abstract: Structure-guided drug design led to new alkylamine renin inhibitors with improved in vitro and in vivo potency. Lead compound 21a, has an IC50 of 0.83nM for the inhibition of human renin in plasma (PRA). Oral administration of 21a at 10mg/kg resulted in >20h reduction of blood pressure in a double transgenic rat model of hypertension. [Copyright &y& Elsevier]
Published: 2010
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Author: Tice, Colin M., Xu, Zhenrong, Yuan, Jing, Simpson, Robert D., Cacatian, Salvacion T., Flaherty, Patrick T., Zhao, Wei, Guo, Joan, Ishchenko, Alexey, Singh, Suresh B., Wu, Zhongren, Scott, Boyd B., Bukhtiyarov, Yuri, Berbaum, Jennifer, Mason, Jennifer, Panemangalore, Reshma, Cappiello, Maria Grazia, Müller, Dominik, Harrison, Richard K., and McGeehan, Gerard M.
Subjects: *ANTIHYPERTENSIVE agents, *DRUG design, *RENIN, *ENZYME inhibitors, *ANIMAL models in research, *HYPERTENSION, *ORAL drug administration, *BLOOD pressure, *LEAD compounds
Abstract: Abstract: Structure-based drug design led to the identification of a novel class of potent, low MW alkylamine renin inhibitors. Oral administration of lead compound 21l, with MW of 508 and IC50 of 0.47nM, caused a sustained reduction in mean arterial blood pressure in a double transgenic rat model of hypertension. [Copyright &y& Elsevier]
Published: 2009
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