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Taihe, China

Staben S.T.,Genentech | Feng J.A.,Genentech | Lyle K.,Genentech | Belvin M.,Genentech | And 20 more authors.
Journal of Medicinal Chemistry | Year: 2014

Structure-based methods were used to design a potent and highly selective group II p21-activated kinase (PAK) inhibitor with a novel binding mode, compound 17. Hydrophobic interactions within a lipophilic pocket past the methionine gatekeeper of group II PAKs approached by these type I 1/2 binders were found to be important for improving potency. A structure-based hypothesis and strategy for achieving selectivity over group I PAKs, and the broad kinome, based on unique flexibility of this lipophilic pocket, is presented. A concentration-dependent decrease in tumor cell migration and invasion in two triple-negative breast cancer cell lines was observed with compound 17. © 2014 American Chemical Society.

Chiruta C.,Salk Institute for Biological Studies | Zhao Y.,Pharmaron Beijing | Tang F.,Pharmaron Beijing | Wang T.,Pharmaron Beijing | Schubert D.,Salk Institute for Biological Studies
Bioorganic and Medicinal Chemistry | Year: 2013

Abstract Using a drug discovery scheme for Alzheimer's disease (AD) that is based upon multiple pathologies of old age, we identified a potent compound with efficacy in rodent memory and AD animal models. Since this compound, J147, is a phenyl hydrazide, there was concern that it can be metabolized to aromatic amines/hydrazines that are potentially carcinogenic. To explore this possibility, we examined the metabolites of J147 in human and mouse microsomes and mouse plasma. It is shown that J147 is not metabolized to aromatic amines or hydrazines, that the scaffold is exceptionally stable, and that the oxidative metabolites are also neuroprotective. It is concluded that the major metabolites of J147 may contribute to its biological activity in animals. © 2013 Elsevier Ltd.All rights reserved.

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