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The synthesis and evaluation of tetrasubstituted aminopyridines, bearing novel azaindazole hinge binders, as potent AKT inhibitors are described. Compound 14c was identified as a potent AKT inhibitor that demonstrated reduced CYP450 inhibition and an improved developability profile compared to those of previously described trisubstituted pyridines. It also displayed dose-dependent inhibition of both phosphorylation of GSK3beta and tumor growth in a BT474 tumor xenograft model in mice.

Structural analogs of leukotriene B 4 (LTB 4 ) were designed using a preferred conformation of LTB 4 (1). Appending an aromatic ring scaffold between LTB 4 carbons 7 and 11 led to quinoline analogs (3) and (1)5. A similar modification to the LTB 74 structure between carbons 7 and 9 led to the pyridine analogs (41) and (46). The compounds of this study were evaluated in receptor binding assays using [ 3 H]LTB 4 and intact human DMSO differentiated U-937 cells. The first analog prepared, quinoline (3), displayed moderate potency in the LTB 4 receptor binding assay (K i =0.9 μM). Modification of (3) by appending an aromatic ring between carbons 2 and 4 of the acid side chain produced a dramatic increase in receptor binding (15, K i =0.01 μM); a further improvement in receptor binding was achieved in the pyridine series (e.g., (41); K i =0.001 μM). The LTB 4 receptor agonist/antagonist activity of the test compounds was determined using a functional assay that relies upon intracellular calcium mobilization induced by LTB 4 . Of the analogs prepared in this report only 3-[2-[6-[3-(3-butoxyphenyl)-3-hydroxypropyl]pyridin-2-yl]-1-hydroxyethyl]benzoic acid (47) demonstrated LTB 4 receptor antagonist activity

AKT inhibitors containing an imidazopyridine aminofurazan scaffold have been optimized. We have previously disclosed identification of the AKT inhibitor GSK690693, which has been evaluated in clinical trials in cancer patients. Herein we describe recent efforts focusing on investigating a distinct region of this scaffold that have afforded compounds (30 and 32) with comparable activity profiles to that of GSK690693.

Overexpression of AKT has an antiapoptotic effect in many cell types, and expression of dominant negative AKT blocks the ability of a variety of growth factors to promote survival. Therefore, inhibitors of AKT kinase activity might be useful as monotherapy for the treatment of tumors with activated AKT. Herein, we describe our lead optimization studies culminating in the discovery of compound 3g (GSK690693). Compound 3g is a novel ATP competitive, pan-AKT kinase inhibitor with IC 50 values of 2, 13, and 9 nM against AKT1, 2, and 3, respectively. An X-ray cocrystal structure was solved with 3g and the kinase domain of AKT2, confirming that 3g bound in the ATP binding pocket. Compound 3g potently inhibits intracellular AKT activity as measured by the inhibition of the phosphorylation levels of GSK3beta. Intraperitoneal administration of 3g in immunocompromised mice results in the inhibition of GSK3beta phosphorylation and tumor growth in human breast carcinoma (BT474) xenografts.

The discovery, proposed binding mode, and optimization of a novel class of Rho-kinase inhibitors are presented. Appropriate substitution on the 6-position of the azabenzimidazole core provided subnanomolar enzyme potency in vitro while dramatically improving selectivity over a panel of other kinases. Pharmacokinetic data was obtained for the most potent and selective examples and one (6n) has been shown to lower blood pressure in a rat model of hypertension.

Focal adhesion kinase (FAK) is a non-receptor tyrosine kinase that integrates signals from integrins and growth factor receptors. FAK has been reported to play a role in the regulation of cell survival, growth, spreading, migration and invasion. Overexpression of FAK mRNA and/or protein has been documented in many human tumors, including cancers of the breast, colon, thyroid, and prostate. FAK is regulated and activated by phosphorylation on multiple tyrosine residues. More significantly, there is evidence that phosphorylated FAK is increased in malignant compared to normal tissues. Accordingly, compounds that inhibit FAK activity are expected to be useful for the treatment of cancer. Cross-screening of the GSK compound collection led to the identification of benzimidazole carboxamides having weak FAK inhibitory activity. As benzimidazole carboxamides are known kinase templates, a structure based hit-to-lead optimization campaign was executed. Team efforts culminated in the rapid identification of a series of substituted benzimidazole carboxamides having highly potent and selective inhibitory activity towards FAK (i.e. FAK IC50 < 10 nM). The structure-based optimization of this series including the synthesis, binding mode, and profile of lead compounds will be described. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3260. doi:10.1158/1538-7445.AM2011-3260