[Show abstract][Hide abstract] ABSTRACT: Activation of the G-protein coupled receptor (GPCR) Takeda G-protein Receptor 5 (TGR5), also known as G-protein Bile Acid Receptor 1 (GPBAR1) has been shown to play a key role in pathways associated with diabetes, the metabolic syndrome and autoimmune disease. Nipecotamide 5 was identified as an attractive starting point after a high-throughput screen (HTS) for receptor agonists. A comprehensive hit-to-lead effort culminated in the discovery of 45h as a potent, selective and bioavailable TGR5 agonist to test in preclinical metabolic disease models. In genetically obese mice (ob/ob), 45h was as effective as a dipeptidyl peptidase-4 (DPP-4) inhibitor at reducing peak glucose levels in an acute oral glucose tolerance test (OGTT), but this effect was lost upon chronic dosing.
[Show abstract][Hide abstract] ABSTRACT: Inhibition of Bcr-Abl kinase activity by imatinib for the treatment of chronic myeloid leukemia (CML) currently serves as the paradigm for targeting dominant oncogenes with small molecules. We recently reported the discovery of GNF-2 (1) and GNF-5 (2) as selective non-ATP competitive inhibitors of cellular Bcr-Abl kinase activity that target the myristate binding site. Here, we used cell-based structure-activity relationships to guide the optimization and diversification of ligands that are capable of binding to the myristate binding site and rationalize the findings based upon an Abl-compound 1 cocrystal. We elucidate the structure-activity relationships required to obtain potent antiproliferative activity against Bcr-Abl transformed cells and report the discovery of new compounds (5g, 5h, 6a, 14d, and 21j-I) that display improved potency or pharmacological properties. This work demonstrates that a variety of structures can effectively target the Bcr-Abl myristate binding site and provides new leads for developing drugs that can target this binding site.
[Show abstract][Hide abstract] ABSTRACT: The second generation of Bcr-Abl inhibitors nilotinib, dasatinib, and bosutinib developed to override imatinib resistance are not active against the T315I "gatekeeper" mutation. Here we describe a type-II T315I inhibitor 2 (GNF-7), based upon a 3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one scaffold which is capable of potently inhibiting wild-type and T315I Bcr-Abl as well as other clinically relevant Bcr-Abl mutants such as G250E, Q252H, Y253H, E255K, E255V, F317L, and M351T in biochemical and cellular assays. In addition, compound 2 displayed significant in vivo efficacy against T315I-Bcr-Abl without appreciable toxicity in a bioluminescent xenograft mouse model using a transformed T315I-Bcr-Abl-Ba/F3 cell line that has a stable luciferase expression. Compound 2 is among the first type-II inhibitors capable of inhibiting T315I to be described and will serve as a valuable lead to design the third generation Bcr-Abl kinase inhibitors.
[Show abstract][Hide abstract] ABSTRACT: A series of 4-amino-6-benzimidazole-pyrimidines was designed to target lymphocyte-specific tyrosine kinase (Lck), a member of the Src-family kinases (SFKs). These type II inhibitors were optimized using a cellular Lck-dependent proliferation assay and are capable of inhibiting Lck at single-digit nanomolar concentrations. This scaffold is likely to serve a valuable template for developing potent inhibitors of a number of SFKs.
[Show abstract][Hide abstract] ABSTRACT: A series of 4-amino-6-benzimidazole-pyrimidines was designed to target lymphocyte-specific tyrosine kinase (Lck), a member of the Src kinase family. Highly efficient parallel syntheses were devised to prepare analogues for SAR studies. A number of these 4-amino-6-benzimidazole-pyrimidines exhibited single-digit nanomolar IC(50)s against Lck in biochemical and cellular assays. These 4-amino-6-benzimidazole-pyrimidines represent a new class of tyrosine kinase inhibitors.
[Show abstract][Hide abstract] ABSTRACT: Chronic myelogenous leukemia (CML) is a myeloproliferative disorder characterized at the molecular level by the expression of Bcr-abl, a 210-kDa fusion protein with deregulated tyrosine kinase activity. Encouraged by the clinical validation of Bcr-abl as the target for the treatment of CML by imatinib, we sought to identify pharmacological agents that could target this kinase by a distinct mechanism. We report the discovery of a new class of Bcr-abl inhibitors using an unbiased differential cytotoxicity screen of a combinatorial kinase-directed heterocycle library. Compounds in this class (exemplified by GNF-2) show exclusive antiproliferative activity toward Bcr-abl-transformed cells, with potencies similar to imatinib, while showing no inhibition of the kinase activity of full-length or catalytic domain of c-abl. We propose that this new class of compounds inhibits Bcr-abl kinase activity through an allosteric non-ATP competitive mechanism.
Nature Chemical Biology 03/2006; 2(2):95-102. DOI:10.1038/nchembio760 · 13.22 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The invention relates to pyrimidine urea derivs. (shown as I; variables defined below; e.g. 3-(2,6-dichloro-3-methoxyphenyl)-1-methyl-1-[6-[[4-(4-methylpiperazin-1-yl)phenyl]amino]pyrimidin-4-yl]urea (II)), to processes for the prepn. of these compds., pharmaceutical compns. contg. same, the use thereof optionally in combination with ≥1 other pharmaceutically active compds. for the therapy of a disease which responds to an inhibition of protein kinase activity, and a method for the treatment of such a disease. Inhibitory activity of some examples of I are included, e.g. N-[3-[3-(6-aminopyrimidin-4-yl)-3-[3-(2-oxopyrrolidin-1-yl)propyl]ureido]-4-methylphenyl]-3-trifluoromethylbenzamide at a concn. of 10 μM inhibits the following kinases by the percentage shown in brackets: wild-type Abl (99%), c-RAF (99%), CSK (97%), c-SRC (100%), FGFR35 (99%), JNK2α2 (93%), lck (100%), MKK6 (88%), p70S6K (81%), ROS (95%), SAPK2α (99%), SAPK2β (99%), Tie2 (100%) and TrkB (99%). For I: n = 0-5; X, Y and Z = N or