Long-Acting Tumor-Activated Prodrug of a TGFβR Inhibitor.

Inhibition of TGFβ signaling in concert with a checkpoint blockade has been shown to provide improved and durable antitumor immune response in mouse models. However, on-target adverse cardiovascular effects have limited the clinical use of TGFβ receptor (TGFβR) inhibitors in cancer therapy. To restrict the activity of TGFβR inhibitors to tumor tissues and thereby widen the therapeutic index, a series of tumor-activated prodrugs of a selective small molecule TGFβR1 inhibitor were prepared by appending to a serine protease substrate and a half-life extension fatty acid carbon chain.

Discovery and Preclinical Pharmacology of an Oral Bromodomain and Extra-Terminal (BET) Inhibitor Using Scaffold-Hopping and Structure-Guided Drug Design.

Inhibition of the bromodomain and extra-terminal (BET) family of adaptor proteins is an attractive strategy for targeting transcriptional regulation of key oncogenes, such as c-MYC. Starting with the screening hit , a combination of structure-activity relationship and protein structure-guided drug design led to the discovery of a differently oriented carbazole with favorable binding to the tryptophan, proline, and phenylalanine (WPF) shelf conserved in the BET family. Identification of an additional lipophilic pocket and functional group optimization to optimize pharmacokinetic (PK) properties culminated in the discovery of (BMS-986158) with excellent potency in binding and functional assays.

Modulation of cofilin phosphorylation by inhibition of the Lim family kinases.

A series of aminothiazoles that are potent inhibitors of LIM kinases 1 and 2 is described. Appropriate choice of substituents led to molecules with good selectivity for either enzyme. An advanced member of the series was shown to effectively interfere with the phosphorylation of the LIM kinases substrate cofilin.

Small molecule antagonist of leukocyte function associated antigen-1 (LFA-1): structure-activity relationships leading to the identification of 6-((5S,9R)-9-(4-cyanophenyl)-3-(3,5-dichlorophenyl)-1-methyl-2,4-dioxo-1,3,7-triazaspiro[4.4]nonan-7-yl)nicotinic acid (BMS-688521).

Leukocyte function-associated antigen-1 (LFA-1), also known as CD11a/CD18 or alpha(L)beta(2), belongs to the beta(2) integrin subfamily and is constitutively expressed on all leukocytes. The major ligands of LFA-1 include three intercellular adhesion molecules 1, 2, and 3 (ICAM 1, 2, and 3). The interactions between LFA-1 and the ICAMs are critical for cell adhesion, and preclinical animal studies and clinical data from the humanized anti-LFA-1 antibody efalizumab have provided proof-of-concept for LFA-1 as an immunological target.

Discovery of novel dihydro-9,10-ethano-anthracene carboxamides as glucocorticoid receptor modulators.

A series of dihydro-9,10-ethano-anthracene-11-carboxamides as novel glucocorticoid receptor modulators is reported. SAR exploration identified compounds from this series displaying a promising dissociation profile in discriminating between transrepression and transactivation activities. 17a is a partial agonist of GR-mediated transactivation which elicits potent and efficacious transrepression in reporter gene assays.

Multiple and single binding modes of fragment-like kinase inhibitors revealed by molecular modeling, residue type-selective protonation, and nuclear overhauser effects.

Fragment-like inhibitors of mitogen-activated protein kinase-activated protein kinase 2 (MK2) include 5-hydroxyisoquinoline (IC50 approximately 85 microM). Modeling studies identified four possible binding modes for this compound. Two-dimensional (1)H-(1)H NOESY data obtained with selectively protonated samples of MK2 in complex with 5-hydroxyisoquinoline demonstrated that two of the four predicted binding modes are well populated.

Pyrrolopyridazine MEK inhibitors.

The synthesis and SAR of a series of pyrrolopyridazine MEK inhibitors are reported. Optimal activity was achieved by incorporation of a 4-phenoxyaniline substituent at C4 and an acylated amine at C6.

Rational design of RAR-selective ligands revealed by RARbeta crystal stucture.

The crystal structure of the ligand-binding domain of RARbeta, a suspect tumour suppressor, reveals important features that distinguish it from the two other RAR isotypes. The most striking difference is an extra cavity allowing RARbeta to bind more bulky agonists. Accordingly, we identified a ligand that shows RARbeta selectivity with a 100-fold higher affinity to RARbeta than to alpha or gamma isotypes.

Aminotriazine 5-HT7 antagonists.

The present studies have identified a series of aminotriazines as novel 5-HT(7) receptor antagonists. Compounds 10 and 17 have high affinity for the 5-HT(7) receptor and do not bind to either the 5-HT(2C) or 5-HT(6) receptors. These compounds produce no agonist effects by themselves, and shift the dose-response curve of 5-CT to the right in the manner of an antagonist.

Inhibition of disease progression by a novel retinoid antagonist in animal models of arthritis.

Objective: To investigate the usefulness of a novel retinoic acid receptor (RAR) antagonist (BMS-189453) in animal models of arthritis.

Methods: BMS-189453 was tested in HIG-82 rabbit synovial fibroblasts to determine its ability to repress collagenase (matrix metalloproteinase-1, MMP-1) mRNA expression in vitro. Cells were stimulated with phorbol myristate acetate or interleukin 1 beta and mRNA quantified by slot-blot analysis.