Identification and structure-based drug design of cell-active inhibitors of interleukin 17A at a novel C-terminal site.

Anti-IL17A therapies have proven effective for numerous inflammatory diseases including psoriasis, axial spondylitis and psoriatic arthritis. Modulating and/or antagonizing protein-protein interactions of IL17A cytokine binding to its cell surface receptors with oral therapies offers the promise to bring forward biologics-like efficacy in a pill to patients. We used an NMR-based fragment screen of recombinant IL17A to uncover starting points for small molecule IL17A antagonist discovery.

Development of Orally Efficacious Allosteric Inhibitors of TNFα via Fragment-Based Drug Design.

Tumor necrosis factor α (TNFα) is a soluble cytokine that is directly involved in systemic inflammation through the regulation of the intracellular NF-κB and MAPK signaling pathways. The development of biologic drugs that inhibit TNFα has led to improved clinical outcomes for patients with rheumatoid arthritis and other chronic autoimmune diseases; however, TNFα has proven to be difficult to drug with small molecules. Herein, we present a two-phase, fragment-based drug discovery (FBDD) effort in which we first identified isoquinoline fragments that disrupt TNFα ligand-receptor binding through an allosteric desymmetrization mechanism as observed in high-resolution crystal structures.

Reagent and Catalyst Capsules: A Chemical Delivery System for Reaction Screening and Parallel Synthesis.

Commercially available hydroxypropyl methylcellulose capsules are employed as a fast, safe, and user-friendly chemical delivery system containing all reagents (catalyst, ligand, and base) for three important transition-metal-catalyzed reactions: Buchwald-Hartwig, Suzuki-Miyaura, and metallophotoredox C-N cross-coupling reactions. This encapsulation methodology simplifies the screening of reaction conditions and the preparation of compound libraries using parallel synthesis in organic solvents or aqueous media. These reagents-containing HPMC capsules are easy to prepare, come in different sizes, and can be stored on the bench under noninert conditions.

A Strategy for the Synthesis of Sulfonamides on DNA.

An efficient method is reported to synthesize sulfonamides on DNA from sulfinic acids or sodium sulfinates and amines in the presence of iodine under mild conditions. This method demonstrates a major expansion of scope of sulfonamide formation on DNA through the utilization of a novel sodium carbonate-sodium sulfinate bifunctional reagent class.

Fragment-Based Discovery of an Apolipoprotein E4 (apoE4) Stabilizer.

Apolipoprotein E is a 299-residue lipid carrier protein produced in both the liver and the brain. The protein has three major isoforms denoted apoE2, apoE3, and apoE4 which differ at positions 112 and 158 and which occur at different frequencies in the human population. Genome-wide association studies indicate that the possession of two apoE4 alleles is a strong genetic risk factor for late-onset Alzheimer's disease (LOAD).

Discovery of Novel Aminotetralines and Aminochromanes as Selective and Competitive Glycine Transporter 1 (GlyT1) Inhibitors.

The glycine transporter 1 (GlyT1) has emerged as a key novel target for the treatment of schizophrenia. Herein, we report the synthesis and biological evaluation of aminotetralines and aminochromanes as novel classes of competitive GlyT1 inhibitors. Starting from a high-throughput screening hit, structure-activity relationship studies led first to the discovery of aminotetralines displaying high GlyT1 potency and selectivity, with favorable pharmacokinetic properties.

De Novo Design, Synthesis, and Biological Evaluation of 3,4-Disubstituted Pyrrolidine Sulfonamides as Potent and Selective Glycine Transporter 1 Competitive Inhibitors.

The development of glycine transporter 1 (GlyT1) inhibitors may offer putative treatments for schizophrenia and other disorders associated with hypofunction of the glutaminergic N-methyl-d-aspartate (NMDA) receptor. Herein, we describe the synthesis and biological evaluation of a series of 3,4-disubstituted pyrrolidine sulfonamides as competitive GlyT1 inhibitors that arose from de novo scaffold design. Relationship of chemical structure to drug-drug interaction (DDI) and bioactivation was mechanistically investigated.

Discovery and optimization of novel constrained pyrrolopyridone BET family inhibitors.

Novel conformationally constrained BET bromodomain inhibitors have been developed. These inhibitors were optimized in two similar, yet distinct chemical series, the 6-methyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-ones (A) and the 1-methyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-ones (B). Each series demonstrated excellent activity in binding and cellular assays, and lead compounds from each series demonstrated significant efficacy in in vivo tumor xenograft models.

SAR of amino pyrrolidines as potent and novel protein-protein interaction inhibitors of the PRC2 complex through EED binding.

Herein we disclose SAR studies of a series of dimethylamino pyrrolidines which we recently reported as novel inhibitors of the PRC2 complex through disruption of EED/H3K27me3 binding. Modification of the indole and benzyl moieties of screening hit 1 provided analogs with substantially improved binding and cellular activities. This work culminated in the identification of compound 2, our nanomolar proof-of-concept (PoC) inhibitor which provided on-target tumor growth inhibition in a mouse xenograft model.

The EED protein-protein interaction inhibitor A-395 inactivates the PRC2 complex.

Polycomb repressive complex 2 (PRC2) is a regulator of epigenetic states required for development and homeostasis. PRC2 trimethylates histone H3 at lysine 27 (H3K27me3), which leads to gene silencing, and is dysregulated in many cancers. The embryonic ectoderm development (EED) protein is an essential subunit of PRC2 that has both a scaffolding function and an H3K27me3-binding function.

Privileged scaffolds in lead generation.

Introduction: The term "privileged scaffold" was coined in 1988 and the strategy was to construct high-affinity ligands from core structures that can bind more than one receptor. Since then, the privileged scaffold-based design has evolved from a stand-alone technology to an integral component of various lead generation platforms.

Areas Covered: In this review, the authors discuss the applications of the privileged scaffold concept in current lead generation.

Targeting aPKC disables oncogenic signaling by both the EGFR and the proinflammatory cytokine TNFα in glioblastoma.

Grade IV glioblastoma is characterized by increased kinase activity of epidermal growth factor receptor (EGFR); however, EGFR kinase inhibitors have failed to improve survival in individuals with this cancer because resistance to these drugs often develops. We showed that tumor necrosis factor-α (TNFα) produced in the glioblastoma microenvironment activated atypical protein kinase C (aPKC), thereby producing resistance to EGFR kinase inhibitors. Additionally, we identified that aPKC was required both for paracrine TNFα-dependent activation of the transcription factor nuclear factor κB (NF-κB) and for tumor cell-intrinsic receptor tyrosine kinase signaling.

Synthesis and biological activity of aminophthalazines and aminopyridazines as novel inhibitors of PGE2 production in cells.

This Letter reports the synthesis and biological evaluation of a collection of aminophthalazines as a novel class of compounds capable of reducing production of PGE(2) in HCA-7 human adenocarcinoma cells. A total of 28 analogs were synthesized, assayed for PGE(2) reduction, and selected active compounds were evaluated for inhibitory activity against COX-2 in a cell free assay. Compound 2xxiv (R(1)=H, R(2)=p-CH(3)O) exhibited the most potent activity in cells (EC(50)=0.

Synthesis and biological activity of 2-aminothiazoles as novel inhibitors of PGE2 production in cells.

This Letter presents the synthesis and biological evaluation of a collection of 2-aminothiazoles as a novel class of compounds with the capability to reduce the production of PGE(2) in HCA-7 human adenocarcinoma cells. A total of 36 analogs were synthesized and assayed for PGE(2) reduction, and those with potent cellular activity were counter screened for inhibitory activity against COX-2 in a cell free assay. In general, analogs bearing a 4-phenoxyphenyl substituent in the R(2) position were highly active in cells while maintaining negligible COX-2 inhibition.

2,4-Diphenyl-6-trifluoro-methyl-2,3-dihydro-1H,5H-pyrrolo-[3,4-c]pyrrole-1,3-dione.

The asymmetric unit of the title compound, C(19)H(11)F(3)N(2)O(2), contains two crystallographically unique mol-ecules which differ in the rotation of a phenyl ring and a -CF(3) substituent. The dihedral angles involving the pyrrole ring and the attached phenyl ring are 62.82 (8) and 71.

Facile, novel two-step syntheses of benzimidazoles, bis-benzimidazoles, and bis-benzimidazole-dihydroquinoxalines.

Three scaffolds of benzimidazoles, bis-benzimidazoles, and bis-benzimidazole-dihydroquinoxalines were synthesized via Ugi/de-protection/cyclization methodology. Benzimidazole forming ring closure was enabled under microwave irradiation in the presence of 10% TFA/DCE. The methodology demonstrates the utility of 2-(N-Boc-amino)-phenyl-isocyanide for the generation of new molecular diversity.

A novel route to synthesize libraries of quinoxalines via Petasis methodology in two synthetic operations.

This communication reveals an innovative and facile procedure to prepare quinoxalines in two synthetic steps. The microwave assisted Petasis reaction is followed by the acid mediated unmasking of an internal amino nucleophile, cyclodehydration and oxidation to give collections of quinoxalines in good to excellent yields.

ERK crosstalks with 4EBP1 to activate cyclin D1 translation during quinol-thioether-induced tuberous sclerosis renal cell carcinoma.

The mammalian target of rapamycin (mTOR) and mitogen-activated protein kinase signaling cascades have been implicated in a number of human cancers. The tumor suppressor gene tuberous sclerosis-2 (Tsc-2) functions as a negative regulator of mTOR. Critical proteins in both pathways are activated following treatment of Eker rats (Tsc-2(EK/+)) with the nephrocarcinogen 2,3,5-tris-(glutathion-S-yl)hydroquinone (TGHQ), which also results in loss of the wild-type allele of Tsc-2 in renal preneoplastic lesions and tumors.

Concise Preparation of Novel Tricyclic Chemotypes: Fused Hydantoin-benzodiazepines.

The following article describes a concise synthesis of a collection of 4,5-dihydro-1H-benzo[e][1,4]diazepines fused to a hydantoin ring. Molecular complexity and biological relevance is high and structures are generated in a mere three steps, employing the Ugi reaction to assemble diversity reagents. The protocol represents a novel UDC (Ugi-deprotect-cyclize) strategy employed in the Ugi-5-component CO(2) mediated condensation, followed by further cyclization under basic conditions, to afford the fused hydantoin.

Two step syntheses of fused quinoxaline-benzodiazepines and bis-benzodiazepines.

A two-step solution phase synthesis employing a double UDC (Ugi/Deprotect/Cyclize) strategy has been utilized to obtain fused 6,7,6,6-quinoxalinone-benzodiazepines and 6,7,7,6-bis-benzodiazepines. Optimization of the methodology to produce these tetracyclic scaffolds was enabled by microwave irradiation, incorporation of trifluoroethanol as solvent, and the use of the convertible isocyanide, 4-tert-butyl cyclohexen-1-yl isocyanide.

Concise Two-Step Solution Phase Syntheses of four novel Dihydroquinazoline scaffolds.

Novel two-step solution phase protocols for the synthesis of dihydroquinazolines and fused dihydroquinazoline-benzodiazepine tetracycles are reported. The methodology employs the Ugi reaction to assemble desired diversity and acid treatment enables ring closing transformations. The protocols are further facilitated by the use of microwave irradiation and n-butyl isocyanide to control the rate of each ring forming transformation.

The design, synthesis, and evaluation of 8 hybrid DFG-out allosteric kinase inhibitors: a structural analysis of the binding interactions of Gleevec, Nexavar, and BIRB-796.

The majority of kinase inhibitors developed to date are competitive inhibitors that target the ATP binding site; however, recent crystal structures of Gleevec (imatinib mesylate, STI571, PDB: 1IEP), Nexavar (Sorafenib tosylate, BAY 43-9006, PDB: 1UWJ), and BIRB-796 (PDB: 1KV2) have revealed a secondary binding site adjacent to the ATP binding site known as the DFG-out allosteric binding site. The recent successes of Gleevec and Nexavar for the treatment of chronic myeloid leukemia and renal cell carcinoma has generated great interest in the development of other kinase inhibitors that target this secondary binding site. Here, we present a structural comparison of the important and similar interactions necessary for Gleevec(R), Nexavar, and BIRB-796 to bind to their respective DFG-out allosteric binding pockets and the selectivity of each with respect to c-Abl, B-Raf, and p38alpha.

2-Butyl-11-phenyl-5,10-dihydro-1H-benzo[e]imidazo[1,5-a][1,4]diazepine-1,3(2H)-dione.

The title compound, C(21)H(21)N(3)O(2), was obtained following a five-step synthetic procedure yielding weakly diffracting rod and needle-shaped crystals which crystallized concomitantly. Structural analysis of a rod-shaped crystal showed that the central seven-membered heterocyclic ring adopts a conformation that is perhaps best described as a distorted boat, with the H-bearing (CH(2) and NH) atoms lying well out of the least-squares mean plane fitted through the other five atoms in the ring (r.m.

2-Propyl 3,3-dibromo-2-hydroxy-pyrrolidine-1-carboxyl-ate.

The title compound, C(8)H(13)Br(2)NO(3), crystallizes as a non-merohedral twin with twin law -0.6 0 0.4/0 - 1 0 /1.