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Discovery of a benzo[e]pyrimido-[5,4-b][1,4]diazepin-6(11H)-one as a Potent and Selective Inhibitor of Big MAP Kinase 1.

ABSTRACT: Kinome-wide selectivity profiling of a collection of 2-amino-pyrido[2,3-d]pyrimidines followed by cellular structure-activity relationship-guided optimization resulted in the identification of moderately potent and selective inhibitors of BMK1/ERK5 exemplified by 11, 18, and 21. For example, 11 possesses a dissociation constant (K(d)) for BMK1 of 19 nM, a cellular IC(50) for inhibiting epidermal growth factor induced BMK1 autophosphorylation of 0.19 ± 0.04 μM, and an Ambit KINOMEscan selectivity score (S(5)) of 0.035. Inhibitors 18 and 21 are also potent BMK1 inhibitors and possess favorable pharmacokinetic properties which enable their use as pharmacological probes of BMK1-dependent phenomena as well as starting points for further optimization efforts.

SUBMITTER: Deng X

PROVIDER: S-EPMC3055678 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Discovery of a Series of 5,11-Dihydro-6H-benzo[e]pyrimido[5,4-b][1,4]diazepin-6-ones as Selective PI3K-δ/γ Inhibitors.

Project description:Dual inhibition of PI3K-δ and PI3K-γ is an established therapeutic strategy for treatment of hematological malignancies. Reported molecules targeting PI3K-δ/γ selectively are chemically similar and based upon isoquinolin-1(2H)-one or quinazolin-4(3H)-one scaffolds. Here we report a chemically distinct series of potent, selective PI3K-δ/γ inhibitors based on a 5,11-dihydro-6H-benzo[e]pyrimido[5,4-b][1,4]diazepin-6-one scaffold with comparable biochemical potency and cellular effects on PI3K signaling. We envisage these molecules will provide useful leads for development of next-generation PI3K-δ/γ targeting therapeutics.

| S-EPMC5066161 | biostudies-literature

Structural determinants for ERK5 (MAPK7) and leucine rich repeat kinase 2 activities of benzo[e]pyrimido-[5,4-b]diazepine-6(11H)-ones.

Project description:The benzo[e]pyrimido-[5,4-b]diazepine-6(11H)-one core was discovered as a novel ERK5 (also known as MAPK7 and BMK1) inhibitor scaffold, previously. Further structure-activity relationship studies of this scaffold led to the discovery of ERK5-IN-1 (26) as the most selective and potent ERK5 inhibitor reported to date. 26 potently inhibits ERK5 biochemically with an IC₅₀ of 0.162 ± 0.006 μM and in cells with a cellular EC₅₀ for inhibiting epidermal growth factor induced ERK5 autophosphorylation of 0.09 ± 0.03 μM. Furthermore, 26 displays excellent selectivity over other kinases with a KINOMEscan selectivity score (S₁₀) of 0.007, and exhibits exceptional bioavailability (F%) of 90% in mice. 26 will serve as a valuable tool compound to investigate the ERK5 signaling pathway and as a starting point for developing an ERK5 directed therapeutic agent.

| S-EPMC3914206 | biostudies-literature

Synthesis and Structure-Activity Relationships of DCLK1 Kinase Inhibitors Based on a 5,11-Dihydro-6H-benzo[e]pyrimido[5,4-b][1,4]diazepin-6-one Scaffold.

Project description:Doublecortin-like kinase 1 (DCLK1) is a serine/threonine kinase that is overexpressed in gastrointestinal cancers, including esophageal, gastric, colorectal, and pancreatic cancers. DCLK1 is also used as a marker of tuft cells, which regulate type II immunity in the gut. However, the substrates and functions of DCLK1 are understudied. We recently described the first selective DCLK1/2 inhibitor, DCLK1-IN-1, developed to aid the functional characterization of this important kinase. Here we describe the synthesis and structure-activity relationships of 5,11-dihydro-6H-benzo[e]pyrimido[5,4-b][1,4]diazepin-6-one DCLK1 inhibitors, resulting in the identification of DCLK1-IN-1.

| S-EPMC8270059 | biostudies-literature

(11-Methyl-pyrido[2,3-b][1,4]benzo-diazepin-6-yl)(phen-yl)methanone.

Project description:In the title compound, C(20)H(15)N(3)O, the diazepine ring adopts a boat conformation. The dihedral angle between pyridine and benzene rings is 55.2 (1)°. The benzoyl phenyl ring forms dihedral angles of 49.4 (1) and 75.9 (1)°, respectively, with the pyridine and benzene rings. In the crystal, mol-ecules are linked into centrosymmetric dimers by pairs of C-H⋯N hydrogen bonds.

| S-EPMC3008030 | biostudies-literature

Mechanism of falcipain-2 inhibition by ?,?-unsaturated benzo[1,4]diazepin-2-one methyl ester.

Project description:Falcipain-2 (FP-2) is a papain-family cysteine protease of Plasmodium falciparum whose primary function is to degrade the host red cell hemoglobin, within the food vacuole, in order to provide free amino acids for parasite protein synthesis. Additionally it promotes host cell rupture by cleaving the skeletal proteins of the erythrocyte membrane. Therefore, the inhibition of FP-2 represents a promising target in the search of novel anti-malarial drugs. A potent FP-2 inhibitor, characterized by the presence in its structure of the 1,4-benzodiazepine scaffold and an ?,?-unsaturated methyl ester moiety capable to react with the Cys42 thiol group located in the active site of FP-2, has been recently reported in literature. In order to study in depth the inhibition mechanism triggered by this interesting compound, we carried out, through ONIOM hybrid calculations, a computational investigation of the processes occurring when the inhibitor targets the enzyme and eventually leads to an irreversible covalent Michael adduct. Each step of the reaction mechanism has been accurately characterized and a detailed description of each possible intermediate and transition state along the pathway has been reported.

| S-EPMC7088093 | biostudies-literature

Computational determination of binding structures and free energies of phosphodiesterase-2 with benzo[1,4]diazepin-2-one derivatives.

Project description:Phosphodiesterase-2 (PDE2) is a key enzyme catalyzing hydrolysis of both cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) that serve as intracellular second messengers. PDE2 has been recognized as an attractive drug target, and selective inhibitors of PDE2 are expected to be promising candidates for the memory enhancer, antidepressant, and anxiolytic agent. In the present study, we examined the detailed binding structures and free energies for PDE2 interacting with a promising series of inhibitors, i.e., benzo[1,4]diazepin-2-one derivatives, by carrying out molecular docking, molecular dynamics (MD) simulations, binding free energy calculations, and binding energy decompositions. The computational results provide valuable insights into the detailed enzyme-inhibitor binding modes including important intermolecular interactions, e.g., the ?-? stacking interactions with the common benzo[1,4]diazepin-2-one scaffold of the inhibitors, hydrogen bonding and hydrophobic interactions with the substituents on the benzo[1,4]diazepin-2-one scaffold. Future rational design of new, more potent inhibitors of PDE2 should carefully account for all of these favorable intermolecular interactions. By use of the MD-simulated binding structures, the calculated binding free energies are in good agreement with the experimental activity data for all of the examined benzo[1,4]diazepin-2-one derivatives. The enzyme-inhibitor binding modes determined and the agreement between the calculated and experimental results are expected to be valuable for future rational design of more potent inhibitors of PDE2.

| S-EPMC3072033 | biostudies-literature

4-(Piperidin-1-yl)-4H-benzo[b]tetra-zolo[1,5-d][1,4]diazepin-5(6H)-one.

Project description:There are two crystallographically unique mol-ecules present in the asymmetric unit of the title compound, C(14)H(16)N(6)O; in both mol-ecules, the seven-membered diazepinone ring adopts a boat-like conformation and the chair conformation piperidine ring is an axial substituent on the diazepinone ring. In the crystal, each mol-ecule forms hydrogen bonds with its respective symmetry equivalents. Hydrogen bonding between mol-ecule A and symmetry equivalents forms two ring motifs, the first formed by inversion-related N-H?O inter-actions and the second formed by C-H?O and C-H?N inter-actions. The combination of both ring motifs results in the formation of an infinite double tape, which propagates in the a-axis direction. Hydrogen bonding between mol-ecule B and symmetry equivalents forms one ring motif by inversion-related N-H?O inter-actions and a second ring motif by C-H?O inter-actions, which propagate as a single tape parallel with the c axis.

| S-EPMC3050344 | biostudies-other

Regiospecific Synthesis and Structural Studies of 3,5-Dihydro-4H-pyrido[2,3-b][1,4]diazepin-4-ones and Comparison with 1,3-Dihydro-2H-benzo[b][1,4]diazepin-2-ones.

Project description:Nine 3,5-dihydro-4H-pyrido[2,3-b][1,4]diazepin-4-ones (17-25), some of which contain fluoro-substituents, have been regiospecifically prepared by reaction of 2,3-diaminopyridines with ethyl aroylacetates. In two cases, open intermediates have been isolated and these are related to the reaction pathway. The X-ray crystal structure of 1-methyl-4-phenyl-3,5-dihydro-4H-pyrido[2,3-b][1,4]diazepin-4-one (23) has been solved (formula, C15H13N3O; crystal system, monoclinic; space group, C2/c). This is an asymmetric unit constituted by a single nonplanar molecule and its conformational enantiomer due to the presence of the seven-membered diazepin-2-one moiety, which introduces a certain degree of torsion in the adjacent pyridine ring. The 1H, 13C, 15N, and 19F NMR spectra were obtained and the chemical shifts, together with those of the previously published 1,3-dihydro-2H-benzo[b][1,4]diazepin-2-ones (1-16), i.e., a total of 544 values, were successfully compared with the chemical shifts calculated at the gauge invariant atomic orbital (GIAO)/Becke, three-parameter, Lee-Yang-Parr (B3LYP)/6-311++G(d,p) level. The seven-membered ring inversion barrier in 5-benzyl-2-phenyl-3,5-dihydro-4H-pyrido[2,3-b][1,4]diazepin-4-one (25) was determined and, in conjunction with the data from the literature, compared with the B3LYP/6-311++G(d,p) computed values. This allowed the determination of several structural effects. The rotation about the exocyclic N1-CR bond was also calculated and its dynamic properties were discussed.

| S-EPMC7542844 | biostudies-literature

Macrophage activation by a substituted pyrimido[5,4-b]indole increases anti-cancer activity.

Project description:Immunotherapy has become a promising new approach for cancer treatment due to the immune system's ability to remove tumors in a safe and specific manner. Many tumors express anti-inflammatory factors that deactivate the local immune response or recruit peripheral macrophages into pro-tumor roles. Because of this, effective and specific ways of activating macrophages into anti-tumor phenotypes is highly desirable for immunotherapy purposes. Here, the use of a small molecule TLR agonist as a macrophage activator for anti-cancer therapy is reported. This compound, referred to as PBI1, demonstrated unique activation characteristics and expression patterns compared to treatment with LPS, through activation of TLR4. Furthermore, PBI1 treatment resulted in anti-tumor immune behavior, enhancing macrophage phagocytic efficiency five-fold versus non-treated macrophages. Additive effects were observed via use of a complementary strategy (anti-CD47 antibody), resulting in ∼10-fold enhancement of phagocytosis, suggesting this small molecule approach could be used in conjunction with other therapeutics.

| S-EPMC6849472 | biostudies-literature

5,7-Dimethyl-2,3-dihydro-1H-1,4-diazepin-4-ium picrate.

Project description:In the cation of the title compound, C(7)H(13)N(2) (+)·C(6)H(2)N(3)O(7) (-), the seven-membered 1,4-diazepine ring forms a twist chair conformation. The two o-nitro groups in the anion are twisted by 35.0?(7) and 36.0?(9)° from the benzene ring. In the crystal, N-H?O hydrogen bonds between the cation and anion along with weak C-H?O hydrogen bonds produce chains along the b axis. C-H?O hydrogen bonds connecting the chains are also present.

| S-EPMC2979234 | biostudies-literature

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