1,2,6-thiadiazinones as novel narrow spectrum calcium/calmodulin-dependent protein kinase kinase 2 (CaMKK2) inhibitors

We demonstrate for the first time that 4H-1,2,6-thiadiazin-4-one (TDZ) can function as a chemotype for the design of ATP-competitive kinase inhibitors. Using insights from a co-crystal structure of a 3,5-bis(arylamino)-4H-1,2,6-thiadiazin-4-one bound to calcium/calmodulin-dependent protein kinase kinase 2 (CaMKK2), several analogues were identified with micromolar activity through targeted displacement of bound water molecules in the active site. Since the TDZ analogues showed reduced promiscuity compared to their 2,4-dianilinopyrimidine counter parts, they represent starting points for development of highly selective kinase inhibitors

Search for single vector-like B quark production and decay via B → bH(b¯b) in pp collisions at √s = 13 TeV with the ATLAS detector

A search is presented for single production of a vector-like B quark decaying into a Standard Model b-quark and a Standard Model Higgs boson, which decays into a b¯b pair. The search is carried out in 139 fb−1 of √s = 13 TeV proton-proton collision data collected by the ATLAS detector at the LHC between 2015 and 2018. No significant deviation from the Standard Model background prediction is observed, and mass-dependent exclusion limits at the 95% confidence level are set on the resonance production cross-section in several theoretical scenarios determined by the couplings cW, cZ and cH between the B quark and the Standard Model W, Z and Higgs bosons, respectively. For a vector-like B occurring as an isospin singlet, the search excludes values of cW greater than 0.45 for a B resonance mass (mB) between 1.0 and 1.2 TeV. For 1.2 TeV < mB < 2.0 TeV, cW values larger than 0.50–0.65 are excluded. If the B occurs as part of a (B, Y) doublet, the smallest excluded cZ coupling values range between 0.3 and 0.5 across the investigated resonance mass range 1.0 TeV < mB < 2.0 TeV

Search for resonances decaying into photon pairs in 139 fb−1 of pp collisions at √s = 13 TeV with the ATLAS detector

Searches for new resonances in the diphoton final state, with spin 0 as predicted by theories with an extended Higgs sector and with spin 2 using a warped extra-dimension benchmark model, are presented using 139 fb−1 of √s = 13 TeV pp collision data collected by the ATLAS experiment at the LHC. No significant deviation from the Standard Model is observed and upper limits are placed on the production cross-section times branching ratio to two photons as a function of the resonance mass

6-Bromo-N-(2-methyl-2H-benzo[d][1,2,3]triazol-5-yl)quinolin-4-amine

We describe a straightforward synthesis of the title compound, incorporating a relatively rare 2-methyl-2H-1,2,3-triazole heterocylic motif as a potential kinase inhibitor motif. The small molecule crystal structure has been resolved, revealing an interesting packing arrangement and overall conformation. We also performed routine characterization with 1H/13C-NMR and liquid chromatography (LC) and high-resolution mass spectra (HRMS)

6-bromo-n-(3-(difluoromethyl)phenyl)quinolin-4-amine

A routine synthesis was performed to furnish the title compound which incorporates a versatile difluoromethyl group on the aniline substitution of a 4-anilinoquinoline kinase inhibitor motif. In addition, the small molecule crystal structure (of the HCL salt) was solved, which uncovered that the difluoromethyl group was disordered within the packing arrangement and also a 126.08(7)_out of plane character between the respective ring systems within the molecule. The compound was fully characterized with 1H/13C-NMR and high-resolution mass spectra (HRMS), with the procedures described.</p

New insights into 4-anilinoquinazolines as inhibitors of cardiac troponin I-interacting kinase (TNNI3K)

We report the synthesis of several related 4-anilinoquinazolines as inhibitors of cardiac troponin I-interacting kinase (TNNi3K). These close structural analogs of 3-((6,7-dimethoxyquinazolin-4-yl)amino)-4-(dimethylamino)-N-methylbenzenesulfonamide (GSK114) provide new understanding of structure-activity relationships between the 4-anilinoquinazoline scaffold and TNNi3K inhibition. Through a small focused library of inhibitors, we observed that the N-methylbenzenesulfonamide was driving the potency in addition to the more traditional quinazoline hinge-binding motif. We also identified a compound devoid of TNNi3K kinase activity due to the addition of a methyl group in the hinge binding region. This compound could serve as a negative control in the study of TNNi3K biology. Small molecule crystal structures of several quinazolines have been solved, supporting observations made about overall conformation and TNNi3K inhibition.</p

Exploration and development of a C-H-activated route to access the [1,2]dithiolo[4,3- b ]indole-3(4 H)-thione core and related derivatives

A robust procedure for the production of [1,2]dithiolo[4,3- b ]indole-3(4 H)-thione analogues using a DABCO/S 2 Cl 2 complex as a sulfur source via a C-H activated approach.</p

Targeting an EGFR water network with 4-anilinoquin(az)oline inhibitors for chordoma

Quinoline- and quinazoline-based kinase inhibitors of the epidermal growth factor receptor (EGFR) have been used to target non-small cell lung cancer (NSCLC) and chordomas with varying amounts of success. We designed and prepared compounds to probe several key structural features including an interaction with Asp855 within the EGFR DGF motif and interactions with the active site water network. EGFR target engagement was then evaluated in a cellular assay, with the inhibitors then profiled in representative cellular models of NSCLC and chordomas. In addition, structure–activity relationship insight into EGFR inhibitor design with potent dimethoxyquin(az)olines identified compounds 1 [N-(3-ethynylphenyl)-6,7-dimethoxyquinolin-4-amine], 4 [N-(3-ethynylphenyl)-6,7-dimethoxyquinazolin-4-amine], and 7 [4-((3-ethynylphenyl)amino)-6,7-dimethoxyquinoline-3-carbonitrile]. We also identified 6,7-dimethoxy-N-(4-((4-methylbenzyl)oxy)phenyl)quinolin-4-amine (compound 18), which is the most potent inhibitor (IC50=310 nm) of the UCH-2 chordoma cell line to date.</p

Investigation of the pentathiepin functionality as an Inhibitor of feline immunodeficiency virus (FIV) via a potential zinc ejection mechanism, as a model for HIV infection

A small diverse library of pentathiepin derivatives were prepared to evaluate their efficacy against the nucleocapsid protein function of the feline immunodeficiency virus (FIV) as a model for HIV, using an in vitro cell culture approach. This study led to the development of nanomolar active compounds with low toxicity

Design and analysis of the 4-anilinoquin(az)oline kinase inhibition profiles of GAK/SLK/STK10 using quantitative structure-activity relationships

The 4-anilinoquinoline and 4-anilinoquinazoline ring systems have been the focus of significant efforts in prior kinase drug discovery programs, which have led to approved medicines. Broad kinome profiles of these compounds have now been assessed with the advent of advanced screening technologies. These ring systems, while originally designed for specific targets including epidermal growth factor receptor (EGFR), but actually display a number of potent collateral kinase targets, some of which have been associated with negative clinical outcomes. We have designed and synthesized a series of 4-anilinoquin(az)olines in order to better understand the structure-activity relationships of three main collateral kinase targets of quin(az)oline-based kinase inhibitors: cyclin G associated kinase (GAK), STE20-like serine/threonine-protein kinase (SLK) and serine/threonine-protein kinase 10 (STK10). This was achieved through a series of quantitative structure-activity relationship (QSAR) analysis, water mapping of the kinase ATP binding sites and extensive small-molecule X-ray structural analysis.</p