Alkynyl Benzoxazines and Dihydroquinazolines as Cysteine Targeting Covalent Warheads and Their Application in Identification of Selective Irreversible Kinase Inhibitors.

With a resurgence in interest in covalent drugs, there is a need to identify new moieties capable of cysteine bond formation that are differentiated from commonly employed systems such as acrylamide. Herein, we report on the discovery of new alkynyl benzoxazine and dihydroquinazoline moieties capable of covalent reaction with cysteine. Their utility as alternative electrophilic warheads for chemical biological probes and drug molecules is demonstrated through site-selective protein modification and incorporation into kinase drug scaffolds. A potent covalent inhibitor of JAK3 kinase was identified with superior selectivity across the kinome and improvements in in vitro pharmacokinetic profile relative to the related acrylamide-based inhibitor. In addition, the use of a novel heterocycle as a cysteine reactive warhead is employed to target Cys788 in c-KIT, where acrylamide has previously failed to form covalent interactions. These new reactive and selective heterocyclic warheads supplement the current repertoire for cysteine covalent modification while avoiding some of the limitations generally associated with established moieties

Small molecule binding sites on the Ras:SOS complex can be exploited for inhibition of Ras activation.

Constitutively active mutant KRas displays a reduced rate of GTP hydrolysis via both intrinsic and GTPase-activating protein-catalyzed mechanisms, resulting in the perpetual activation of Ras pathways. We describe a fragment screening campaign using X-ray crystallography that led to the discovery of three fragment binding sites on the Ras:SOS complex. The identification of tool compounds binding at each of these sites allowed exploration of two new approaches to Ras pathway inhibition by stabilizing or covalently modifying the Ras:SOS complex to prevent the reloading of Ras with GTP. Initially, we identified ligands that bound reversibly to the Ras:SOS complex in two distinct sites, but these compounds were not sufficiently potent inhibitors to validate our stabilization hypothesis. We conclude by demonstrating that covalent modification of Cys118 on Ras leads to a novel mechanism of inhibition of the SOS-mediated interaction between Ras and Raf and is effective at inhibiting the exchange of labeled GDP in both mutant (G12C and G12V) and wild type Ras

Inhibitors of the tyrosine kinase EphB4.:part 2: structure-based discovery and optimisation of 3,5-bis substituted anilinopyrimidines

Crystallographic studies of a range of 3-substituted anilinopyrimidine inhibitors of EphB4 have highlighted two alternative C-2 aniline conformations and this discovery has been exploited in the design of a highly potent series of 3,5-disubstituted anilinopyrimidines. The observed range of cellular activities has been rationalised on the basis of physicochemical and structural characteristics

Effect of tether length on endo/exo stereoselectivity in alkene–arene meta‐photocycloaddition reactions towards the Aphidocolin/Stemodin scaffolds

Intramolecular alkene-arene meta-photocycloadditions are powerful transformations that use the enhanced reactivity of photoexcited benzene rings to facilitate addition of an alkene 1,3 across donor groups and form complex three-dimensional fused-ring systemsfrom readily accessible starting materials. Intramolecular examples havetraditionallybeen restricted to 3-memberedtethers, with cycloaddition resulting from exo-conformation. However, by judicious tether design we have demonstratedthat a 4-membered tether can also proceed in good yield; interestingly,viaan endo-exciplex(1.2:1) enabling access to both natural product skeletons and interesting scaffolds for medicinal chemistry research

Effect of Tether Length on endo / exo Stereoselectivity in Alkene–Arene meta ‐Photocycloaddition Reactions towards the Aphidocolin/Stemodin Scaffolds

Intramolecular alkene‐arene meta‐photocycloadditions are powerful transformations that use the enhanced reactivity of photoexcited benzene rings to facilitate addition of an alkene 1,3 across donor groups and form complex three‐dimensional fused‐ring systems from readily accessible starting materials. Intramolecular examples have traditionally been restricted to three‐membered tethers, with cycloaddition resulting from exo‐conformation. However, by judicious tether design we have demonstrated that a four‐membered tether can also proceed in good yield; interestingly, via an endo exciplex (1.2 : 1) enabling access to both natural product skeletons and interesting scaffolds for medicinal chemistry research

The impact of detailed urban-scale processing on the composition, distribution, and radiative forcing of anthropogenic aerosols

Detailed urban-scale processing has not been included in global 3D chemical transport models due to its large computational demands. Here we present a metamodel for including this processing, and compare it with the use of the traditional approach of dilution of emissions into large grid boxes. This metamodel is used in a global 3D model to simulate the effects of cities around the world on aerosol chemistry, physics, and radiative effects at the global scale. We show that the biases caused by ignoring urban processing on the global values of total aerosol surface concentration, the total aerosol column abundance, the aerosol optical depth (AOD), the absorbing aerosol optical depth (AAOD), and the top of the atmosphere radiative forcing (TOA) respectively are +26 ± +26 ± [subscript 3[superscript 2]]%, +51 ± +26 ± [subscript 10[superscript 12]]%, +42 ± [subscript 8[superscript 10]]%, +8 ± [subscript 16[superscript 18]]%, and −0.27 ± [subscript 0.14[superscript 0.10]] W/m2. These results show that failure to consider urban scale processing leads to significantly more negative aerosol radiative forcing compared to when detailed urban scale processing is considered.United States. Dept. of Energy (Grant DE‐FG02‐94ER61937)National Science Foundation (U.S.) (Grant AGS‐0944121)Singapore. National Research FoundationSingapore-MIT Alliance. Center for Environmental Sensing and Monitorin

Discovery of AZD8931, an equipotent, reversible inhibitor of signaling by EGFR, HER2, and HER3 receptors

[Image: see text] Deregulation of HER family signaling promotes proliferation and tumor cell survival and has been described in many human cancers. Simultaneous, equipotent inhibition of EGFR-, HER2-, and HER3-mediated signaling may be of clinical utility in cancer settings where the selective EGFR or HER2 therapeutic agents are ineffective or only modestly active. We describe the discovery of AZD8931 (2), an equipotent, reversible inhibitor of EGFR-, HER2-, and HER3-mediated signaling and the structure–activity relationships within this series. Docking studies based on a model of the HER2 kinase domain helped rationalize the increased HER2 activity seen with the methyl acetamide side chain present in AZD8931. AZD8931 exhibited good pharmacokinetics in preclinical species and showed superior activity in the LoVo tumor growth efficacy model compared to close analogues. AZD8931 is currently being evaluated in human clinical trials for the treatment of cancer

Discovery and Optimization of a Novel Series of Dyrk1B Kinase Inhibitors To Explore a MEK Resistance Hypothesis

Potent and selective inhibitors of Dyrk1B kinase were developed to explore the hypothesis, based on siRNA studies, that Dyrk1B may be a resistance mechanism in cells undergoing a stress response