Antibody-drug conjugates (ADC) target cytotoxic drugs to antigen-positive cells for treating cancer. After internalization, ADCs with noncleavable linkers are catabolized to amino ...acid-linker-warheads within the lysosome, which then enter the cytoplasm by an unknown mechanism. We hypothesized that a lysosomal transporter was responsible for delivering noncleavable ADC catabolites into the cytoplasm. To identify candidate transporters, we performed a phenotypic shRNA screen with an anti-CD70 maytansine-based ADC. This screen revealed the lysosomal membrane protein SLC46A3, the genetic attenuation of which inhibited the potency of multiple noncleavable antibody-maytansine ADCs, including ado-trastuzumab emtansine. In contrast, the potencies of noncleavable ADCs carrying the structurally distinct monomethyl auristatin F were unaffected by SLC46A3 attenuation. Structure-activity experiments suggested that maytansine is a substrate for SLC46A3. Notably, SLC46A3 silencing led to relative increases in catabolite concentrations in the lysosome. Taken together, our results establish SLC46A3 as a direct transporter of maytansine-based catabolites from the lysosome to the cytoplasm, prompting further investigation of SLC46A3 as a predictive response marker in breast cancer specimens.
The Cell division cycle 7 (Cdc7) protein kinase is essential for DNA replication and maintenance of genome stability. We systematically explored thiazole-based compounds as inhibitors of Cdc7 kinase ...activity in cancer cells. Our studies resulted in the identification of a potent, selective Cdc7 inhibitor that decreased phosphorylation of the direct substrate MCM2 in vitro and in vivo, and inhibited DNA synthesis and cell viability in vitro.
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•Inhibition of Cdc7 kinase may not be limited by cytotoxicity to regular cells.•Compounds with low MW and high binding efficiencies were found in the HTS.•Our SAR studies systematically explored all substituents on the core of thiazoles.•We discovered selective Cdc7 inhibitors that showed potency in vitro and in vivo.•The synthesis of every compound in this manuscript is illustrated.
Spontaneous emission of quantum dot systems in laterally structured microcavities that exhibit photon confinement in all three directions has been studied by time-resolved photoluminescence ...spectroscopy. For on-resonance conditions, we find that the dot emission rate is increased substantially over that of the unstructured planar cavity. For off-resonance conditions, we are able to suppress the emission rate by an order of magnitude by using cavities with metal coatings, which we attribute to the suppression of leaky optical modes in these structures.
The total stratospheric inorganic bromine burden (Bry) was derived from balloon‐borne bromine monoxide (BrO) observations performed with the LPMA/DOAS (Limb Profile Monitor of the ...Atmosphere/Differential Optical Absorption Spectroscopy) balloon payload in the last ten years. The measurements show that significantly more ozone‐depleting bromine ((4.1or 4.3 ± 2.5) ppt) reaches the stratosphere than the atmospheric transport of the major stratospheric bromine source gases, methyl bromide (CH3Br) and all halons can account for. The major contributors to this discrepancy are varying amounts of bromine tied in inorganic gases, particulate matter and very short‐lived substances (VSLS) of natural origin. Despite the significant contribution of stratospheric bromine from natural processes, international protocols introduced to limit the production of brominated gases have been effective by slowing down the overall growth of Bry.
The complicated structure of the neutron cannot be calculated using first-principles calculations due to the large colour charge of quarks and the self-interaction of gluons. Its simplest structure ...observables are the electromagnetic form factors1, which probe our understanding of the strong interaction. Until now, a small amount of data has been available for the determination of the neutron structure from the time-like kinematical range. Here we present measurements of the Born cross section of electron–positron annihilation reactions into a neutron and anti-neutron pair, and determine the neutron’s effective form factor. The data were recorded with the BESIII experiment at centre-of-mass energies between 2.00 and 3.08 GeV using an integrated luminosity of 647.9 pb−1. Our results improve the statistics on the neutron form factor by more than a factor of 60 over previous measurements, demonstrating that the neutron form factor data from annihilation in the time-like regime is on par with that from electron scattering experiments. The effective form factor of the neutron shows a periodic behaviour, similar to earlier observations of the proton form factor. Future works—both theoretical and experimental—will help illuminate the origin of this oscillation of the electromagnetic structure observables of the nucleon.Form factors encode the structure of nucleons. Measurements from electron–positron annihilation at BESIII reveal an oscillating behaviour of the neutron electromagnetic form factor, and clarify a long-standing photon–nucleon interaction puzzle.
We describe the structural optimization of a lead compound 1 that exhibits dual inhibitory activities against FLT3 and CDK4. A series of pyrido4′,3′:4,5pyrrolo2,3-dpyrimidine derivatives was ...synthesized, and SAR analysis, using cell-based assays, led to the discovery of 28 (AMG 925), a potent and orally bioavailable dual inhibitor of CDK4 and FLT3, including many FLT3 mutants reported to date. Compound 28 inhibits the proliferation of a panel of human tumor cell lines including Colo205 (Rb+) and U937 (FLT3WT) and induced cell death in MOLM13 (FLT3ITD) and even in MOLM13 (FLT3ITD, D835Y), which exhibits resistance to a number of FLT3 inhibitors currently under clinical development. At well-tolerated doses, compound 28 leads to significant growth inhibition of MOLM13 xenografts in nude mice, and the activity correlates with inhibition of STAT5 and Rb phosphorylation.
A search for the charged lepton flavor violating decay J/ψ → e± τ∓ with τ∓ → π∓ π0 ντ is performed with about 10 × 10 9 J/ψ events collected with the BESIII detector at the BEPCII. No significant ...signal is observed, and an upper limit is set on the branching fraction B (J/ψ → e± τ∓) < 7.5 × 10−8 at the 90% confidence level. This improves the previously published limit by two orders of magnitude.
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