No abstract

AXL kinase is heavily involved in tumorigenesis, metastasis, and drug resistance of many cancers, and several AXL inhibitors are in clinical investigations. Recent studies demonstrated that the N-terminal distal region of AXL plays more important roles in cell invasiveness than its C-terminal kinase domain. Therefore, degradation of AXL may present a novel superior therapeutic approach than the kinase inhibitor therapy. Herein, we report the discovery of a series of new AXL PROTAC degraders. One representative compound 6n potently depletes AXL with a DC50 value of 5 nM in MDA-MB-231 TNBC cells. It also demonstrates significantly improved potencies against the AXL signaling activation, cell proliferation, migration and invasion of TNBC cells comparing with the corresponding kinase inhibitor. Moreover, the compound exhibits promising therapeutic potential both in patient-derived organoids and a xenograft mouse model of MDA-MB-231 cells.

The community structures and diversity of bacteria and archaea were investigated at 4 depths (1.5, 2.0, 2.5, and 3.0 m) in permafrost sediments in the Tianshan Mountains, using denaturing gradient gel electrophoresis of 16S rRNA gene amplified by polymerase chain reaction. Phylogenetic analysis of the dominant bands sequenced revealed the presence of rich diversity of bacteria, which could be related to the Proteobacteria, Actinobacteria, Acidobacteria, Gemmatimonadetes, Bacteroidetes, Firmicutes, and Chloroflexi. The Proteobacteria, consisting of the alpha, beta, gamma and epsilon subdivisions, were clearly the dominant group at all depths studied. Archaeal diversity was relatively low and archaeal 16S rRNA gene sequences were grouped into 3 phylogenetic clusters within the 2 kingdoms Euryarchaeota and Crenarchaeota. Within the Euryarchaeota, methanogen-related group II was most abundant at shallow depth (1.5 m), whereas halobacterium-related group I dominated at greater depths. The low-temperature Crenarchaeota group was detected only at 2.5 and 3.0 m. Specific-depth distribution of methanogen-related Euryarchaeota group II and denitrifying bacteria of the genus Pseudomonas dominated at 1.5 m depth, accompanied by a distinct peak in the ratio of NH4-N to NO3/NO2-N, implying the potential capacity of these organisms in near-surface permafrost to release the greenhouse gases N2O and CH4.