We
herein report the conventional and microscale parallel synthesis
of selective inhibitors of human blood coagulation factor XIIa and
thrombin exhibiting a 1,2,4-triazol-5-amine scaffold. Structural variations
of this scaffold allowed identifying derivative 21i,
a potent 29 nM inhibitor of FXIIa, with improved selectivity over
other tested serine proteases and also finding compound 21m with 27 nM inhibitory activity toward thrombin. For the first time,
acylated 1,2,4-triazol-5-amines were proved to have anticoagulant
properties and the ability to affect thrombin- and cancer-cell-induced
platelet aggregation. Performed mass spectrometric analysis and molecular
modeling allowed us to discover previously unknown interactions between
the synthesized inhibitors and the active site of FXIIa, which uncovered
the mechanistic details of FXIIa inhibition. Synthesized compounds
represent a promising starting point for the development of novel
antithrombotic drugs or chemical tools for studying the role of FXIIa
and thrombin in physiological and pathological processes.
The targeted degradation of histone deacetylase 6 (HDAC6) by heterobifunctional degraders constitutes a promising approach to treat HDAC6-driven diseases. Previous HDAC6 selective degraders utilised a hydroxamic acid as a zinc-binding...
Syndecan-1 (Sdc-1) upregulation is associated with poor prognosis in breast cancer. Sdc-1 knockdown results in reduced angiogenesis and the dysregulation of tissue factor (TF) pathway constituents. Here, we evaluate the regulatory mechanisms and functional consequences of the Sdc-1/TF-axis using Sdc-1 knockdown and overexpression approaches in MCF-7 and MDA-MB-231 breast cancer cells. Gene expression was analyzed by means of qPCR. Thrombin generation and cell migration were detected. Cell-cycle progression and apoptosis were investigated using flow cytometry. In MDA-MB-231 cells, IL6, IL8, VEGF, and IGFR-dependent signaling affected TF pathway expression depending on Sdc-1. Notably, Sdc-1 depletion and TF pathway inhibitor (TFPI) synergistically affected PTEN, MAPK, and STAT3 signaling. At the functional level, the antiproliferative and pro-apoptotic effects of TFPI depended on Sdc-1, whereas Sdc-1’s modulation of cell motility was not affected by TFPI. Sdc-1 overexpression in MCF-7 and MDA-MB-231 cells led to increased TF expression, inducing a procoagulative phenotype, as indicated by the activation of human platelets and increased thrombin formation. A novel understanding of the functional interplay between Sdc-1 and the TF pathway may be compatible with the classical co-receptor role of Sdc-1 in cytokine signaling. This opens up the possibility of a new functional understanding, with Sdc-1 fostering coagulation and platelet communication as the key to the hematogenous metastatic spread of breast cancer cells.
The targeted degradation of histone deacetylase 6 (HDAC6) by heterobifunctional degraders constitutes a promising approach to treat HDAC6-driven diseases. Previous HDAC6 selective degraders utilised a hydroxamic acid as a zinc-binding group (ZBG) which features mutagenic and genotoxic potential. Here we report the development of a new class of selective HDAC6 degraders based on a difluoromethyl-1,3,4-oxadiazole (DFMO) warhead as ZBG.
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