CIC-DUX4 sarcoma (CDS) is a highly aggressive and metastatic small round type of predominantly pediatric sarcoma driven by a fusion oncoprotein comprising the transcriptional repressor Capicua (CIC) fused to the C-terminal transcriptional activation domain of DUX4. CDS rapidly develops resistance to chemotherapy, thus novel specific therapies are greatly needed. We demonstrate that CIC-DUX4 requires P300/CBP to induce histone H3 acetylation, activate its targets, and drive oncogenesis. We describe the synthetic route to a selective and highly potent P300/CBP inhibitor named iP300w and related stereoisomers, and find that iP300w efficiently suppresses CIC-DUX4 transcriptional activity and reverses CIC-DUX4 induced acetylation. iP300w is active at 100-fold lower concentrations than related stereoisomers or A-485. At low doses, iP300w shows specificity to CDS cancer cell lines, rapidly inducing cell cycle arrest and preventing growth of established CDS xenograft tumors when delivered in vivo. The effectiveness of iP300w to inactivate CIC-DUX4 highlights a promising therapeutic opportunity for CDS.
SARS-CoV-2 is the
causative agent behind the COVID-19
pandemic.
The main protease (Mpro, 3CLpro) of SARS-CoV-2
is a key enzyme that processes polyproteins translated from the viral
RNA. Mpro is therefore an attractive target for the design
of inhibitors that block viral replication. We report the diastereomeric
resolution of the previously designed SARS-CoV-2 Mpro α-ketoamide
inhibitor 13b. The pure (S,S,S)-diastereomer, 13b-K, displays an IC50 of 120 nM against the Mpro and EC50 values of 0.8–3.4 μM for
antiviral activity in different cell types. Crystal structures have
been elucidated for the Mpro complexes with each of the
major diastereomers, the active (S,S,S)-13b (13b-K), and the nearly inactive (R,S,S)-13b
(13b-H); results for the latter reveal a novel binding
mode. Pharmacokinetic studies show good levels of 13b-K after inhalative as well as after peroral administration. The active
inhibitor (13b-K) is a promising candidate for further
development as an antiviral treatment for COVID-19.
A synthesis of highly functionalized nitroalkenes is reported that utilizes a cross metathesis (CM) reaction between simple aliphatic nitro compounds and a range of substituted alkenes. This chemistry offers a simple and attractive route to nitroalkenes that would otherwise be difficult to prepare, and that have a very useful application as precursors to a variety of heterocyclic entities.
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