Microbial
β-glucuronidases (GUSs) cause severe gut toxicities that limit
the efficacy of cancer drugs and other therapeutics. Selective inhibitors
of bacterial GUS have been shown to alleviate these side effects.
Using structural and chemical biology, mass spectrometry, and cell-based
assays, we establish that piperazine-containing GUS inhibitors intercept
the glycosyl-enzyme catalytic intermediate of these retaining glycosyl
hydrolases. We demonstrate that piperazine-based compounds are substrate-dependent
GUS inhibitors that bind to the GUS–GlcA catalytic intermediate
as a piperazine-linked glucuronide (GlcA, glucuronic acid). We confirm
the GUS-dependent formation of inhibitor–glucuronide conjugates
by LC–MS and show that methylated piperazine analogs display
significantly reduced potencies. We further demonstrate that a range
of approved piperazine- and piperidine-containing drugs from many
classes, including those for the treatment of depression, infection,
and cancer, function by the same mechanism, and we confirm through
gene editing that these compounds selectively inhibit GUS in living
bacterial cells. Together, these data reveal a unique mechanism of
GUS inhibition and show that a range of therapeutics may impact GUS
activities in the human gut.
Increased
activity of the lysine methyltransferase NSD2 driven
by translocation and activating mutations is associated with multiple
myeloma and acute lymphoblastic leukemia, but no NSD2-targeting chemical
probe has been reported to date. Here, we present the first antagonists
that block the protein–protein interaction between the N-terminal
PWWP domain of NSD2 and H3K36me2. Using virtual screening and experimental
validation, we identified the small-molecule antagonist 3f, which binds to the NSD2-PWWP1 domain with a K
d of 3.4 μM and abrogates histone H3K36me2 binding to
the PWWP1 domain in cells. This study establishes an alternative approach
to targeting NSD2 and provides a small-molecule antagonist that can
be further optimized into a chemical probe to better understand the
cellular function of this protein.
We recently reported the medicinal chemistry reoptimization of a known human tyrosine kinase inhibitor, lapatinib, against a variety of parasites responsible for numerous tropical diseases, including human African trypanosomiasis ( Trypanosoma brucei), Chagas disease ( T. cruzi), Leishmaniasis ( Leishmania spp.), and malaria ( Plasmodium falciparum). Herein, we report our continuing efforts to optimize this series against P. falciparum. Through the design of a library of compounds focused on reducing the lipophilicity and molecular weight, followed by an SAR exploration, we have identified NEU-1953 (40). This compound is a potent inhibitor of P. falciparum with an improved ADME profile over the previously reported compound, NEU-961 (3).
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