CD73 is an extracellular mediator
of purinergic signaling. When
upregulated in the tumor microenvironment, CD73 has been implicated
in the inhibition of immune function through overproduction of adenosine.
Traditional efforts to inhibit CD73 have involved antibody therapy
or the development of small molecules, the most potent of which mimic
the acidic and ionizable structure of the enzyme’s natural
substrate, adenosine 5′-monophosphate (AMP). Here, we report
the systematic discovery of a novel class of non-nucleotide CD73 inhibitors
that are more potent than all other nonphosphonate inhibitor classes
reported to date. These efforts have culminated in the discovery of
4-({5-[4-fluoro-1-(2H-indazol-6-yl)-1H-1,2,3-benzotriazol-6-yl]-1H-pyrazol-1-yl}methyl)benzonitrile
(73, IC50 = 12 nM) and 4-({5-[4-chloro-1-(2H-indazol-6-yl)-1H-1,2,3-benzotriazol-6-yl]-1H-pyrazol-1-yl}methyl)benzonitrile (74, IC50 = 19 nM). Cocrystallization of 74 with human
CD73 demonstrates a competitive binding mode. These compounds show
promise for the improvement of drug-like character via the attenuation
of the acidity and low membrane permeability inherent to known nucleoside
inhibitors of CD73.
Identification of agents that target human leukemia stem cells (LSCs) is an important consideration for the development of new therapies. The present study demonstrates that rocaglamide and silvestrol, closely related natural products from the flavagline class of compounds, are able to preferentially kill functionally defined LSCs while sparing normal stem and progenitor cells. In addition to efficacy as single agents, flavaglines sensitize leukemia cells to several anti-cancer compounds, including front-line chemotherapeutic drugs used to treat leukemia patients. Mechanistic studies indicate that flavaglines strongly inhibit protein synthesis, leading to the reduction of short-lived anti-apoptotic proteins. Notably though, treatment with flavaglines alone or in combination with other drugs, yields a much stronger cytotoxic activity towards leukemia cells than the translational inhibitor temsirolimus. These results indicate that the underlying cell death mechanism of flavaglines is more complex than simply inhibiting general protein translation. Global gene expression profiling and cell biological assays identified Myc inhibition and the disruption of mitochondrial integrity to be features of flavaglines, which we propose contribute to their efficacy in targeting leukemia cells. Together, these findings indicate that rocaglamide and silvestrol are distinct from clinically available translational inhibitors and represent promising candidates for the treatment of leukemia.
The
1,6-conjugate addition of nucleophiles to dienyl diketones
produces either cyclopentenone or 2H-pyran products
with high selectivity through either Nazarov (4π) or 6π
electrocyclization, respectively. The outcome of the reaction is dependent
upon the nature of the nucleophile used. Nucleophiles that are anionic
or easily deprotonated exclusively produce cyclopentenones via Nazarov
cyclization, whereas the neutral nucleophile DABCO promotes 6π
cyclization to afford 2H-pyrans. Experimental evidence
is presented for both retro-4π and -6π electrocyclization
in these systems, lending support to the bifurcated mechanistic hypothesis
proposed for these cyclizations.
AB680 is a highly potent CD73 small molecule inhibitor discovered and developed by Arcus Biosciences, currently in clinical trials for the treatment of pancreatic cancer. Here, we report the development of a scalable and practical method for the manufacturing of the azaindazole central core. This synthesis features an N-oxide formation followed by an α-chlorination with POCl 3 leading to the formation of 4,6-dichloro-1H-pyrazolo [3,4-b]pyridine 1 in high yield and 99.5% UV purity. This method was successfully performed on multikilogram scale to support the synthesis of AB680.
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