Photoaffinity Probe Reveals the Potential Target of Harringtonolide for Cancer Cell Migration Inhibition
Natural products have
historically provided a wealth of diverse
structures that can serve as leads for medicinal chemistry optimization
or for the discovery of therapeutically relevant biological pathways.
In many cases, the in vitro and/or in vivo activity can be readily confirmed, even though a molecular understanding
of the putative target and pathway remains unknown. In this issue,
Kong, Luo, and co-workers identify the putative pharmacological target
and pathways engaged by harringtonolide, a cephalotane-derived diterpenoid
that has been explored for a variety of indications including inhibition
of plant growth, antiviral autoinflammatory, and antiproliferative
activities (DOI: 10.1021/acsmedchemlett.1c00625). Interestingly, despite bearing multiple potential electrophilic
sites for covalently engaging a protein, harringtonolide remains unreactive
toward nucleophiles. To identify potential targets, the research team
synthesized a harringtonolide-based photoaffinity probe to identify
and validate the receptor for activated C kinase 1 (RACK1) as the
putative target. They further demonstrated that inhibition of RACK1
suppresses cell migration and the epithelial–mesenchymal transition
process by inhibiting the FAK/Src/STAT3 signaling pathway, which has
been actively targeted by other therapeutics. Ultimately, validation
of this target provides opportunities to rationally develop harringtonolide
analogues for a variety of diseases states.
Discovery of TAK-925 as a Potent, Selective, and Brain-Penetrant Orexin 2 Receptor Agonist
The orexin A and B receptors have
been validated as important regulators
of sleep-wakefulness cycles. In particular, agonism of orexin receptor
type 2 (OX2R) has been proposed as a promising therapeutic target
for treating narcolepsy type 1 (NT1). Though both peptide- and nonpeptide-based
agonists have been reported, the physicochemical properties of the
published molecules do not enable permeation of the blood-brain barrier,
which is required to engage OX2R. In this issue, a research team from
Takeda reports on a hit-to-lead optimization from a high throughput
screen to deliver TAK-925, a clinical candidate for treatment of NT1
(DOI: 10.1021/acsmedchemlett.1c00626). By addressing
issues of stereochemistry and optimizing lipophilic moieties, the
team was able to deliver a therapeutic candidate with appropriate
potency, selectivity, and CNS permeability and stability to enable
human trials. Interestingly, X-ray structural data and NMR studies
suggest that TAK-925 adopts an unusual axial–axial conformation
to engage OX2R. Overall, this program has delivered a promising therapeutic
candidate for narcolepsy and other potential disorders related to
the orexin system.
Conversion of a PROTAC Mutant Huntingtin Degrader into Small-Molecule Hydrophobic Tags Focusing on Drug-like Properties
Many neurodegenerative
disorders are associated with the progressive
aggregation of misfolded proteins. Neuroscientists have long sought
to develop therapeutics that reduce the buildup of accumulated proteins.
One potential strategy might involve the selective degradation of
misfolded proteins using heterobifunctional protein targeting chimeras
(PROTACs) that exploit one moiety to bind the protein of interest
and a second one to recruit an E3 ubiquitin ligase to promote ubiquitinoylation
and proteasomal degradation. Though useful for many targets, the heterobifunctional
nature of PROTACs typically impart molecular properties that disfavor
permeation of the blood brain barrier (BBB), which impedes translation
to neurological diseases. In this issue, research teams from the Universities
of Tokyo, Tohoku, and Osaka and the Tokyo Institute of Technology
report on an alternative CNS-penetrant hydrophobic tagging approach
for degrading mutant huntingtin (mHtt), a protein that aggregates
in the brains of individuals with Huntington’s disease (DOI: 10.1021/acsmedchemlett.1c00500). To enable CNS permeation,
the team optimized a series of hydrophobic degrons that promote degradation
of mHtt through mimicking the protein misfolding process. By reducing
the hydrogen bond donor count, molecular weight, and polar surface
area, the team delivered bifunctional degraders that bear improved
CNS drug-like properties and identified an analogue that crosses the
blood-brain barrier in mice. This strategy provides optimism for extending
degrader strategies to other CNS-related diseases.