The
activation of the cyclic GMP-AMP synthase-stimulator of interferon
gene (STING) pathway has been associated with the pathogenesis of
many autoimmune and inflammatory disorders, and small molecules targeting
STING have emerged as a new therapeutic strategy for the treatment
of these diseases. While several STING inhibitors have been identified
with potent anti-inflammatory effects, we would like to explore STING
degraders based on the proteolysis-targeting chimera (PROTAC) technology
as an alternative strategy to target the STING pathway. Thus, we designed
and synthesized a series of STING protein degraders based on a small-molecule
STING inhibitor (C-170) and pomalidomide (a CRBN ligand).
These compounds demonstrated moderate STING-degrading activities.
Among them, SP23 achieved the highest degradation potency
with a DC50 of 3.2 μM. Importantly, SP23 exerted high anti-inflammatory efficacy in a cisplatin-induced acute
kidney injury mouse model by modulating the STING signaling pathway.
Taken together, SP23 represents the first PROTAC degrader
of STING deserving further investigation as a new anti-inflammatory
agent.
Novel
enzyme-triggerable cell penetrating peptide (ETCPP) dendrimers
with a camptothecin (CPT) warhead were designed and synthesized based
on an amphiphilic penetrating peptide (FKKFFRKLL, discovered by us
before). Among the newly synthesized ETCPP dendrimer conjugates, BL_Oc-SS-CPT
(a high-generation dendrimer) exhibited the highest activity with
IC50s in the nanomolar range (31–747 nM) against
a panel of cancer cells, which is 3–10 times better than that
of CPT. BL_Oc-SS-CPT remained intact during transit to target cells
and in normal tissues with a plasma half-life of 4.2 h, 2.3-fold longer
than that of the monomer (1.8 h). Once reaching the tumor site, BL_Oc-SS-CPT
gradually released CPT in the presence of excessive matrix metalloproteinase-2/9
and GSH in cancer cells. Importantly, BL_Oc-SS-CPT exhibited excellent
in vivo tumor targeting capability and antitumor efficacy with benign
toxicity profiles. Thus, the novel ETCPP dendrimer-based drug delivery
system (e.g., BL_Oc-SS-CPT) represents a safe and effective strategy
for targeted cancer therapy.
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