Nodal and Activin belong to the TGF-β superfamily and are important regulators of embryonic stem cell fate. Here we investigated whether Nodal and Activin regulate self-renewal of pancreatic cancer stem cells. Nodal and Activin were hardly detectable in more differentiated pancreatic cancer cells, while cancer stem cells and stroma-derived pancreatic stellate cells markedly overexpressed Nodal and Activin, but not TGF-β. Knockdown or pharmacological inhibition of the Nodal/Activin receptor Alk4/7 in cancer stem cells virtually abrogated their self-renewal capacity and in vivo tumorigenicity, and reversed the resistance of orthotopically engrafted cancer stem cells to gemcitabine. However, engrafted primary human pancreatic cancer tissue with a substantial stroma showed no response due to limited drug delivery. The addition of a stroma-targeting hedgehog pathway inhibitor enhanced delivery of the Nodal/Activin inhibitor and translated into long-term, progression-free survival. Therefore, inhibition of the Alk4/7 pathway, if combined with hedgehog pathway inhibition and gemcitabine, provides a therapeutic strategy for targeting cancer stem cells.
Visceral leishmaniasis (VL), caused by the protozoan parasites Leishmania donovani and Leishmania infantum, is one of the major parasitic diseases worldwide. There is an urgent need for new drugs to treat VL, because current therapies are unfit for purpose in a resource-poor setting. Here, we describe the development of a preclinical drug candidate, GSK3494245/DDD01305143/compound 8, with potential to treat this neglected tropical disease. The compound series was discovered by repurposing hits from a screen against the related parasite Trypanosoma cruzi. Subsequent optimization of the chemical series resulted in the development of a potent cidal compound with activity against a range of clinically relevant L. donovani and L. infantum isolates. Compound 8 demonstrates promising pharmacokinetic properties and impressive in vivo efficacy in our mouse model of infection comparable with those of the current oral antileishmanial miltefosine. Detailed mode of action studies confirm that this compound acts principally by inhibition of the chymotrypsin-like activity catalyzed by the β5 subunit of the L. donovani proteasome. High-resolution cryo-EM structures of apo and compound 8-bound Leishmania tarentolae 20S proteasome reveal a previously undiscovered inhibitor site that lies between the β4 and β5 proteasome subunits. This induced pocket exploits β4 residues that are divergent between humans and kinetoplastid parasites and is consistent with all of our experimental and mutagenesis data. As a result of these comprehensive studies and due to a favorable developability and safety profile, compound 8 is being advanced toward human clinical trials.
SUMMARY
Genetic inhibition of PI3K signaling increases energy expenditure,
protects from obesity and metabolic syndrome, and extends longevity. Here, we
show that two pharmacological inhibitors of PI3K, CNIO-PI3Ki and GDC-0941,
decrease the adiposity of obese mice without affecting their lean mass.
Long-term treatment of obese mice with low doses of CNIO-PI3Ki reduces body
weight until reaching a balance that is stable for months as long as the
treatment continues. CNIO-PI3Ki treatment also ameliorates liver steatosis and
decreases glucose serum levels. The above observations have been recapitulated
in independent laboratories and using different oral formulations of CNIO-PI3Ki.
Finally, daily oral treatment of obese rhesus monkeys for 3 months with low
doses of CNIO-PI3Ki decreased their adiposity and lowered their serum glucose
levels, in the absence of detectable toxicities. Therefore, pharmacological
inhibition of PI3K is an effective and safe anti-obesity intervention that could
reverse the negative effects of metabolic syndrome in humans.
The supplemental information file originally published with this article inadvertently showed Figure S6 in the place of Figure S4. A corrected version has now been posted online in its place. We apologize for any confusion caused.
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