Prolyl endopeptidase inhibitor Y-29794 blocks the IRS1-AKT-mTORC1 pathway and inhibits survival and in vivo tumor growth of triple-negative breast cancer

Q3 · MEDICINE

Article

Author: Calhoun, Sarah ; Shim, Daeun ; Duan, Lei ; Maki, Carl G. ; Levenson, Victor V. ; Perez, Ricardo E

Prolyl endopeptidase (PREP), also known as prolyl oligopeptidase (POP), is an enzyme that cleaves short peptides (<30 amino acids in length) on the C-terminal side of proline. PREP is highly expressed in multiple carcinomas and is a potential target for cancer therapy. A potent inhibitor of PREP, Y-29794, causes long-lasting inhibition of PREP in mouse tissues. However, there are no reports on Y-29794 effects on cancer cell and tumor proliferation. Using cell line models of aggressive triple-negative breast cancer (TNBC), we show here that Y-29794 inhibited proliferation and induced death in multiple TNBC cell lines. Cell death induced by Y-29794 coincided with inhibition of the IRS1-AKT-mTORC1 survival signaling pathway, although stable depletion of PREP alone was not sufficient to reduce IRS1-AKT-mTORC1 signaling or induce death. These results suggest that Y-29794 elicits its cancer cell killing effect by targeting other mechanisms in addition to PREP. Importantly, Y-29794 inhibited tumor growth when tested in xenograft models of TNBC in mice. Induction of cell death in culture and inhibition of xenograft tumor growth support the potential utility of Y-29794 or its derivatives as a treatment option for TNBC tumors.

01 Oct 1997·The Journal of pharmacology and experimental therapeutics

Prevention of amyloid-like deposition by a selective prolyl endopeptidase inhibitor, Y-29794, in senescence-accelerated mouse.

Article

Author: Kato, A ; Nakajima, T ; Sakai, Y ; Fukunari, A

Our study was performed to assess the hypothesis that prolyl endopeptidase (PEP) would be functionally involved in the senescence-accelerated amyloid formation and that long-term inhibition of prolyl endopeptidase would suppress the progression of A beta-like deposition in the hippocampus of the senescence-accelerated mouse (SAM). Granular structures of A beta-LI were observed in the hippocampus and around cerebral microvessels of the SAM after immunohistochemical staining with specific anti-A beta antibody. Repeated treatment of the SAM with Y-29794 (1, 10, 20 mg/kg, p.o.), a specific inhibitor of prolyl endopeptidase, significantly reduced the number and density of A beta-positive granular structures in the hippocampus of the SAM, after digital image analysis with NIH Image software. Furthermore, the characteristic biphasic distribution of the digitized density of the granules was significantly modulated after the treatment with Y-29794. These results suggest that chronic treatment of the SAM with Y-29794, a nonpeptide inhibitor of prolyl endopeptidase, prevents the progression of A beta-like deposition in the hippocampus of the SAM.

01 Jul 1992·Neuroscience LettersQ4 · MEDICINE

Y-29794 — a non-peptide prolyl endopeptidase inhibitor that can penetrate into the brain

Q4 · MEDICINE

Article

Author: Takanori Ohe ; Jun-ichi Maeda ; Akira Kato ; Yuji Ono ; Tohru Nakajima

A novel non-peptide prolyl endopeptidase (PPCE) inhibitor, Y-29794, has been identified. Y-29794 selectively and competitively inhibited rat brain PPCE (Ki = 0.95 nM) in a reversible manner. Ex vivo study demonstrated that Y-29794 could penetrate into brain to exhibit dose-dependent and long-lasting inhibition. Furthermore, Y-29794 was found to potentiate the effect of TRH on the release of ACh in the rat hippocampus. These results indicate that Y-29794 is an orally active, potent and specific PPCE inhibitor and should be of value in studies on the physiological role of the enzyme in neuropeptide metabolism especially in memory process.

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Indication	Highest Phase	Country/Location	Organization	Date
Cognition Disorders	Preclinical	JP	Mitsubishi Pharma Corp.	-

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