作者: Gabizon, Ronen ; Herishanu, Yair ; Brandis, Alexander ; Shulman, Ziv ; Gehrtz, Paul ; Shorer, Yamit ; Katz, Ben-Zion ; Avram, Liat ; Aharoni, Hila ; Albeck, Shira ; Gurwicz, Neta ; Livnah, Ella ; Shraga, Amit ; Unger, Tamar ; London, Nir

Proteolysis targeting chimeras (PROTACs) represent an exciting inhibitory modality with many advantages, including substoichiometric degradation of targets. Their scope, though, is still limited to date by the requirement for a sufficiently potent target binder. A solution that proved useful in tackling challenging targets is the use of electrophiles to allow irreversible binding to the target. However, such binding will negate the catalytic nature of PROTACs. Reversible covalent PROTACs potentially offer the best of both worlds. They possess the potency and selectivity associated with the formation of the covalent bond, while being able to dissociate and regenerate once the protein target is degraded. Using Bruton's tyrosine kinase (BTK) as a clinically relevant model system, we show efficient degradation by noncovalent, irreversible covalent, and reversible covalent PROTACs, with <10 nM DC₅₀'s and >85% degradation. Our data suggest that part of the degradation by our irreversible covalent PROTACs is driven by reversible binding prior to covalent bond formation, while the reversible covalent PROTACs drive degradation primarily by covalent engagement. The PROTACs showed enhanced inhibition of B cell activation compared to ibrutinib and exhibit potent degradation of BTK in patient-derived primary chronic lymphocytic leukemia cells. The most potent reversible covalent PROTAC, RC-3, exhibited enhanced selectivity toward BTK compared to noncovalent and irreversible covalent PROTACs. These compounds may pave the way for the design of covalent PROTACs for a wide variety of challenging targets.

2017-06-01·Actas Urológicas Españolas4区 · 医学

PCA3 como biomarcador de segunda línea en un programa de screening oportunista prospectivo, aleatorizado y controlado

4区 · 医学

Article

作者: Rubio, L ; Molina, A ; Domínguez-Escrig, J L ; Collado, A ; Vanaclocha, M ; Gómez-Ferrer, A ; Martínez, F ; Casanova, J ; Ramírez-Backhaus, M ; Lopez-Guerrero, J A ; Rubio-Briones, J ; Dumont, R ; Sala, D ; Fernández-Serra, A

OBJECTIVESPCA3 performance as a single second line biomarker is compared to the European Randomised Study of Screening for Prostate Cancer risk calculator model 3 (ERSPC RC-3) in an opportunistic screening in prostate cancer (PCa).MATERIAL AND METHODS5,199 men, aged 40-75y, underwent prostate-specific antigen (PSA) screening and digital rectal examination (DRE). Men with a normal DRE and PSA ≥3ng/ml had a PCA3 test done. All men with PCA3 ≥35 underwent an initial biopsy (IBx) -12 cores-. Men with PCA3 <35 were randomized 1:1 to either IBx or observation. We compared them to those obtained with ERSPC RC-3.RESULTSPCA3 test was performed on 838 men (16.1%). In PCA3(+) and PCA3(-) groups, global PCa detection rates were 40.9% and 14.7% with a median follow-up (FU) of 21.7 months (P<.001). In the PCA3(+) arm (n=301, 35.9%), PCa was identified in 115 men at IBx (38.2%). In the randomized arm, 256 underwent IBx and PCa was found in 46 (18.0%) (P<.001). The biopsy-sparing potential would have been 64.1% as opposed to 76.6% if we had used ERSPC RC-3. However, the estimated false negative cases for HGPCa would have been reduced by 37.1% (89 to 56 patients). Moreover, if we had applied PCA3-35 to avoid IBx, 14.7% PCa and 9.1% of clinical significant PCa patients would not have been diagnosed during this FU.CONCLUSIONSWhen PCA3-35 is used as a second-line biomarker when PSA ≥3ng/ml and DRE is normal, IBx could be avoided in 12.5% less than if ERSPC RC-3 is used and would reduce the false negative cases by 36.2%. At a FU of 21.7 months, this dual protocol would miss 9.1% of clinically significant PCa, so strict FU is mandatory with established biopsy criteria based on PSA and DRE in cases with PCA3 <35.

2006-04-01·Journal of Ethnopharmacology2区 · 医学

Anti-HIV-1 activities of extracts from the medicinal plant Rhus chinensis

2区 · 医学

Article

作者: Qiong Gu ; Rui-Rui Wang ; Ji-Jun Chen ; Shun-Ying Li ; Yong-Tang Zheng ; Liu-Meng Yang

Rhus chinensis, a species used in folk medicine by Chinese native people, the anti-HIV-1 activities of the petroleum ether, ethyl acetate, butanol and aqueous extract of Rhus chinensis, named as RC-1, RC-2, RC-3 and RC-4, respectively, was evaluated. The petroleum ether extract RC-1 can inhibit the syncytium formation and HIV-1 p24 antigen at non-cytotoxic concentrations, the 50% effective concentration (EC50) were 0.71 and 0.93 microg/ml, respectively. The therapeutic index (TI) was about 100. RC-1 had no activity on inhibiting HIV-1 recombinant RT and HIV-1 entry into host cells. Results showed that RC-1 was effective against HIV-1 and Rhus chinensis would be a useful medicinal plant for the chemotherapy of HIV-1 infection. RC-1 might inhibit the post steps or target the new sites of HIV-1 replication.

100 项与 RC-03 (RongCan Biotech) 相关的药物交易

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