By using a proteolysis-targeting chimera (PROTAC) strategy that couples an allosteric, reversible PTP inhibitor with an E3 ligase targeting ligand through a well-designed linker, the first molecule to successfully inhibit PTP activity through degradation has been developed.

30 Sep 2019·BLOOD RESEARCH

The prevalence and risk factors of inhibitor development of FVIII in previously treated patients with hemophilia A

Article

Author: You, Chur Woo ; Kim, Ju Young

BACKGROUNDRisk factors for the development of inhibitors in previously untreated patients (PUPs) have been reported; this is not the case in previously treated patients (PTPs) owing to fewer studies. Risk factors may differ for the development of PTP versus PUP inhibitors. We aimed to identify risk factors for PTP inhibitor development.METHODSParticipants were patients at a hemophilia treatment center in Korea with current or past history of factor VIII or factor IX alloantibodies. Observed inhibitors were classified as PUP or PTP inhibitors based on the cumulative number of exposure days. We compared the type and severity of hemophilia, mutation type, and family history of inhibitor between PUPs and PTPs. Events within 3 months before the first inhibitor detection, such as change of the factor concentrate used, short-term high exposure or continuous infusion of factor concentrate, history of surgery, infection, diagnosis of cancer, use of immunosuppressive or immunomodulator agents, and vaccination were compared between PUPs and PTPs.RESULTSWe observed 5 PUP inhibitors and 5 PTP inhibitors in 115 patients with hemophilia A. Events that might be related to the development of inhibitors within 3 months prior to the first inhibitor detection were observed in all 5 PTPs. On the contrary, no such events were observed in any PUPs. The observed events included a change in the factor concentrate used, subsequent chemotherapy, and short-term high exposure to factor concentrates for controlling hemorrhage and surgeries.CONCLUSIONOur results suggest a greater role of nongenetic factors in PTP inhibitor development.

01 Jun 2019·Journal of Affective DisordersQ2 · MEDICINE

Role of DNA hypomethylation in lateral habenular nucleus in the development of depressive-like behavior in rats

Q2 · MEDICINE

Article

Author: Yuan, Hai-Bo ; Zhang, Chun-Xiao ; Shen, Xiang-Feng ; Liu, Yong-Feng ; Xue, Hui ; Wang, Guo-Qiang

BACKGROUNDLateral habenula nucleus (LHb) has recently been noted for its role in stress-induced depressive disorder. Yet little is known about the mechanisms by which external stimuli or depression induces pathological alteration in the LHb.METHODSChronic unpredictable mild stress (CUMS) was employed to model depressive-like behaviors in adult rats. We examined expressions of DNA methyltransferases (Dnmts) mRNA and protein and global DNA methylation levels in LHb of CUMS-induced depressive rats. Then 5-aza-2'-deoxycytidine (5-aza), a Dnmts inhibitor, was infused into the LHb of native rats to test the effects of hypomethylation in the LHb. The gene expressions in the LHb and the levels of 5-HT and its metabolite 5-hydroxyindoleacetic acid (5-HIAA) in dorsal raphe nucleus (DRN) were examined in 5-aza infusion rats by quantitative real-time PCR and high performance liquid chromatography, respectively.RESULTSRats were exposed to CUMS for 21 days and depressive-like behaviors were induced as expected. We observed significant decrease in mRNA and protein expressions of Dnmt1 and DNA hypomethylation in LHb of depressive rats. These phenomenon suggests that CUMS-induced depressive-like behaviors are related with DNA hypomethylation in the LHb. Local 5-aza infusion into LHb of native rat resulted in global DNA hypomethylation in the LHb and induced depressive-like behaviors which are featured with lack of interest and investment in the environment, behavioral despair and anhedonia. Moreover, DNA hypomethylation in the LHb increased transcription of β calcium/calmodulin dependent protein kinase II and glutamate receptor 1 in the LHb and attenuated the levels of 5-HT and 5-HIAA in the DRN. Our data suggested that alteration of DNA methylation in the LHb may control 5-HT neuronal activity in the DRN to regulate emotional state.CONCLUSIONSDNA hypomethylation in the LHb is involved in the development of depressive-like behavior and suitable methylation state contributes to the emotional stabilization.

100 Deals associated with PTPs inhibitor

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Indication	Highest Phase	Country/Location	Organization	Date
Autoimmune Diseases	Discovery	US	Procter & Gamble Co.	01 Nov 2020
Autoimmune Diseases	Discovery	US	Ontogen Corp.	01 Nov 2020
Diabetes Mellitus	Discovery	US	Ontogen Corp.	01 Nov 2020
Diabetes Mellitus	Discovery	US	Procter & Gamble Co.	01 Nov 2020
Neoplasms	Discovery	US	Ontogen Corp.	01 Nov 2020
Neoplasms	Discovery	US	Procter & Gamble Co.	01 Nov 2020

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