A double blind, randomized, placebo-controlled, adaptive 24-week Phase IIb trial to evaluate the efficacy of vafidemstat in negative symptoms and cognitive impairment associated with schizophrenia. (EVOLUTION study).

Start Date06 Jul 2021

Sponsor / Collaborator-

EUCTR2020-003469-20-BG / Unknown statusPhase 2

A double blind, randomized, placebo-controlled, adaptive 14-week Phase IIb trial to evaluate the efficacy and safety of vafidemstat in an adult borderline personality disorder (BPD) population (PORTICO) - PORTICO

Start Date17 May 2021

Sponsor / Collaborator

Oryzon Genomics SA

NCT04932291 / CompletedPhase 2

"A Double-blind, Randomized, Placebo-controlled, Adaptive 14-week Phase IIb Trial to Evaluate the Efficacy and Safety of Vafidemstat in an Adult Borderline Personality Disorder (BPD) Population (PORTICO)"

PORTICO is a Phase IIb study to evaluate the efficacy and safety of vafidemstat in an adult borderline personality disorder (BPD) population.

Start Date26 Mar 2021

Sponsor / Collaborator

Oryzon Genomics SA

100 Clinical Results associated with MAO-B x KDM1A

100 Translational Medicine associated with MAO-B x KDM1A

0 Patents (Medical) associated with MAO-B x KDM1A

Literatures (Medical) associated with MAO-B x KDM1A

01 May 2023·European Journal of Medicinal Chemistry

Design, synthesis and in vitro/in vivo anticancer activity of tranylcypromine-based triazolopyrimidine analogs as novel LSD1 inhibitors

Article

Author: Song, Junying ; Ma, Huifen ; Wang, Pan ; Ma, Jinlian ; Zhang, Zijuan ; Li, Lixin ; Zhang, Feiyu ; Qiao, Yonghui ; Zhang, Xiaowei ; Xie, Zhishen ; Ma, Liying ; Yuan, Yong ; Zhang, Zhenqiang ; Sun, Yiran ; Li, Zhonghua ; Su, Yunfang ; Li, Xiaofang

Histone lysine specific demethylase 1 (LSD1) is responsible for the demethylation of mono-/dimethylated lysine residue on histone proteins. LSD1 plays an extensive and essential role in the pathogenesis and progression of many human diseases such as cancers, and thus is becoming an attractive therapeutic target for cancer treatment. Tranylcypromine (TCP) is an important chemical template for developing irreversible LSD1 inhibitors, representing a major chemotype of clinical candidates. Here we report a novel pool of TCP derivatives with triazolopyrimidine as a privileged heterocylic motif. Starting from ticagrelor, a clinically available antiplatelet agent, as a hit compound, our medicinal efforts have led to the identification of compound 9j with nanomolar inhibitory potency against LSD1 as well as broad-spectrum antiproliferative activities against tumor cells. Enzyme studies show that compound 9j is selective over MAO-A/B enzymes, and also cellular active to elevate the expression of H3K4me2 by inhibiting LSD1 in cells. Furthermore, in a H1650 xenograft mouse model, oral administration of compound 9j at low 10 and 20 mg/kg dosages could enable a significant reduction in tumor size and a remarkable extension of survival. The current work is expected to provide an additional strategy to achieve new TCP-based LSD1 inhibitors.

31 Dec 2022·Journal of Enzyme Inhibition and Medicinal ChemistryQ2 · MEDICINE

Heterocycle-containing tranylcypromine derivatives endowed with high anti-LSD1 activity

Q2 · MEDICINE

ArticleOA

Author: Valente, Sergio ; Zwergel, Clemens ; Altucci, Lucia ; Mattevi, Andrea ; Rodriguez, Veronica ; Mai, Antonello ; Benedetti, Rosaria ; Corinti, Davide ; Noce, Beatrice ; Caroli, Jonatan ; Chianese, Ugo ; Fioravanti, Rossella ; Viña, Dolores ; Di Bello, Elisabetta

As regioisomers/bioisosteres of 1a, a 4-phenylbenzamide tranylcypromine (TCP) derivative previously disclosed by us, we report here the synthesis and biological evaluation of some (hetero)arylbenzoylamino TCP derivatives 1b-6, in which the 4-phenyl moiety of 1a was shifted at the benzamide C3 position or replaced by 2- or 3-furyl, 2- or 3-thienyl, or 4-pyridyl group, all at the benzamide C4 or C3 position. In anti-LSD1-CoREST assay, all the meta derivatives were more effective than the para analogues, with the meta thienyl analogs 4b and 5b being the most potent (IC₅₀ values = 0.015 and 0.005 μM) and the most selective over MAO-B (selectivity indexes: 24.4 and 164). When tested in U937 AML and prostate cancer LNCaP cells, selected compounds 1a,b, 2b, 3b, 4b, and 5a,b displayed cell growth arrest mainly in LNCaP cells. Western blot analyses showed increased levels of H3K4me2 and/or H3K9me2 confirming the involvement of LSD1 inhibition in these assays.

01 Apr 2022·Bioorganic ChemistryQ2 · CHEMISTRY

Design, synthesis and biological evaluation of 2-aminopyrimidine-based LSD1 inhibitors

Q2 · CHEMISTRY

Article

Author: Zhao, Dongmei ; Wang, Jiming ; Zhang, Xiangyu ; Cheng, Maosheng ; Zhao, Liyu ; Wang, Xinran ; Zhang, Cai

AZD9291, with excellent pharmaceutical properties, has been reported to have certain LSD1 inhibitory activity. Therefore, we carried out structural optimization based on the AZD9291 skeleton to increase the LSD1 inhibitory potential of the compound. Then, a series of 2-aminopyrimidine derivatives were designed and synthesized as LSD1 inhibitors, and their structure-activity relationships were studied. The most promising compound, X43, with an IC₅₀ of 0.89 μM showed remarkable LSD1 selectivity not only to EGFR^wt (>100-fold) but also to MAO-A/B (>50-fold). Further studies showed that X43 inhibited LSD1 activity and induced the apoptosis of A549 cells in a dose-dependent manner. Meanwhile, compound X43 showed a superior ability to inhibit the proliferation of A549 and THP-1 cells, with IC₅₀ values of 1.62 μM and 1.21 μM, respectively. Then, analyses of the stability of human liver microsomes, CYP inhibition and in vivo pharmacokinetics in rats showed that X43 had favorable profiles in vitro and in vivo and the potential for further study. Our findings suggested that a 2-aminopyrimidine-based LSD1 inhibitor deserves further investigation as a treatment for LSD1-overexpressing cancer.

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