Delving into the Latest Updates on Dual-target bacterial topoisomerase inhibitors (Bugworks Research) with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms-

Target

Bacterial DNA gyrase x Topoisomerase IV

Mechanism

Bacterial DNA gyrase inhibitors, Topoisomerase IV inhibitors

Therapeutic Areas

Infectious Diseases

Active Indication

Bacterial Infections

Inactive Indication-

Originator Organization

BUGWORKS Research, Inc.Startup

Active Organization

BUGWORKS Research, Inc.Startup

Inactive Organization-

Drug Highest PhasePreclinical

First Approval Date-

Regulation-

Author: Qian, Dalong ; Sikandar, Shaheen S ; Somlo, George ; Lam, Jessica ; Kuo, Angera H ; Parashurama, Natesh ; Antony, Jane ; Kalisky, Tomer ; Dirbas, Frederick M ; Sanchez, Kassandra ; Newman, Aaron ; Sim, Sopheak ; Clarke, Michael F ; Lobo, Neethan A ; Li, Linus ; Quake, Stephen R ; Adorno, Maddalena ; Heitink, Luuk S ; Gulati, Gunsagar S ; Zabala, Maider

SMAD pathways govern epithelial proliferation, and transforming growth factor β (TGF-β and BMP signaling through SMAD members has distinct effects on mammary development and homeostasis. Here, we show that LEFTY1, a secreted inhibitor of NODAL/SMAD2 signaling, is produced by mammary progenitor cells and, concomitantly, suppresses SMAD2 and SMAD5 signaling to promote long-term proliferation of normal and malignant mammary epithelial cells. In contrast, BMP7, a NODAL antagonist with context-dependent functions, is produced by basal cells and restrains progenitor cell proliferation. In normal mouse epithelium, LEFTY1 expression in a subset of luminal cells and rare basal cells opposes BMP7 to promote ductal branching. LEFTY1 binds BMPR2 to suppress BMP7-induced activation of SMAD5, and this LEFTY1-BMPR2 interaction is specific to tumor-initiating cells in triple-negative breast cancer xenografts that rely on LEFTY1 for growth. These results suggest that LEFTY1 is an endogenous dual-SMAD inhibitor and that suppressing its function may represent a therapeutic vulnerability in breast cancer.

01 May 2016·Thoracic cancerQ3 · MEDICINE

MEK inhibitor can reverse the resistance to bevacizumab in A549 cells harboring Kirsten rat sarcoma oncogene homolog mutation

Q3 · MEDICINE

ArticleOA

Author: Liu, Zhentao ; Shen, Zhirong ; Wang, Zhijie ; Wang, Yuan ; Wang, Yaping ; Yang, Xiaodan ; Yan, Ping ; Wang, Jie ; Bai, Hua

Abstract:

Background:

Bevacizumab (BV) is broadly used to treat a number of cancers; however, BV resistance mechanisms and strategies to overcome this resistance are yet to be determined.

Methods:

We established xenograft mice models harboring Kirsten rat sarcoma oncogene homolog (KRAS) mutations based on the A549 cell line, and tested the responses of xenograft tumors to a series of drugs in ex vivo and in vivo experiments. Changes in transcriptive level were analyzed by ribonucleic acid (RNA) sequencing and the expressions of connexins were determined by immunohistochemistry staining.

Results:

A549 cell mutation type (KRAS G12S) was confirmed by sequencing. After treating the xenograft tumors with BV, the median interval time from BV administration to tumor volume more than 2.5‐fold of the original was 37 days, compared with 21 days in the control (P = 0.025). A549 cells showed resistantance to selumitinib (MEK inhibitor) but were sensitive to selumitinib plus BEZ235 (phosphoinositide 3‐kinase/mammalian target of rapamycin dual inhibitor). However, selumitinib could effectively reverse the resistance to BV in in vivo experiments. RNA sequencing showed that mouse genes, but not human genes, activated the mitogen‐activated protein kinase signaling pathway, accompanied by activation of the Wnt and Hedgehog pathways. Connexin43 (S261) was phosphorylated before and during BV treatment, and subsequently transitioned to negative phosphorylated‐connexin 43‐S261 after resistance to BV.

Conclusion:

Combining an MEK inhibitor with BV was a potential strategy to reverse initial BV resistance. Phosphorylated‐connexin 43 might be associated with the response to BV.

01 Aug 2013·European psychiatry : the journal of the Association of European PsychiatristsQ2 · MEDICINE

Interactions between transcranial direct current stimulation (tDCS) and pharmacological interventions in the Major Depressive Episode: Findings from a naturalistic study

Q2 · MEDICINE

ArticleOA

Author: M. Giacopuzzi ; R. Ferrucci ; B. Dell’Osso ; P.S. Boggio ; E. Scelzo ; M. Bortolomasi ; F. Fregni ; A.R. Brunoni ; A.C. Altamura

Abstract:

Background::

Transcranial direct current stimulation (tDCS) is a non-invasive, neuromodulatory technique with an emerging role for treating major depression.

Objective::

To investigate the interactions between tDCS and drug therapy in unipolar and bipolar depressed patients who were refractory for at least one pharmacological treatment.

Methods::

This was a naturalistic study using data from 54 female and 28 male patients (mean age of 54 years) that consecutively visited our psychiatric unit. They received active tDCS (five consecutive days, 2 mA, anodal stimulation over the left and cathodal over the right dorsolateral prefrontal cortex, twice a day, 20 minutes). The outcome variable (mood) was evaluated using the Beck Depression Inventory (BDI) and the Hamilton Depression Rating Scale (HDRS). Predictor variables were age, gender, disorder and pharmacological treatment (seven dummy variables). We performed univariate and multivariate analyses as to identify predictors associated to the outcome.

Results::

After 5 days of treatment, BDI and HDRS scores decreased significantly (29% ± 36%, 18% ± 9%, respectively, P < 0.01 for both). Benzodiazepine use was independently associated with a worse outcome in both univariate (β = 4.92, P < 0.01) and multivariate (β = 5.8, P < 0.01) analyses; whereas use of dual-reuptake inhibitors positively changed tDCS effects in the multivariate model (β = –4.7, P = 0.02). A similar trend was observed for tricyclics (β = –4, P = 0.06) but not for antipsychotics, non-benzodiazepine anticonvulsants and other drugs.

Conclusion::

tDCS over the DLPFC acutely improved depressive symptoms. Besides the inherent limitations of our naturalistic design, our results suggest that tDCS effects might vary according to prior pharmacological treatment, notably benzodiazepines and some antidepressant classes. This issue should be further explored in controlled studies.

100 Deals associated with Dual-target bacterial topoisomerase inhibitors (Bugworks Research)

Login to view more data