Author: Aktolun, Muhammed ; Gudermann, Thomas ; Nadezhdin, Kirill D ; Kurnikova, Maria G ; Chubanov, Vladimir ; Sobolevsky, Alexander I ; Shalygin, Alexey ; Correia, Leonor ; Neuberger, Arthur

TRP channels are implicated in various diseases, but high structural similarity between them makes selective pharmacological modulation challenging. Here, we study the molecular mechanism underlying specific inhibition of the TRPM7 channel, which is essential for cancer cell proliferation, by the anticancer agent CCT128930 (CCT). Using cryo-EM, functional analysis, and MD simulations, we show that CCT binds to a vanilloid-like (VL) site, stabilizing TRPM7 in the closed non-conducting state. Similar to other allosteric inhibitors of TRPM7, NS8593 and VER155008, binding of CCT is accompanied by displacement of a lipid that resides in the VL site in the apo condition. Moreover, we demonstrate the principal role of several residues in the VL site enabling CCT to inhibit TRPM7 without impacting the homologous TRPM6 channel. Hence, our results uncover the central role of the VL site for the selective interaction of TRPM7 with small molecules that can be explored in future drug design.

01 Apr 2023·Environmental Pollution

PM2.5 induces cardiac malformations via PI3K/akt2/mTORC1 signaling pathway in zebrafish larvae

Article

Author: Chen, Tao ; Chen, Jin ; Aniagu, Stanley ; Zhao, Xiahao ; Jiang, Yan

Growing evidence indicates that maternal fine particulate matter (PM2.5) exposure is linked with congenital heart diseases in the offspring. To explore the underlying molecular mechanisms, we tested the effects of a number of pharmaceutical inhibitors, and found that suppressing the PI3K/akt signaling pathway had a protective effect against cardiac defects in zebrafish larvae exposed to extractable organic matter (EOM) from PM2.5. Using genetic knockdown and a specific akt2 pharmacological inhibitor, CCT128930, we demonstrated that akt2 activation is essential to EOM-induced heart malformations. Next, we found that the EOM-induced akt2 overactivation enhances intracellular reactive oxygen species (ROS)/mitochondrial ROS production, decreases mitochondrial membrane potential levels, and elicits intrinsic apoptosis in the heart of zebrafish embryos. In addition, EOM-induced akt2 activation decreased active β-catenin levels and inhibited the expression of Wnt target genes axin2 and nkx2.5. We further demonstrated that mTORC1 phosphorylation mediates the adverse effects of akt2 on intrinsic apoptosis and canonical Wnt signaling in the heart of zebrafish larvae exposed to EOM. Moreover, EOM-induced akt2 activation is mediated via aryl hydrocarbon receptor (AHR)/ROS-induced PTEN inhibition. In conclusion, our results indicate that PM2.5 activates PI3K/akt2/mTORC1 signaling via AHR/ROS-induced PTEN suppression, which leads to mitochondrial-mediated intrinsic apoptosis and Wnt signaling suppression, resulting in cardiac defects in zebrafish larvae.

01 Jun 2021·Biochemical and Biophysical Research CommunicationsQ3 · BIOLOGY

CCT128930 is a novel and potent antagonist of TRPM7 channel

Q3 · BIOLOGY

Article

Author: Gao, Zhaobing ; Zheng, Yueming ; Chen, Xueqin ; Guan, Ziyue ; Ji, Yonghua ; Fang, Sui

Transient receptor potential melastatin 7 (TRPM7) channels represent a major magnesium (Mg²⁺)-uptake component in mammalian cells and are negatively modulated by internal Mg²⁺. However, few TRPM7 modulators were identified so far, which hindered the understanding of the TRPM7 channel functions. In this study, we identified that CCT128930, an ATP-competitive protein kinase B inhibitor reported previously, was a potent TRPM7 channel antagonist. The inhibition of CCT128930 on TRPM7 was independent of intracellular Mg²⁺. In the absence and presence of 300 μM Mg²⁺ in pipette solution, the IC₅₀ values were 0.86 ± 0.11 μM and 0.63 ± 0.09 μM, respectively. Subtype selectivity data showed that CCT128930 preferentially inhibited TRPM7 channels compared to TRPM6 and TRPM8 isoforms. In addition, CCT128930 was found to be able to reduce the endogenous TRPM7-like currents in SH-SY5Y neuroblastoma cells. At last, multiple residues in the superficial part of the TRPM7 selectivity filter were identified to be critical for the inhibitory activity of CCT128930 which are different from the determinants of Mg²⁺ and reported TRPM7 antagonists. Our results indicated that CCT128930 is a novel and potent TRPM7 channel antagonist.

100 Deals associated with CCT-128930

R&D Status

10 top R&D records.

to view more data

Indication	Highest Phase	Country/Location	Organization	Date
Neoplasms	Preclinical	GB	Astex Pharmaceuticals, Inc.	09 Feb 2011
Neoplasms	Preclinical	GB	Cancer Research UK Cancer Therapeutics Unit	09 Feb 2011

Clinical Result

Indication

Phase

Evaluation

View All Results

Translational Medicine

Boost your research with our translational medicine data.

view full example data

Deal

Boost your decision using our deal data.

view full example data

Core Patent

Boost your research with our Core Patent data.

view full example data

Clinical Trial

Identify the latest clinical trials across global registries.

view full example data

Approval

Accelerate your research with the latest regulatory approval information.

view full example data

Regulation

Understand key drug designations in just a few clicks with Synapse.

view full example data

Chat with Hiro

Get started for free today!

Accelerate Strategic R&D decision making with Synapse, PatSnap’s AI-powered Connected Innovation Intelligence Platform Built for Life Sciences Professionals.

Start your data trial now!

Synapse data is also accessible to external entities via APIs or data packages. Empower better decisions with the latest in pharmaceutical intelligence.

Bio

Bio Sequences Search & Analysis

Chemical

Chemical Structures Search & Analysis


No Data

CCT-128930

Overview

Basic Info

Structure

Related

R&D Status

Clinical Result

Translational Medicine

Deal

Core Patent

Clinical Trial

Approval

Regulation