mTOR x ATR

Last update 08 May 2025

Basic Info

Related Targets

mTORATR

Drugs associated with mTOR x ATR

SPK 98

Target

ATR x mTOR

Mechanism

ATR inhibitors [+1]

Active Org.

Indian Institute of Technology Gandhinagar

Originator Org.

Indian Institute of Technology Gandhinagar

Active Indication

Neoplasms

Inactive Indication-

Drug Highest PhasePreclinical

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

100 Clinical Results associated with mTOR x ATR

100 Translational Medicine associated with mTOR x ATR

0 Patents (Medical) associated with mTOR x ATR

108

Literatures (Medical) associated with mTOR x ATR

01 Feb 2025·Autophagy

Function of CSNK2/CK2 selectively affects the endoplasmic reticulum and the Golgi apparatus in mtor-mediated autophagy induction

Article

Author: Berkane, Rayene ; Stolz, Alexandra ; Sanz-Martinez, Pablo

Selective macroautophagy/autophagy of the endoplasmic reticulum, known as reticulophagy/ER-phagy, is essential to maintain ER homeostasis. We recently showed that members of the autophagy receptor family RETREG/FAM134 are regulated by phosphorylation-dependent ubiquitination. In an unbiased screen we had identified several kinases downstream of MTOR with profound impact on reticulophagy flux, including ATR and CSNK2/CK2. Inhibition of CSNK2 by SGC-CK2-1 prevented regulatory ubiquitination of RETREG1/FAM134B and RETREG3/FAM134C upon autophagy activation as well as the formation of high-density RETREG1- and RETREG3-clusters. Here we report on additional resource data of global proteomics upon CSNK2 and ATR inhibition, respectively. Our data suggests that the function of CSNK2 is mainly limited to the ER/reticulophagy and Golgi/Golgiphagy, while ATR inhibition by VE-822 affects the vast majority of organelles/selective autophagy pathways.Abbreviation: ATRi: ATR inhibitor VE-822; CSNK2i: CSNK2 inhibitor SGC-CK2-1; ER: endoplasmic reticulum.

01 Jan 2025·Advances in Biological Regulation

Making PI3K superfamily enzymes run faster

Review

Author: Williams, Roger L ; Ohashi, Yohei ; Perisic, Olga ; Islam, Md Saiful ; Dessus, Antoine N ; Gong, Grace Q ; Špokaitė, Saulė ; Hay, Iain M ; Bourguet, Maxime ; Anandapadamanaban, Madhangopal

The phosphoinositide 3-kinase (PI3K) superfamily includes lipid kinases (PI3Ks and type III PI4Ks) and a group of PI3K-like Ser/Thr protein kinases (PIKKs: mTOR, ATM, ATR, DNA-PKcs, SMG1 and TRRAP) that have a conserved C-terminal kinase domain. A common feature of the superfamily is that they have very low basal activity that can be greatly increased by a range of regulatory factors. Activators reconfigure the active site, causing a subtle realignment of the N-lobe of the kinase domain relative to the C-lobe. This realignment brings the ATP-binding loop in the N-lobe closer to the catalytic residues in the C-lobe. In addition, a conserved C-lobe feature known as the PIKK regulatory domain (PRD) also can change conformation, and PI3K activators can alter an analogous PRD-like region. Recent structures have shown that diverse activating influences can trigger these conformational changes, and a helical region clamping onto the kinase domain transmits regulatory interactions to bring about the active site realignment for more efficient catalysis. A recent report of a small-molecule activator of PI3Kα for application in nerve regeneration suggests that flexibility of these regulatory elements might be exploited to develop specific activators of all PI3K superfamily members. These activators could have roles in wound healing, anti-stroke therapy and treating neurodegeneration. We review common structural features of the PI3K superfamily that may make them amenable to activation.

01 Nov 2024·Biochimica et Biophysica Acta (BBA) - Reviews on Cancer

Targeting DNA damage response in pancreatic ductal adenocarcinoma: A review of preclinical and clinical evidence

Review

Author: Nazari, Somayeh ; Saso, Luciano ; Moosavi, Fatemeh ; Hassani, Bahareh ; Firuzi, Omidreza

Pancreatic ductal adenocarcinoma (PDAC) is associated with one of the most unfavorable prognoses across all malignancies. In this review, we investigate the role of inhibitors targeting crucial regulators of DNA damage response (DDR) pathways, either as single treatments or in combination with chemotherapeutic agents and targeted therapies in PDAC. The most prominent clinical benefit of PARP inhibitors' monotherapy is related to the principle of synthetic lethality in individuals harboring BRCA1/2 and other DDR gene mutations as predictive biomarkers. Moreover, induction of BRCAness with inhibitors of RTKs, including VEGFR and c-MET and their downstream signaling pathways, RAS/RAF/MEK/ERK and PI3K/AKT/mTOR in order to expand the application of PARP inhibitors in patients without DDR mutations, has also been addressed. Other DDR-targeting agents beyond PARP inhibitors, including inhibitors of ATM, ATR, CHEK1/2, and WEE1 have also demonstrated their potential in preclinical models of PDAC and may hold promise in future studies.

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