FKBP12 (FK506-binding protein 1A ligand), mTOR modulators(Serine/threonine-protein kinase mTOR modulators), mTORC1 inhibitors(Mammalian target of Rapamycin (mTORC1) inhibitors)

Therapeutic Areas

NeoplasmsNervous System DiseasesOther Diseases

Active Indication

GlioblastomaAlcohol Use Disorder

Inactive Indication-

Originator Organization

University of California

AstraZeneca PLC

Memorial Sloan Kettering Cancer Center

Active Organization

Memorial Sloan Kettering Cancer Center

University of California

AstraZeneca PLC

+ [1]

Inactive Organization-

Drug Highest PhasePreclinical

First Approval Date-

Regulation-

100 Clinical Results associated with RapaLink-1

100 Translational Medicine associated with RapaLink-1

100 Patents (Medical) associated with RapaLink-1

Literatures (Medical) associated with RapaLink-1

01 Apr 2024·Current Molecular Medicine

The mTOR Signaling Pathway and mTOR Inhibitors in Cancer: Next-generation Inhibitors and Approaches

Review

Author: Akgul, Busra ; Kelleci, Kübra ; Korkut, Şenay Vural ; Ihlamur, Murat ; Abamor, Emrah Şefik ; Zengin, Yağmur

Abstract:mTOR is a serine/threonine kinase that plays various roles in cell growth, proliferation, and metabolism. mTOR signaling in cancer becomes irregular. Therefore, drugs targeting mTOR have been developed. Although mTOR inhibitors rapamycin and rapamycin rapalogs (everolimus, rapamycin, temsirolimus, deforolimus, etc.) and new generation mTOR inhibitors (Rapalink, Dual PI3K/mTOR inhibitors, etc.) are used in cancer treatments, mTOR resistance mechanisms may inhibit the efficacy of these drugs. Therefore, new inhibition approaches are developed. Although these new inhibition approaches have not been widely investigated in cancer treatment, the use of nanoparticles has been evaluated as a new treatment option in a few types of cancer.:This review outlines the functions of mTOR in the cancer process, its resistance mechanisms, and the efficiency of mTOR inhibitors in cancer treatment. Furthermore, it discusses the next-generation mTOR inhibitors and inhibition strategies created using nanoparticles.:Since mTOR resistance mechanisms prevent the effects of mTOR inhibitors used in cancer treatments, new inhibition strategies should be developed. Inhibition approaches are created using nanoparticles, and one of them offers a promising treatment option with evidence supporting its effectiveness.

01 Aug 2023·SLAS Technology

In vitro delivery of mTOR inhibitors by kidney-targeted micelles for autosomal dominant polycystic kidney disease

Article

Author: Chung, Eun Ji ; Li, Hui ; Cox, Alysia ; Tung, Madelynn ; Hallows, Kenneth R

Autosomal dominant polycystic kidney disease (ADPKD) is the most common genetic kidney disease and is characterized by the formation of renal cysts and the eventual development of end-stage kidney disease. One approach to treating ADPKD is through inhibition of the mammalian target of rapamycin (mTOR) pathway, which has been implicated in cell overproliferation, contributing to renal cyst expansion. However, mTOR inhibitors, including rapamycin, everolimus, and RapaLink-1, have off-target side effects including immunosuppression. Thus, we hypothesized that the encapsulation of mTOR inhibitors in drug delivery carriers that target the kidneys would provide a strategy that would enable therapeutic efficacy while minimizing off-target accumulation and associated toxicity. Toward eventual in vivo application, we synthesized cortical collecting duct (CCD) targeted peptide amphiphile micelle (PAM) nanoparticles and show high drug encapsulation efficiency (>92.6%). In vitro analysis indicated that drug encapsulation into PAMs enhanced the anti-proliferative effect of all three drugs in human CCD cells. Analysis of in vitro biomarkers of the mTOR pathway via western blotting confirmed that PAM encapsulation of mTOR inhibitors did not reduce their efficacy. These results indicate that PAM encapsulation is a promising way to deliver mTOR inhibitors to CCD cells and potentially treat ADPKD. Future studies will evaluate the therapeutic effect of PAM-drug formulations and ability to prevent off-target side effects associated with mTOR inhibitors in mouse models of ADPKD.

09 Dec 2022·ScienceQ1 · CROSS-FIELD

IFITM proteins assist cellular uptake of diverse linked chemotypes

Q1 · CROSS-FIELD

Article

Author: Greninger, Patricia ; Seeliger, Markus A. ; Lou, Kevin ; Gilbert, Luke A. ; Wassarman, Douglas R. ; Benes, Cyril H. ; Moore, Megan K. ; Shokat, Kevan M. ; Zhang, Ziyang ; Yang, Tangpo ; Paung, YiTing ; Egan, Regina K. ; O’Loughlin, Thomas A. ; Taunton, Jack

The search for cell-permeable drugs has conventionally focused on low-molecular weight (MW), nonpolar, rigid chemical structures. However, emerging therapeutic strategies break traditional drug design rules by employing flexibly linked chemical entities composed of more than one ligand. Using complementary genome-scale chemical-genetic approaches we identified an endogenous chemical uptake pathway involving interferon-induced transmembrane proteins (IFITMs) that modulates the cell permeability of a prototypical biopic inhibitor of MTOR (RapaLink-1, MW: 1784 g/mol). We devised additional linked inhibitors targeting BCR-ABL1 (DasatiLink-1, MW: 1518 g/mol) and EIF4A1 (BisRoc-1, MW: 1466 g/mol), uptake of which was facilitated by IFITMs. We also found that IFITMs moderately assisted some proteolysis-targeting chimeras and examined the physicochemical requirements for involvement of this uptake pathway.

100 Deals associated with RapaLink-1

R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Glioblastoma	Preclinical	US	Memorial Sloan Kettering Cancer Center	14 Sep 2022
Glioblastoma	Preclinical	GB	AstraZeneca PLC	14 Sep 2022
Glioblastoma	Preclinical	US	University of California	14 Sep 2022
Alcohol Use Disorder	Preclinical	US	The University of California, San Francisco	27 Jul 2021

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