Delving into the Latest Updates on TL-118 (Teligene) with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

(R)-N-(5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a] pyrimidin-3-yl)-4-((4-methylpiperazin-1-yl)methyl)benzamide sulfate hydrate

Target

NTRK

Mechanism

NTRK inhibitors(Neurotrophic tyrosine kinase receptor inhibitors)

Therapeutic Areas

NeoplasmsNervous System Diseases

Active Indication

Solid tumorNTRK fusion-positive solid tumorsAdvanced Malignant Solid Neoplasm+ [1]

Inactive Indication-

Originator Organization

Suzhou Teligene Ltd.

Active Organization

Suzhou Teligene Ltd.

Inactive Organization-

Drug Highest PhasePhase 2

First Approval Date-

RegulationOrphan Drug (US)

Login to view timeline

Primary objective: To evaluate the efficacy of TL118 in treating patients with advanced tumors that are positive for NTRK1/2/3 fusion genes. Secondary objective: To evaluate the safety of TL118 in treating patients with advanced tumors that are positive for NTRK1/2/3 fusion genes; to evaluate the population pharmacokinetic (PopPK) characteristics of TL118 in treating patients with advanced tumors that are positive for NTRK1/2/3 fusion genes.

Start Date02 Mar 2023

Sponsor / Collaborator

Suzhou Teligene Ltd.

CTR20210067 / CompletedPhase 1

一项随机、开放、单剂量、两周期、双交叉评价高脂餐对健康受试者单次口服TL118药代动力学影响的临床试验

[Translation] A randomized, open-label, single-dose, two-period, double-crossover clinical trial to evaluate the effect of a high-fat meal on the pharmacokinetics of TL118 in healthy subjects

主要目的：评价高脂饮食对健康成年受试者单次口服TL118的药代动力学影响。次要目的：评价健康成年受试者单次口服TL118的安全性和耐受性。

[Translation]

Primary objective: To evaluate the effect of a high-fat diet on the pharmacokinetics of TL118 in healthy adult subjects after a single oral administration. Secondary objective: To evaluate the safety and tolerability of TL118 in healthy adult subjects after a single oral administration.

Start Date26 May 2021

Sponsor / Collaborator

Suzhou Teligene Ltd.

100 Clinical Results associated with TL-118 (Teligene)

Login to view more data

100 Translational Medicine associated with TL-118 (Teligene)

Login to view more data

100 Patents (Medical) associated with TL-118 (Teligene)

Login to view more data

37

Literatures (Medical) associated with TL-118 (Teligene)

28 May 2023·Pharmaceuticals (Basel, Switzerland)

Synthesis and Preclinical Evaluation of Novel ⁶⁸Ga-Labeled (R)-Pyrrolidin-2-yl-boronic Acid-Based PET Tracers for Fibroblast Activation Protein-Targeted Cancer Imaging.

Article

Author: Bénard, François ; Lin, Kuo-Shyan ; Kuo, Hsiou-Ting ; Bendre, Shreya ; Wong, Antonio A W L ; Merkens, Helen ; Zhang, Zhengxing

Fibroblast activation protein (FAP) is a membrane-tethered serine protease overexpressed in the reactive stromal fibroblasts of >90% human carcinomas, which makes it a promising target for developing radiopharmaceuticals for the imaging and therapy of carcinomas. Here, we synthesized two novel (R)-pyrrolidin-2-yl-boronic acid-based FAP-targeted ligands: SB02055 (DOTA-conjugated (R)-(1-((6-(3-(piperazin-1-yl)propoxy)quinoline-4-carbonyl)glycyl)pyrrolidin-2-yl)boronic acid) and SB04028 (DOTA-conjugated ((R)-1-((6-(3-(piperazin-1-yl)propoxy)quinoline-4-carbonyl)-D-alanyl)pyrrolidin-2-yl)boronic acid). ^natGa- and ⁶⁸Ga-complexes of both ligands were evaluated in preclinical studies and compared to previously reported ^natGa/⁶⁸Ga-complexed PNT6555. Enzymatic assays showed that FAP binding affinities (IC₅₀) of ^natGa-SB02055, ^natGa-SB04028 and ^natGa-PNT6555 were 0.41 ± 0.06, 13.9 ± 1.29 and 78.1 ± 4.59 nM, respectively. PET imaging and biodistribution studies in HEK293T:hFAP tumor-bearing mice showed that while [⁶⁸Ga]Ga-SB02055 presented with a nominal tumor uptake (1.08 ± 0.37 %ID/g), [⁶⁸Ga]Ga-SB04028 demonstrated clear tumor visualization with ~1.5-fold higher tumor uptake (10.1 ± 0.42 %ID/g) compared to [⁶⁸Ga]Ga-PNT6555 (6.38 ± 0.45 %ID/g). High accumulation in the bladder indicated renal excretion of all three tracers. [⁶⁸Ga]Ga-SB04028 displayed a low background level uptake in most normal organs, and comparable to [⁶⁸Ga]Ga-PNT6555. However, since its tumor uptake was considerably higher than [⁶⁸Ga]Ga-PNT6555, the corresponding tumor-to-organ uptake ratios for [⁶⁸Ga]Ga-SB04028 were also significantly greater than [⁶⁸Ga]Ga-PNT6555. Our data demonstrate that (R)-(((quinoline-4-carbonyl)-d-alanyl)pyrrolidin-2-yl)boronic acid is a promising pharmacophore for the design of FAP-targeted radiopharmaceuticals for cancer imaging and radioligand therapy.

14 Apr 2023·ACS Pharmacology & Translational Science

Discovery of a High-Affinity Fluoromethyl Analog of [¹¹C]5-Cyano-N-(4-(4-methylpiperazin-1-yl)-2-(piperidin-1-yl)phenyl)furan-2-carboxamide ([¹¹C]CPPC) and Their Comparison in Mouse and Monkey as Colony-Stimulating Factor 1 Receptor Positron Emission Tomography Radioligands

Article

Author: Jenkins, Madeline D. ; Liow, Jeih-San ; Morse, Cheryl L. ; Innis, Robert B. ; Pike, Victor W. ; Montero Santamaria, Jose A. ; Altomonte, Stefano ; Yan, Xuefeng ; Zoghbi, Sami S.

[¹¹C]CPPC has been advocated as a radioligand for colony-stimulating factor 1 receptor (CSF1R) with the potential for imaging neuroinflammation in human subjects with positron emission tomography (PET). This study sought to prepare fluoro analogs of CPPC with higher affinity to provide the potential for labeling with longer-lived fluorine-18 (t _1/2 = 109.8 min) and for delivery of higher CSF1R-specific PET signal in vivo. Seven fluorine-containing analogs of CPPC were prepared and four were found to have high inhibitory potency (IC₅₀ in low to sub-nM range) and selectivity at CSF1R comparable with CPPC itself. One of these, a 4-fluoromethyl analog (Psa374), was investigated more deeply by labeling with carbon-11 (t _1/2 = 20.4 min) for PET studies in mouse and monkey. [¹¹C]Psa374 showed high peak uptake in monkey brain but not in mouse brain. Pharmacological challenges revealed no CSF1R-specific binding in either species at baseline. [¹¹C]CPPC also failed to show specific binding at baseline. Moreover, both [¹¹C]Psa374 and [¹¹C]CPPC showed brain efflux transporter substrate behavior in both species in vivo, although Psa374 did not show liability toward human efflux transporters in vitro. Further development of [¹¹C]Psa374 in non-human primate models of neuroinflammation with demonstration of CSF1R-specific binding would be required to warrant the fluorine-18 labeling of Psa374 with a view to possible application in human subjects.

08 Sep 2022·Journal of Medicinal ChemistryQ1 · MEDICINE

Discovery of (R)-N-Benzyl-2-(2,5-dioxopyrrolidin-1-yl)propanamide [(R)-AS-1], a Novel Orally Bioavailable EAAT2 Modulator with Drug-like Properties and Potent Antiseizure Activity In Vivo

Q1 · MEDICINE

Article

Author: Gawel, Kinga ; Latacz, Gniewomir ; Socała, Katarzyna ; Bahar, Ivet ; Gedschold, Robin ; Cheng, Mary Hongying ; Mogilski, Szczepan ; Fontana, Andréia C. K. ; Szulczyk, Bartłomiej ; Szafarz, Małgorzata ; Müller, Christa E. ; Rapacz, Anna ; Wlaź, Piotr ; Reeb, Katelyn ; Abram, Michał ; Esguerra, Camila V. ; Kalinowska-Tłuścik, Justyna ; Kamiński, Krzysztof ; Jakubiec, Marcin ; Nieoczym, Dorota ; Kamiński, Rafał M. ; Wyska, Elżbieta

(R)-7 [(R)-AS-1] showed broad-spectrum antiseizure activity across in vivo mouse seizure models: maximal electroshock (MES), 6 Hz (32/44 mA), acute pentylenetetrazol (PTZ), and PTZ-kindling. A remarkable separation between antiseizure activity and CNS-related adverse effects was also observed. In vitro studies with primary glia cultures and COS-7 cells expressing the glutamate transporter EAAT2 showed enhancement of glutamate uptake, revealing a stereoselective positive allosteric modulator (PAM) effect, further supported by molecular docking simulations. (R)-7 [(R)-AS-1] was not active in EAAT1 and EAAT3 assays and did not show significant off-target activity, including interactions with targets reported for marketed antiseizure drugs, indicative of a novel and unprecedented mechanism of action. Both in vivo pharmacokinetic and in vitro absorption, distribution, metabolism, excretion, toxicity (ADME-Tox) profiles confirmed the favorable drug-like potential of the compound. Thus, (R)-7 [(R)-AS-1] may be considered as the first-in-class small-molecule PAM of EAAT2 with potential for further preclinical and clinical development in epilepsy and possibly other CNS disorders.

100 Deals associated with TL-118 (Teligene)

Login to view more data

R&D Status

10 top R&D records.

Login

to view more data

Indication	Highest Phase	Country/Location	Organization	Date
Solid tumor	Phase 2	US	Suzhou Teligene Ltd.	16 Mar 2023
Solid tumor	Phase 2	CN	Suzhou Teligene Ltd.	16 Mar 2023
NTRK fusion-positive solid tumors	Phase 2	CN	Suzhou Teligene Ltd.	02 Mar 2023
NTRK fusion-positive solid tumors	Phase 2	US	Suzhou Teligene Ltd.	02 Mar 2023
Advanced Malignant Solid Neoplasm	Phase 1	CN	Suzhou Teligene Ltd.	08 Oct 2019
NTRK fusion-positive Central Nervous System Neoplasms	IND Approval	CN	Suzhou Teligene Ltd.	29 Dec 2022