Discovery of an Orally Efficacious MYC Inhibitor for Liver Cancer Using a GNMT-Based High-Throughput Screening System and Structure–Activity Relationship Analysis

Q1 · MEDICINE

Article

Author: Yang, Ming-Hui ; Chen, Yeh-Long ; Chen, Yi-Ming Arthur ; Chen, Marcelo ; Tzeng, Cherng-Chyi ; Tseng, Chih-Hua ; Kant, Rajni ; Tyan, Yu-Chang ; Chen, Wei-Cheng ; You, Kaiting ; Li, Wei-You ; Wang, Wen-Chieh ; Yen, Chia-Hung

Glycine-N-methyl transferase (GNMT) downregulation results in spontaneous hepatocellular carcinoma (HCC). Overexpression of GNMT inhibits the proliferation of liver cancer cell lines and prevents carcinogen-induced HCC, suggesting that GNMT induction is a potential approach for anti-HCC therapy. Herein, we used Huh7 GNMT promoter-driven screening to identify a GNMT inducer. Compound K78 was identified and validated for its induction of GNMT and inhibition of Huh7 cell growth. Subsequently, we employed structure-activity relationship analysis and found a potent GNMT inducer, K117. K117 inhibited Huh7 cell growth in vitro and xenograft in vivo. Oral administration of a dosage of K117 at 10 mpk (milligrams per kilogram) can inhibit Huh7 xenograft in a manner equivalent to the effect of sorafenib at a dosage of 25 mpk. A mechanistic study revealed that K117 is an MYC inhibitor. Ectopic expression of MYC using CMV promoter blocked K117-mediated MYC inhibition and GNMT induction. Overall, K117 is a potential lead compound for HCC- and MYC-dependent cancers.

01 Sep 2019·Chemico-biological interactions

Pharmacokinetics of K117 and K127, two novel antidote candidates to treat Tabun poisoning.

Article

Author: Kalász, H ; Karvaly, G ; Tekes, K ; Jung, Y-S ; Kuca, K ; Adeghate, E ; Nurulain, S ; Musilek, K

AIMSK117 and K127 are bis-pyridinium aldoximes but K117 is a bis-pyridinium bis-aldoxime while K127 has only one single aldoxime in addition to its amide substituent. Is there any difference in pharmacokinetics in these compounds that otherwise have the same chemical structure? Both K117 and K127 are developed as antidotes in acetylcholinesterase and butyrylcholinesterase poisoning in terrorist attacks or intoxication with other organophosphorous compounds. Their distributions have been scouted in the bodies of rats.MAIN METHODSWhite male Wistar rats were intramuscularly injected. The animals were sacrificed, tissue samples were homogenized, and either K117 or K127 concentrations were determined using reversed-phase high-performance liquid chromatography.KEY FINDINGSBoth K117 and K127 were present in all tissues that were analyzed including blood (serum), the brains, cerebrospinal fluid, the eyes, livers, kidneys, lungs and testes. Their pharmacokinetics and body distributions are similar.SIGNIFICANCEEither K117 or K127 meets the essential requirements for antidotes. Dose dependence and kinetics of their distribution were compared to that of other pyridinium aldoximes.

01 Sep 2009·Basic & Clinical Pharmacology & ToxicologyQ3 · MEDICINE

Reactivation of Human Brain Homogenate Cholinesterases Inhibited by Tabun using Newly Developed Oximes K117 and K127

Q3 · MEDICINE

Article

Author: Martina Hrabinova ; Yung Sik Jung ; Jana Karasová ; Kamil Musilek ; Miroslav Pohanka ; Ondrej Soukup ; Kamil Kuca ; Lucie Musilova ; Jiri Cabal ; Daniel Jun ; Ladislav Novotný

Abstract: Newly developed acetylcholinesterase reactivators K117 [1,5‐bis(4‐hydroxyiminomethylpyridinium)‐3‐oxapentane dichloride] and K127 [(1‐(4‐hydroxyiminomethylpyridinium)‐5‐(4‐carbamoylpyridinium)‐3‐oxapentane dibromide)] were tested for their potency to reactivate tabun‐inhibited human brain cholinesterases. Pralidoxime and trimedoxime were chosen as standard reference reactivators. Human tissue was used, as that was closer on the real treatment of human beings. As a result, oxime K127 was found as the best tested reactivator according to the constant kr, characterizing the overall reactivation process. On the contrary, the maximal reactivation ability expressed as percentage of reactivation was the best for trimedoxime. This differences were caused as a result of using the enzyme from different species. Due to this, experiments on human tissue should be conducted after in vitro and in vivo tests on animals to eliminate such important failures of promising oximes.

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Indication	Highest Phase	Country/Location	Organization	Date
Hepatocellular Carcinoma	Preclinical	Taiwan Province	Fu Jen Catholic University	01 Jul 2021

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