Protein tyrosine phosphatase non-receptor type 2 (PTPN2) is ubiquitously expressed, primarily in hematopoietic and placental cells. Critical negative regulator of the JAK-STAT pathway, PTPN2 functions to directly regulate signaling through cytokine receptors, including IFNγ. Thus, enhancing IFNγ sensing and signaling through the inhibition of PTPN2 is a potential therapeutic strategy to improve the efficacy of cancer immunotherapy regimens. Historically, phosphatases are difficult drug targets; due to an intrinsic physicochemical profile of phosphatase inhibitors, finding bioavailable molecules is a great challenge. ZE00-0388 demonstrates sub-nanomolar PTPN2/N1 inhibitory activity and outstanding over 1000-fold selectivity against all other phosphatases. ZE00-0388 demonstrated complete tumor remission in combination with the anti-mPD-1 recombinant mAb therapy in the murine colon adenocarcinoma MC38 in vivo model. ZE00-0388 demonstrates good safety and tolerability; its ADME properties confirm that ZE00-0388 is suitable for further development for combination therapies. Alexei Pushechnikov, Vladislav Parchinsky, Aleksei Riakhovskii, Stepan Mochalov, Ruben Karapetian, Amy Burd, Nikolay Savchuk, Iain Dukes, Ruben Abagyan. Discovery and preclinical evaluation of a potent, orally bioavailable, highly selective, small molecule PTPN2/1 inhibitor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 5607.
Синтезированы новые замещенные 5-гидрокси-2-аминометил-1H-индол-3-карбоновые кислоты и их производные. Изучена их противовирусная активность по отношению к вирусам бычьей вирусной диареи (BVDV), гепатита C (HCV) и А/Аичи/2/69 (H3N2) гриппа. Установлено, что из синтезированных соединений заметной активностью по отношению к указанным вирусам обладают лишь гидрохлориды этиловых эфиров 5-гидрокси-2-(диметиламинометил)-1-метил-6-пиридин-3-ил- и 5-гидрокси-2-(диметиламинометил)-1-метил-6-фтор-1H-индол-3-карбоновой кислоты, которые не только в микромолярных концентрациях эффективно подавляли репликацию вируса гриппа А/Аичи/2/69 (H3N2) в культуре клеток, но и в дозе 25 мг/кг/день проявили высокую эффективность, превышающую эффективность арбидола, на модели гриппозной пневмонии мышей, инфицированных вирусом гриппа А/Аичи/2/69 (H3N2) мышей.
New substituted ethyl 1,2-dimethyl-5-hydroxy-1 H -indole-3-carboxylates and 7,8-dimethyl-1,2,3,7-tetrahydro[1,3]oxazino[5,6-e]indole-9-carboxylates, including arbidol analogs, and also 6-hydroxy-1-dimethyl-7-(pyridin-3-yl)-4,5-dihydropyrrolo[4,3,2-de]isoquinolin-3(1 H )-ones and 1,4-dimethyl-2-(phenylsulfonylmethyl)-7-(pyridin-3-yl)-pyrrolo[4,3,2-de]isoquinoline-3,6(1H,4H)-dione, have been synthesized. The antiviral activity of these compounds against influenza A/New Caledonia/20/99 (H 1 N 1 ), bovine viral diarrhea (BVDV) and hepatitis C (HCV) viruses has been studied in vitro . Among all the drugs studied, only two compounds (ethyl 5-hyroxy-4-(dimethylaminomethyl)-1-methyl-6-piridine-3-yl-2-(phenylsulfonylmethyl)-1 H -indole-3-carboxylate and 5-hyroxy-1,2-dimethyl-6-fluoro-1 H -indole-3-carboxylate) significantly inhibited HCV in the in vitro-infected cultured human hepatoma (Huh 7.3) cells (with EC 50 of 6.6 and 9.8 mM, respectively).
A series of new 2-substituted 8-methyl-5-(2-piridinylethyl)-2,3,4,5-tetrahydro-1 H -pyrido[4,3- b ]indoles have been synthesized and their activity profiles have been studied on a broad panel of therapeutic targets including GPC receptors, ion channels and neurotransmitter transporters. One of the studied compounds, 2-methyl-3-{2-[8-methyl-5-(2-pyridin-2-ylethyl)-2,3,4,5-tetrahydro[4,3- b ]indol-2-yl]ethyl}-6,7,8,9-tetrahydropyrido[1,2- a ]pyrimidin-4-one was found to be a highly active antagonist of adrenergic α 1A , α 1B , α 1D , α 2A receptors and serotonin 5-HT 2A , 5-HT 2B , 5-HT 2C , 5-HT 7 receptors. The obtained results are considered in terms of structure – activity relationships. It is established that, in the rest of the synthesized compounds, the introduction of bulky substituents in position «2» of 8-methyl-5-(2-pyridinylethyl)-2,3,4,5-tetrahydro-1 H -pyrido[4,3- b ]indoles leads to a decrease in activity of the corresponding derivatives as compared to that of 2,8-dimethyl analogs.
A series of new 3-(arylsulfonyl)-2-(methylthio)pyrazolo[1,5- a ]pyrimidines containing amino substituent in position 7 have been synthesized and their 5-HT6 receptor antagonist activity has been studied. It is established that the transition from 7-amino and 7-dimethylamino derivatives to 7-aminoalkyl derivatives is accompanied by a significant decrease in the activity, and a similar effect is observed upon replacement of methyl group in position 5 with phenyl or 5-thiophen-2-yl substituents. Maximum (picomolar) activity in the obtained series of compounds was displayed by 5-methyl-2-(methylthio)-3-(phenylsulfonyl)pyrazolo[1,5- a ]pyrimidine-7-amine and N,N,5,6-tetramethyl-2-(methylthio)-3-(phenylsulfonyl)pyrazolo[1,5- a ]pyrimidine-7-amine ( K i = 700 pM). The first representative of hydrogenated pyrazolo[1,5- a ]pteridines – 5,6,9-trimethyl-2-(methylthio)-3-(phenylsulfonyl)-6,7,8,9-tetrahydropyrazolo[1,5- a ]pteridin (with K i = 14,4 nM) was synthesized. The discovered structure – 5-HT 6 antagonist activity relationship and observed regularities confirm the validity of the adopted pharmacophore model, which allows it to be used in the search for effective drug candidates.
