Highly cytotoxic maytansine derivatives are widely used in targeted tumor delivery. Structure-activity studies published earlier suggested the C9 carbinol to be a key element necessary to retain the potency. However, in 1984 a patent was published by Takeda in which the synthesis of 9-thioansamitocyn (AP3SH) was described and its activity in xenograft models was shown. In this article we summarize the results of an extended study of the anti-tumor properties of AP3SH. Like other maytansinoids, it induces apoptosis and arrests the cell cycle in the G2/M phase. It is metabolized in liver microsomes predominately by C3A4 isoform and doesn't inhibit any CYP isoforms except CYP3A4 (midazolam, IC50 7.84 μM). No hERG inhibition, CYP induction or mutagenicity in Ames tests were observed. AP3SH demonstrates high antiproliferative activity against 25 tumor cell lines and tumor growth inhibition in U937 xenograft model. Application of AP3SH as a cytotoxic payload in drug delivery system was demonstrated by us earlier.

In our efforts to extend the possible application of highly cytotoxic maytansine derivatives as a payload in drug delivery systems we found that thiol group in 9 thioansamitocib P3 could be successfully used to create a disulfide linker to the carrier

Triple-negative breast cancer (TNBC) with estrogen receptor (ER), progesterone receptor (PR) and HER2 (c-erbB-2, neu) being negatively expressed in patient cancer tissues displayed its unique clinical pathological difference from other types of breast cancers. TNBC is more common in younger patients and more likely to have a family history of breast cancer. TNBCs more likely have poor prognosis and postsurgical recurrence, with strong invasiveness and metastasis. However, there is lack of effective and TNBC-targeting drugs. The non-typical CDK16 was found highly expressed in TNBCs and clearly associated with prognosis and survival of patients. CDK16 could promote the progression and metastasis of TNBC by phosphorylating PRC1. Knockdown of CDK16 could significantly suppress tumor growth and metastasis. Furthermore, in our studies, rebastinib acting as a CDK16 inhibitor displayed its strong suppression of TNBC tumor growth in a dose-dependent manner, indicating rebastinib or its analogs could be druggable and likely used to treat TNBC patients. Citation Format: Haihua Xiao, Huangyu Jiang, Kunxian Feng, Mengli Yang, Jinping Yang, Chengfang Jian, Yuan Tian, Natalya Vasilevich, Lichun Sun. The application of CDK16 inhibitors in the treatment of triple-negative breast cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5345.

Multiple drug-targeting strategies have been applied to drug development in order to reduce the toxic side effects of the traditional chemotherapy while enhancing its anti-tumor efficacy. Various peptides, proteins and antibodies are usually used to conjugate cytotoxic agents via acting as drug delivery vehicles. In our previous studies, we identified that peptides displayed their efficacious functions to deliver small molecules or oligo DNA to the target sites through ligand-receptor interactions and quick internalization. In our present study, we attempt to synthesize serial drug conjugates via coupling these compounds to peptide or protein vehicles. Tye1001, one of these conjugates, displayed similar potent anti-proliferation activities in lymphoma cells and many other cancer cells compared to the small molecule itself. In particular, this conjugate significantly enhanced its potent anti-tumor efficacy in xenografts. Meanwhile, this conjugate has much less toxic side effects. In our in vivo assays, the similar results were also observed in multiple other tumors such as gastric cancer and leukemia. Our findings provide a more potential druggable opportunity in the clinical applications of cancer patients and the treatment of different types of cancers. Citation Format: Lichun Sun, Mengli Yang, Haihua Xiao, Yuan Tian, Natalya Vasilevich, Joseph Fuselier, David Coy. The targeting drug conjugate Tye1001 displayed its potent anti-tumor efficacy in lymphoma. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4957.

BACKGROUND/AIM:High resistance of triple-negative breast cancer has prompted scientists to look for new targets susceptible to treatment. CDK16 has been suggested as a promising target whose inhibition can lead to tumor growth suppression. Rebastinib, a potent inhibitor of CDK16, has been reported to exhibit anti-tumor activity both in vitro and in vivo.MATERIALS AND METHODS:The anticancer activity of rebastinib was studied in vitro using cell proliferation, cell cycle arrest and cell apoptosis assays and in vivo in xenograft tumor models using MDA-MB-231 and MDA-MB-468-derived tumors. The safety and drug-like properties of rebastinib were assessed using a panel of Absorption, Distribution, Metabolism, and Excretion (ADME) assays, Ames tests, human Ether-a-go-go Related Gene (hERG) experiments and pharmacokinetic studies in mice and rats.RESULTS:Rebastinib demonstrates antitumor activity against breast cancer both in vitro and in vivo. However, the response of the tumor strongly depends on the type of triple-negative breast cancer. Rebastinib-induced cell cycle arrest was observed in G0/G1 phase suggesting a more complex mechanism than just CDK16 inhibition. ADME and PK studies confirmed the drug-like properties and reasonable safety of rebastinib.CONCLUSION:Our studies confirmed rebastinib to be a promising drug candidate for breast cancer treatment with high oral bioavailability and reasonable safety. Our data suggest that the mechanism of action of rebastinib is not limited to CDK16 inhibition but also involves other pathways. This does not diminish the importance of rebastinib as a drug candidate, but reveals the presence of several mechanisms, suggesting a wider scope of possible applications.

Туберкулез самая смертоносная бактериальная инфекция из известных человеку, при этом ее лечение осложнено появлением и быстрым распространением штаммов возбудителя, Mycobacterium tuberculosis, с множественной и широкой лекарственной устойчивостью (МЛУ и ШЛУ). В результате главным требованием к разрабатываемым противотуберкулезным препаратам является использование новых классов химических соединений, поражающих новые биомишени. Серин-треониновые протеинкиназы (СТПК) перспективные мишени, а аминопиридины и аминопири-мидины, ранее не применявшиеся в качестве противотуберкулезных препаратов, имеют предсказанную активность в отношении СТПК. В данной работе в тест-системе Mycobacterium smegmatis aphVIII+, предназначенной для отбора ингибиторов СТПК на клеточном уровне, был проведен скрининг 192 соединений двух указанных классов. Сначала отобрали 53 соединения с субингибирующей концентрацией до 100 нмоль/диск. Из них 22 соединения проявили активность в тест-системе как ингибиторы СТПК, которая была подтверждена in vitro на белке PknA М. tuberculosis (наивысшее значение показателя ингибирования 26,9 ± 6,1 %). Также отобранные соединения тестировали на токсичность in vitro на клетках фибробластов эмбриона человека с использованием МТТ-теста. В результате для дальнейших исследований в качестве новых препаратов для борьбы с МЛУ-туберкулезом были отобраны 3 ингибитора СТПК с относительно высокой активностью и относительно низкой токсичностью.

A procedure for macrocyclization of compounds with potential tuberculocidal activity was developed in order to obtaining compounds with a lower degree of inhibition of the key CYP 3A4 cytochrome.

Tuberculosis (TB) is the world's deadliest bacterial infection. Its causative agent Mycobacterium tuberculosis evolves into rapidly spreading multidrug-resistant and extensively drug-resistant (MDR and XDR) strains, which complicates the treatment. Therefore, the use of novel target-specific chemical compounds is crucial for the development of effective antituberculosis agents. Serine/threonine protein kinases (STPKs) of M. tuberculosis are currently considered as attractive drug targets. In turn, aminopyridines and aminopyrimidines that have not been used for TB treatment so far exhibit inhibitory activity towards STPKs. In this study we screened 192 aminopyridine-and aminopyrimidine-based compounds using the Mycobacterium smegmatis aphVIII+ test system designed to screen for active STPKs inhibitors. First, we selected 53 compounds with subinhibiting concentrations of up to 100 nmol/disk. Of them, 22 showed STPKs-inhibiting activity in the test system, which was confirmed in vitro on the M. tuberculosis PknA protein with a maximum of 26.9 +/- 6.1 %. Toxicity testing was performed in vitro on human embryo fibroblasts using the MTT-assay. Ultimately, 3 relatively active and relatively non-toxic STPKs inhibitors were selected for further research as drug candidates for MDR-TB treatment.

А.А.Аксенова, к.х.н., И.И.Афанасьев, к.х.н.ооо "новые научные технологии", группа

A general pharmachophore model for various types of Ser/Thr kinases was developed. Search for the molecules fitting to this pharmacophore among ASINEX proprietary library revealed a number of compounds, which were tested and appeared to possess some activity against several Ser/Thr kinases such as Aurora A, Aurora B and Haspin. The possibility of performing the fine‐tuning of the general Ser/Thr pharmacophore to desired types of kinase to get active and selective inhibitors was exemplified by Aurora A kinase. As a result, several hits in 3–5 nm range of activity against Aurora A kinase with rather good selectivity and ADME properties were obtained.

Based on an earlier suggested general pharnacophore approach, compounds active against tuberculosis virulent strain H37Rv were obtained. The main drawback of these compounds was an almost complete CYP 3A4 inhibition, which presumably could be overcome by macrocyclization. Three 15-16-membered macrocyclic scaffolds with pharmacophore groups located in appropriate positions were designed and synthetic schemes for their achievement were elaborated. Testing of these compounds against CYP450 enzymes confirmed generally lower inhibition of key cytochromes CYP 3A4 and CYP2D6 by the macrocyclic compounds compared to acyclic prototypes.

Using general Ser/Thr pharmacophore approach suggested by us previously we have designed two series of compounds capable to suppress the growth of virulent Mycobacterium Tuberculosis strain (H37Rv). We suggest that this inhibition is caused by mycobacterial PknB inhibition.

Based on the data for compounds known from the literature to be active against various types of Ser/Thr kinases, a general pharmachophore model for these types of kinases was developed. The search for the molecules fitting to this pharmacophore among the ASINEX proprietary library revealed a number of compounds, which were tested and appeared to possess some activity against Ser/Thr kinases such as Aurora A, Aurora B and Haspin. Our work on the optimization of these molecules against Aurora A kinase allowed us to achieve several hits in a 3–5 nM range of activity with rather good selectivity and Absorption, Distribution, Metabolism, and Excretion (ADME) properties, and cytotoxicity against 16 cancer cell lines. Thus, we showed the possibility to fine-tune the general Ser/Thr pharmacophore to design active and selective compounds against desired types of kinases.

The general model of epitope‐type MDM2 inhibitor was developed based on the structural information on the complexes between MDM2 and various low molecular weight ligands found in the PDB database. Application of this model to our in‐house library has led us to a new scaffold capable of interrupting protein–protein interactions. A synthetic library based on this and related scaffolds resulted in new classes of compounds that possess biochemical and cellular activity and good pharmacokinetic properties. We assume that such general approach to PPI inhibitors design may be useful for the development of inhibitors of various PPI types, including Bcl/XL.

A new class of alpha-helix mimetics, based on the phenyl-pyrazole-phenyl (6-5-6) system, has been designed and synthesized. The ability of the new compounds to inhibit PPIs was confirmed using an MDM2-p53 binding assay. The library, containing completely new compounds, revealed an excellent hit rate of 15%, had satisfactory physicochemical properties (similar to 38% soluble compounds), and the ligand efficiency of the best compound was 0.21 (0.22 for nutlin-3 in the same assay). Dual mode of action of these inhibitors was suggested based on computer modeling: depending on the nature of their substituents they could act as either an alpha-helix backbone mimetic or an alpha-helix binding epitope mimetic.

A specific, sensitive, rapid and reproducible method for the determination of flomoxef in human plasma using high-performance liquid chromatography-tandem mass spectrometry was developed and validated. Flomoxef was detected using an electrospay ionization method operated in negative-ion mode. Chromatographic separation was performed in gradient elution mode on a Luna® C18(2) column (3 μM, 20 × 4.0 mm) at a flow rate of 1 mL/min and runtime 3.5 min. The mobile phase consisted of acetonitrile and water containing 0.1% formic acid as additive. Extraction of flomoxef from plasma and precipitation of plasma proteins was performed with acetonitrile with an absolute recovery of 86.4 ± 1.6%. The calibration curve was linear with a correlation coefficient of 0.999 over the concentration range 10-5000 ng/mL and the lower limit of quantification was 10 ng/mL. The intra- and inter-day precisions were <11.8%, while the accuracy ranged from 99.6 to 109.0%. A stability study of flomoxef revealed that it could be successfully analyzed at 4 ºС over 24 h, but it was unstable in solutions at room temperature during short-term storage (4 h) and several freeze-thaw cycles.

ADVERTISEMENT RETURN TO ISSUEPREVPerspectiveNEXTLessons from Natural Products Chemistry Can Offer Novel Approaches for Synthetic Chemistry in Drug DiscoveryMiniperspectiveNatalya I. Vasilevich*, Roman V. Kombarov, Dmitry V. Genis, and Michael A. KirpichenokView Author Information Asinex, 20 Geroev Panfilovtsev Str., Moscow, 125480, Russia*Phone: +7 (495) 780 34 10. E-mail: [email protected]Cite this: J. Med. Chem. 2012, 55, 16, 7003–7009Publication Date (Web):June 19, 2012Publication History Received13 March 2012Published online2 July 2012Published inissue 23 August 2012https://pubs.acs.org/doi/10.1021/jm300344vhttps://doi.org/10.1021/jm300344vreview-articleACS PublicationsCopyright © 2012 American Chemical SocietyRequest reuse permissionsArticle Views5741Altmetric-Citations42LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InRedditEmail Other access optionsGet e-Alertsclose SUBJECTS:Addition reactions,Aldol reactions,Medicinal chemistry,Pharmaceuticals,Redox reactions Get e-Alerts

An analysis of the chemical environment of the oxygen atoms in the DNP database compared to the CMC and SCD databases was performed. Some structural clusters were identified which are predominant among the natural products and can be considered as distinctive features of NPs. Fifty-three oxygen-containing structural fragments that are distinctive for the DNP (distinctive set of fragments DSF) in comparison with the SCD have been identified. A new descriptor Mc was introduced for describing the ratio of atoms involved in the DSF to the total number of heavy atoms. A significant difference in the Mc values among the reference databases allowed the use of a specific cluster of the DSF as a tool for performing similarity searches for oxygen-containing NP molecules, or for evaluation or comparison of databases according to their NP-likeness. An example illustrating that the suggested approach could allow not only estimating the NP-likeness, but also serve as a tool for designing new NP-like compounds is provided. The suggested approach for NP-likeness evaluation moves away from the traditional ideas of scaffolds, cycles, linkers and substituents.