Dual inhibitors of human epidermal growth factor receptor 2 (HER2) and epidermal growth factor receptor (EGFR) have been investigated for breast, lung, gastric, prostate, and other cancers; one, lapatinib, is currently approved for breast cancer. To develop novel HER2/EGFR dual kinase inhibitors, we designed and synthesized pyrrolo[3,2-d]pyrimidine derivatives capable of fitting into the receptors' ATP binding site. Among the prepared compounds, 34e showed potent HER2 and EGFR (HER1) inhibitory activities as well as tumor growth inhibitory activity. The X-ray cocrystal structures of 34e with both HER2 and EGFR demonstrated that 34e interacts with the expected residues in their respective ATP pockets. Furthermore, reflecting its good oral bioavailability, 34e exhibited potent in vivo efficacy in HER2-overexpressing tumor xenograft models. On the basis of these findings, we report 34e (TAK-285) as a promising candidate for clinical development as a novel HER2/EGFR dual kinase inhibitor.
BackgroundExosomes are a subset of extracellular vesicles 30–200 nm in diameter secreted from cells, which contain functional mRNAs and microRNAs. Cerebrospinal fluid (CSF) is the primary source for liquid biopsy to examine diseases in central nervous system. To date, there is no available method to analyze exosomal mRNAs comprehensively in human CSF.MethodsThe main purpose of this study is to established the methodology of comprehensive analysis of exosomal mRNAs in CSF by a highly sensitive next-generation sequencing. The signatures of CSF exosomal mRNAs were then compared between four normal healthy donors and four sporadic amyotrophic lateral sclerosis patients to identify disease-related biomarkers. Differentially expressed genes were identified by DESeq2.ResultsRNA sequencing from CSF exosomes was successfully performed, that was demonstrated by the high pearson’s product-moment correlation coefficient (r = 0.993) in the technical replicates. Also, position coverage analysis revealed that most detected mRNAs retained their integrity throughout their full-length in CSF exosomes. In CSF exosomes from normal healthy donors, an average of 14,807 genes were detected, of which 4580 genes were commonly detected among four individuals, including neuron-enriched genes such as TUBB3 and CAMK2A. In comparison with exosomal mRNAs in CSF from four patients with amyotrophic lateral sclerosis, 543 genes were significantly changed, as represented by CUEDC2. Gene Ontology analysis and pathway analysis with these genes revealed functional enrichment of ubiquitin-proteasome pathway, oxidative stress response, and unfolded protein response. These pathways are related to pathomechanisms of amyotrophic lateral sclerosis.ConclusionWe successfully established the methodology of comprehensive analysis of exosomal mRNAs in human CSF. It was shown to be useful to identify disease biomarkers for central nervous system. Several genes, such as CUEDC2, in CSF exosomes were suggested to be candidate disease biomarkers for amyotrophic lateral sclerosis.Electronic supplementary materialThe online version of this article (10.1186/s12920-019-0473-z) contains supplementary material, which is available to authorized users.
To develop novel human epidermal growth factor receptor 2 (HER2)/epidermal growth factor receptor (EGFR) kinase inhibitors, we explored pyrrolo[3,2-d]pyrimidine derivatives bearing bicyclic fused rings designed to fit the back pocket of the HER2/EGFR proteins. Among them, the 1,2-benzisothiazole (42m) ring was selected as a suitable back pocket binder because of its potent HER2/EGFR binding and cell growth inhibitory (GI) activities and pseudoirreversibility (PI) profile as well as good bioavailability (BA). Ultimately, we arrived at our preclinical candidate 51m by optimization of the N-5 side chain to improve CYP inhibition and metabolic stability profiles without a loss of potency (HER2/EGFR inhibitory activity, IC(50), 0.98/2.5 nM; and GI activity BT-474 cells, GI(50), 2.0 nM). Reflecting the strong in vitro activities, 51m exhibited potent tumor regressive efficacy against both HER2- and EGFR-overexpressing tumor (4-1ST and CAL27) xenograft models in mice at oral doses of 50 mg/kg and 100 mg/kg.
Indolmycin (1), isolated from an African strain of Streptomyces albus, 1) exhibits antibacterial activity against Staphylococci.2) Recently, our screening group found that 1 also has potent antibacterial activity against Helicobacter pylori (H. pylori) and it is a promising anti-H. pylori agent.3)Although syntheses of 1, including its racemate, have been reported by several groups, 4) none of them is satisfactory for large scale synthesis because of low diastereoselectivity or involving too many chemical processes. Therefore, it was necessary to develop a stereoselective practical synthetic route to 1 for further study. In this paper, we wish to report a convenient and practical stereoselective synthesis of 1 from epoxy ester 3 as a starting material, through hydroxy ester 2 (Chart 1), and we show its application to the preparation of metabolites. ChemistryPreparation of an Intermediate Hydroxy Ester (؎)-2 Initially we started to study the diastereoselective synthesis of (Ϯ)-1 from (Ϯ)-3 which was easily prepared from ethyl crotonate by oxidation with m-chloroperbenzoic acid. We investigated the condensation of indolyl magnesium halide with (Ϯ)-3 although the coupling reaction of (Ϯ)-3 with indole in the presence of Lewis acid was reported.4e) Indole was treated with methyl magnesium bromide in ethyl ether to form indolyl magnesium bromide and the complex was isolated. Addition of (Ϯ)-3 to the reaction mixture gave the desired hydroxy ester (Ϯ)-2 in 48% yield after purification with silica gel column chromatography. The moderate yield was due to poor solubility of indolyl magnesium bromide in ethyl ether. It was reported that addition of dichloromethane to indolyl magnesium halide in ethyl ether brought the complex into a clear solution.5) Addition of (Ϯ)-3 to a solution of indolyl magnesium bromide in ethyl ether and dichloromethane gave (Ϯ)-2 in a better yield of 65%. By increasing the amount of methyl magnesium bromide (2.2 eq to 3) the yield was improved to 79% (Chart 2). Although the yield was satisfactory, it was necessary to purify the crude product by silica gel column chromatography to remove unreacted indole and by-products. As it was found that the hydroxy acid (Ϯ)-4 was easily purified by extraction and recrystallization, crude (Ϯ)-2 was hydrolyzed to (Ϯ)-4 and after purification, esterification of (Ϯ)-4 gave pure (Ϯ)-2 (Chart 2). Thus we accomplished the preparation of the racemic hydroxy ester (Ϯ)-2. Formation of the Oxazolone Ring Although Schach von Wittenau and Els 4e) and Preobrazhenskaya et al. 4a) reported that (Ϯ)-1 was prepared through formation of an oxazolone ring with N,NЈ-dimethylguanidine from the hydroxy ester (Ϯ)-2, the yields were very low, partly because the epimerization at C5 position of the oxazolone ring occurred in the alkaline medium. After intensive examination of the reaction, we found that epimerization was suppressed in tertbutanol below room temperature but the reaction was very slow (data was not shown). Therefore, we gave up the preparation of (Ϯ)-1 from the hydroxy es...
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