Pyrimido[4,5‐ d ]pyrimidin‐4(1 H )‐one Derivatives as Selective Inhibitors of EGFR Threonine 790 to Methionine 790 (T790M) Mutants

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/99681/1/8387_ftp.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/99681/2/anie_201302313_sm_miscellaneous_information.pd

Pyrimido[4,5‐ d ]pyrimidin‐4(1 H )‐one Derivatives as Selective Inhibitors of EGFR Threonine 790 to Methionine 790 (T790M) Mutants

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/99673/1/8545_ftp.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/99673/2/ange_201302313_sm_miscellaneous_information.pd

Discovery of BRAF/HDAC Dual Inhibitors Suppressing Proliferation of Human Colorectal Cancer Cells

The combination of histone deacetylase inhibitor and BRAF inhibitor (BRAFi) has been shown to enhance the antineoplastic effect and reduce the progress of BRAFi resistance. In this study, a series of (thiazol-5-yl)pyrimidin-2-yl)amino)-N-hydroxyalkanamide derivatives were designed and synthesized as novel dual inhibitors of BRAF and HDACs using a pharmacophore hybrid strategy. In particular, compound 14b possessed potent activities against BRAF, HDAC1, and HDAC6 enzymes. It potently suppressed the proliferation of HT-29 cells harboring BRAFV600E mutation as well as HCT116 cells with wild-type BRAF. The dual inhibition against BRAF and HDAC downstream proteins was validated in both cells. Collectively, the results support 14b as a promising lead molecule for further development and a useful tool for studying the effects of BRAF/HDAC dual inhibitors

Azetidines Kill Multidrug-Resistant <i>Mycobacterium tuberculosis</i> without Detectable Resistance by Blocking Mycolate Assembly

Tuberculosis (TB) is the leading cause of global morbidity and mortality resulting from infectious disease, with over 10.6 million new cases and 1.4 million deaths in 2021. This global emergency is exacerbated by the emergence of multidrug-resistant MDR-TB and extensively drug-resistant XDR-TB; therefore, new drugs and new drug targets are urgently required. From a whole cell phenotypic screen, a series of azetidines derivatives termed BGAz, which elicit potent bactericidal activity with MIC99 values &lt;10 μM against drug-sensitive Mycobacterium tuberculosis and MDR-TB, were identified. These compounds demonstrate no detectable drug resistance. The mode of action and target deconvolution studies suggest that these compounds inhibit mycobacterial growth by interfering with cell envelope biogenesis, specifically late-stage mycolic acid biosynthesis. Transcriptomic analysis demonstrates that the BGAz compounds tested display a mode of action distinct from the existing mycobacterial cell wall inhibitors. In addition, the compounds tested exhibit toxicological and PK/PD profiles that pave the way for their development as antitubercular chemotherapies. </p

Rapid detection of traditional Chinese medicine with neuraminidase inhibitory activities based on high-throughput and virtual screening strategy

Background: Oseltamivir, a neuraminidase inhibitor (NAI), is the primary and first-line anti-influenza drug. In recent years, more and more oseltamivir resistant strains appeared frequently. Purpose: To identify anti-influenza candidates to overcome oseltamivir resistance from traditional Chinese medicine. Methods: High-throughput screening platform was used to screen candidates with oseltamivir sensitive and resistant neuraminidase (NA) inhibitory activities from traditional Chinese medicine (TCM) and in validation of potential active components in vitro. Molecular docking is used for virtual screening of TCM compound libraries and analysis of the molecular mechanism of active compounds. Results: Six out of 188 TCM formula granules were screened out with good inhibitory activities in oseltamivir sensitive (H5N1) and resistant NA (H274Y mutant). A compound library containing 679 candidates in the above six plants were docked into binding pockets of H5N1 NA and its H274Y mutant. The results indicated that diverse structural types, including flavonoids glycosides, alkaloids, caffeoylquinic acid derivatives, etc. showed good docking scores on the two NAs. Furthermore, 10 representative compounds tested in vitro showed inhibitory activities in both oseltamivir sensitive and resistant NA. The docking simulations revealed that natural TCM molecules bind with NA in an absolute different mode compared with oseltamivir, which occupy the extra cavities adjacent to the active site of NA, thus might make them non-susceptible to be influenced by mutation around the active sites. Conclusions: The combination of high-throughput screening and molecular docking can efficiently screen out candidates that have the potential to overcome oseltamivir resistance from TCM

Three new highly oxygenated sterols and one new dihydroisocoumarin from the marine sponge-derived fungus Cladosporium sp SCSIO41007

Three new highly oxygenated sterols (1-3) and a new dihydroisocoumarin (7) together with six known compounds were isolated from the extracts of the culture of a sponge-derived fungus Cladosporium sp. SCSIO41007. The structures of all new compounds (1-3, 7) were determined by the extensive spectroscopic analysis including NMR, MS, IR, and W. Their absolute configurations were determined by X-ray single-crystal and CD data analysis. Compound 2 exhibited weak inhibitory activity against H3N2 with the IC50 value of 16.2 mu M

Design and synthesis of pinanamine derivatives as anti-influenza A M2 ion channel inhibitors

The adamantanes are a class of anti-influenza drugs that inhibit the M2 ion channel of the influenza A virus. However recently, the clinical effectiveness of these drugs has been called into question due to the emergence of adamantane-insensitive A/M2 mutants. Although we previously reported (1R,2R,3R,5S)-3-pinanamine 3 as a novel inhibitor of the wild type influenza A virus M2 protein (WT A/M2), limited inhibition was found for adamantane-resistant M2 mutants. In this study, we explored whether newly synthesized pinanamine derivatives were capable of inhibiting WT A/M2 and selected adamantane-resistant M2 mutants. Several imidazole and guanazole derivatives of pinanamine were found to inhibit WT A/M2 to a comparable degree as amantadine and one of these compounds 12 exhibits weak inhibition of A/M2-S31N mutant and it is marginally more effective in inhibiting S31N. M2 than amantadine. This study provides a new insight into the structural nature of drugs required to inhibit WT A/M2 and its mutants

JND4135, a New Type II TRK Inhibitor, Overcomes TRK xDFG and Other Mutation Resistance In Vitro and In Vivo

The tropomyosin receptor kinases (TRKs) have been validated as effective targets in anticancer drug discovery. Two first-generation TRK inhibitors have been approved into market and displayed an encouraging therapeutic response in cancer patients harboring TRK fusion proteins. However, acquired resistance mediated by secondary TRK mutations especially in the xDFG motif remains an unsolved challenge in the clinic. Herein, we report the preclinical pharmacological results of JND4135, a new type II pan-TRK inhibitor, in overcoming TRK mutant resistance, including the xDFG mutations in vitro and in vivo. At a low nanomolar level, JND4135 displays a strong activity against wild-type TRKA/B/C and secondary mutations involving xDFG motif substitutions in kinase assays and cellular models; occupies the TRK proteins for an extended time; and has a slower dissociation rate than other TRK inhibitors. Moreover, by intraperitoneal injection, JND4135 exhibits tumor growth inhibition (TGI) of 81.0% at a dose of 40 mg/kg in BaF3-CD74-TRKA-G667C mice xenograft model. Therefore, JND4135 can be considered as a lead compound for drug discovery overcoming the resistance of TRK inhibitor drugs mediated by xDFG mutations

GZD2202, a novel TrkB inhibitor, suppresses BDNF-mediated proliferation and metastasis in neuroblastoma models

Collective data suggest tropomyosin-related kinase B (TrkB), which is correlated with the growth, migration and poor prognosis of neuroblastoma (NB), is a potential target for NB target therapy. Several Phase I/II pan-Trk inhibitors display impressive clinical outcomes but still no drug has been approved for general use. In this paper, we report a novel structural TrkB inhibitor GZD2202, a structural derivative of our previously identified DDR1 antagonists. GZD2202 demonstrates a moderate selectivity between Trk B/C and TrkA. GZD2202 suppresses the brain-derived neurotrophic factor (BDNF) -mediated TrkB signalling pathway, proliferation, migration and invasion in SH-SY5Y-TrkB neuroblastoma cells, and causes about 36.1% growth inhibition in a SH-SY5Y-TrkB neuroblastoma xenograft model