Most patients suffering from non–small cell lung cancer (NSCLC) have epidermal growth factor receptor (EGFR) overexpression. Currently, EGFR tyrosine kinase inhibitors (TKIs) that act as the ATP‐analogs and monoclonal antibodies (MAbs) to EGFR‐ectodomain that block intracellular signaling are used for the treatment of advanced NSCLC. Unfortunately, adverse effects due to the TKI off‐target and drug resistance occur in a significant number of the treated patients while some NSCLC genotypes do not respond to the therapeutic MAbs. Thus, a more effective remedy for the treatment of EGFR‐overexpressed cancers is deemed necessary. In this study, VH/VHH displayed‐phage clones that are bound to recombinant EGFR‐TK were fished‐out from a humanized‐camel VH/VHH phage display library. VH/VHH of three phage‐infected Escherichia coli clones (VH18, VHH35, and VH36) were linked molecularly to nonaarginine (R9) for making them cell penetrable. R9‐VH18, R9‐VHH35, and R9‐VH36 were cytotoxic to human adenocarcinomic alveolar basal epithelial cells (A549) at the fifty percent inhibitory concentration (IC50) 0.181 ± 0.132, 0.00961 ± 0.00516, and 0.00996 ± 0.00752 μM, respectively, which were approximately 1000‐fold more effective than small molecular TKIs. R9‐VH18 and R9‐VH36 also delayed cancer cell migration in a scratch‐wound assay. Computerized homology modeling and intermolecular docking revealed that VH18 and VHH35 used CDR3 to interact with EGFR‐TK residues close to the catalytic site, which might sterically hinder the ATP‐binding of the TK; VH36 used CDR2 to bind at the asymmetric dimerization surface, which might disrupt EGFR dimerization leading to inhibition of intracellular signaling. The humanized‐cell penetrable nanobodies have a high potential for developing further towards a clinical application.

A series of 2,4 diamino-pyrimidines have been identified from an analysis of open access high throughput anti-malarial screening data reported by GlaxoSmithKline at the 3D7 and resistant Dd2 strains. SAR expansion has been performed using structural knowledge of the most plausible parasite target. Seventeen new analogs have been synthesized and tested against the resistant K1 strain of Plasmodium falciparum (Pf). The cytotoxicity of the compounds was assessed in Vero and A549 cells and their selectivity towards human kinases including JAK2 and EGFR were undertaken. We identified compound 5n and 5m as sub-micromolar inhibitors, with equivalent anti-malarial activity to Chloroquine (CQ). Compounds 5d and 5k, μM inhibitors of Pf, displayed improved cytotoxicity with weak inhibition of the human kinases.

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BackgroundDue to their extensive self-renewal and multilineage differentiation capacity, human embryonic stem cells (hESCs) have great potential for studying developmental biology, disease modeling, and developing cell replacement therapy. The first hESC line was generated in 1998 by culturing inner cell mass (ICM) cells isolated from human blastocysts using an immunosurgery technique. Since then, many techniques including mechanical ICM isolation, laser dissection, and whole embryo culture have been used to derive hESC lines. However, the hESC derivation efficiency remains low, usually less than 50%, and it requires a large number of human embryos to derive a significant number of hESC lines. Due to a shortage of and restricted access to human embryos, a novel approach with better hESC derivation efficiency is badly needed to decrease the number of embryos used.MethodsWe hypothesized that the low hESC derivation efficiency might be due to extensive proliferation of trophoblast (TE) cells which could interfere with ICM proliferation. We therefore developed a methodology to minimize TE cell proliferation by culturing ICM in a feeder-free system for 3 days before transferring them onto feeder cells.ResultsThis minimized trophoblast cell proliferation (MTP) technique could be successfully used to derive hESCs from normal, abnormal, and frozen–thawed embryos with better derivation efficiency of more than 50% (range 50–100%; median 70%).ConclusionsWe successfully developed a better hESC derivation methodology using the “MTP” culture system. This methodology can be effectively used to derive hESCs from both normal and abnormal embryos under feeder-free conditions with higher efficiency when compared with other methodologies. With this methodology, large-scale production of clinical-grade hESCs is feasible.Electronic supplementary materialThe online version of this article (10.1186/s13287-018-0866-5) contains supplementary material, which is available to authorized users.