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.

The epidermal growth factor receptor (EGFR) was found to be overexpressed in several cancers, especially in lung cancers. Finding new effective drug against EGFR is the key to cancer treatment. In this study, the GOLD docking algorithm was used to virtually screen for novel human EGFR inhibitors from the NCI database. Thirty‐four hit compounds were tested for EGFR‐tyrosine kinase (TK) inhibition. Two potent compounds, 1‐amino‐4‐(4‐[4‐amino‐2‐sulfophenyl]anilino)‐9,10‐dioxoanthracene‐2‐sulfonic acid (NSC125910), and nogalamycin N‐oxide (NSC116555) were identified with IC50 values against EGFR‐TK comparable to gefitinib; 16.14 and 37.71 nM, respectively. However, only NSC116555 demonstrated cytotoxic effects against non–small‐cell lung cancer, A549, shown in the cell cytotoxicity assay with an IC50 of 0.19 + 0.01 µM, which was more potent than gefitinib. Furthermore, NSC116555 showed cytotoxicity against A549 via apoptosis in a dose‐dependent manner.

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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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